JP2014102255A - Treatment method using ammonia-scavenging drugs - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a treatment method using ammonia-scavenging drugs.SOLUTION: The invention provides a method for determining a dose and a schedule of a dose of PBA prodrugs used to treat nitrogen retention states, or ammonia accumulation disorders, and for adjusting the dose of the PBA prodrugs, by measuring urinary excretion of phenylacetylglutamine and/or total urinary nitrogen. The invention provides a method to select an appropriate dosage of the PBA prodrug on the basis of dietary protein intake of a patient, or previous treatment administered to the patient. The method is applicable to selecting or modifying a dosing regimen for a subject receiving an orally administered ammonia scavenging drug.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority over US Provisional Patent Application No. 61 / 093,234, filed Aug. 29, 2008, which is hereby incorporated by reference herein. The entirety of which is incorporated by reference. This application is also US Provisional Patent Application No. 61 / 048,830, filed Aug. 29, 2008 (Invention: “Treating special populations with living liver-scavenging compounds”, inventor: Sgar )is connected with.

TECHNICAL FIELD The present invention relates to a nitrogen retention state (particularly a combination of urea cycle disorder (UCD) and hepatic encephalopathy (HE), which administers a compound that aids in elimination of waste nitrogen from the body. It relates to the treatment of patients with exacerbated cirrhosis. The compounds can be administered orally as small molecule drugs and the present invention provides a method for delivering such compounds to a patient and selecting an appropriate dosage.

BACKGROUND ART Drug administration is usually based on the measurement of blood active drug species levels in conjunction with clinical assessment of treatment response. However, the present invention is based on evidence that for certain prodrugs of phenylacetic acid (PAA), measurement of blood levels of prodrugs (eg, PBA) or PAA formed from prodrugs is unreliable. Furthermore, evaluation of treatment effects by measuring blood ammonia levels is also inconvenient because it is necessary to collect multiple blood samples under carefully controlled conditions. Since blood ammonia levels are affected by a variety of factors, including dietary protein, blood ammonia levels also cannot provide a direct measure of the amount of ammonia that a drug is mobilized for excretion. The present invention demonstrates that the prodrug of phenylbutyric acid (PBA) behaves similarly to sodium PBA in that the measurement of PBA levels is unreliable in assessing its effectiveness. The present invention provides a novel method of administration in patients with nitrogen retention status (particularly patients with clinical symptoms of liver disease and hepatic encephalopathy and UCD patients). The present invention is particularly applicable to prodrugs that are liberated or metabolized to form phenylacetic acid (ie, prodrugs of PAA) and prodrugs that are metabolized to form PBA.

  Hepatic encephalopathy refers to a neurological sign spectrum that occurs frequently in patients with cirrhosis or certain other types of liver disease.

Urea cycle disorders include some inherited deficiencies of enzymes or transporters required for the synthesis of urea from ammonia. The urea circuit is shown in FIG. FIG. 1 also shows how certain ammonia scavengers act to help excrete excess ammonia. Enzymes including these enzyme committee (EC) numbers and genotypes include:
Carbamyl phosphate synthetase (CPS; EC number 6.3.4.16; autosomal recessive),
Ornithine transcarbamylase (OTC; EC number 2.1.3.3; X-linked),
Argininosuccinate synthetase (ASS; EC number 6.3.4.5; autosomal recessive),
Argininosuccinate lyase (ASL; EC number 4.3.2.1; autosomal recessive),
Arginase (ARG; EC number 3.5.3.1; autosomal recessive), and N-acetylglutamine synthetase (NAGS1; EC number 2.3.1.1; autosomal recessive)
Mitochondrial transporter deficient states that mimic many features of urea cycle enzyme deficiency include:
・ Ornithine translocase deficiency (hyperornithine, hyperammonemia, homocitrulinuria, or HHH syndrome)
Citrine (aspartate glutamate transporter) deficiency Common features of UCD and hepatic encephalopathy that can be treated by the methods of the present invention are the accumulation of excess waste nitrogen in the body and hyperammonemia. In normal individuals, the body's inherent waste nitrogen excretion capacity is higher than the body's waste nitrogen production, so waste nitrogen does not accumulate and ammonia does not increase to harmful levels. For patients with nitrogen storage conditions (such as UCD or HE), the body's inherent waste nitrogen excretion capacity based on a normal diet containing significant amounts of protein is lower than the body's waste nitrogen production. As a result, nitrogen increases in the body of a patient with a nitrogen retention disorder, and usually blood ammonia is excessive. This has a variety of toxic effects, and drugs that assist the elimination of excess ammonia are an important part of the overall management strategy for such disorders.

  To avoid an increase in ammonia toxic levels in patients with nitrogen reserves, dietary intake of protein (a major source of exogenous waste nitrogen) must be balanced with the patient's ability to excrete excess ammonia. I must. Although dietary protein can be limited, a healthy diet requires significant amounts of protein, especially for growing children. Therefore, in addition to controlling dietary protein intake, drugs that help excrete nitrogen are used to reduce ammonia increase (hyperammonemia). The ability to excrete excess ammonia in the patient being treated can be considered as the sum of the patient's endogenous nitrogen excretion capacity (if any) and the amount of additional nitrogen excretion capacity provided by the nitrogen scavenger. The method of the present invention uses a variety of different drugs that reduce excess waste nitrogen and ammonia by conversion to an easily excreted form (such as phenylacetylglutamine (PAGN)). In some embodiments, the present invention determines the dosage of an oral drug that forms PAA in vivo, where PAA is converted to PAGN and then excreted in the urine to assist in excretion of excess nitrogen or It relates to the method of adjustment.

  Based on previous studies in each UCD patient who reported that 80-90% of the nitrogen scavenger sodium phenylbutyrate is excreted in the urine as PAGN (eg, Non-Patent Document 1; Non-Patent Document 2) Current treatment guidelines typically envisage complete conversion of sodium phenylbutyrate or other PAA prodrugs to PAGN (eg, Non-Patent Document 3) or incomplete dosing The relation of conversion is not annotated (for example, Non-Patent Document 4).

  Current treatment guidelines recommend dosing four times daily using PBA based on the fact that when administered in the form of sodium PBA, PBA is rapidly absorbed from the intestine and exhibits a short blood half-life. (Urea Cycle Disorders Conference Group 'Consensus Statement' 2001).

  Sodium phenylbutyrate administration is currently recommended that the dosage should not exceed 600 mg / kg (for patients up to 20 kg body weight) or in any case should not exceed 20 grams in total.

Brusilow, Pediatric Research, vol. 29, 147-50 (1991) Brusilow and Finkelstien, J.A. Metabolism, vol. 42, 1336-39 (1993) Berry et al. , J .; Pediatrics, vol. 138, S56-S61 (2001) Singh, Urea Cycle Disorders Conference Group ‘Consensus Statement from the Conference of the Parents of Japan Cycles Distributors’. 138 (1), S1-S5 (2001)

DISCLOSURE OF EMBODIMENTS OF THE INVENTION The present invention relates to nitrogen scavengers (sodium phenylbutyrate and glyceryl tri- [or] administered orally based on urinary excretion and / or total urinary nitrogen of the drug metabolite phenylacetylglutamine (PAGN). 4-phenylbutyrate] (including HPN-100)) and provide a new approach for determining and adjusting the dose. The present invention is based on the bioavailability of these drugs, some of which have been routinely evaluated based on the systemic blood levels of the drugs themselves or the active species produced in vivo from these drugs: Definition of healthy human volunteers, adults with liver disease, or UCD patients who received ammonia scavengers did not accurately predict the removal of waste nitrogen or a decrease in plasma ammonia, and orally administered sodium phenylbutyrate ( The conversion of NaPBA or sodium PBA) to PAGN and then to urinary PAGN is based on the discovery that it is incomplete, typically about 60-75%. The prodrug of phenylbutyrate (PBA, the active ingredient in sodium phenyl (butyric acid), sodium salt of PBA with a small amount of inactive ingredient) is itself a phenylacetic acid (PAA) It is a prodrug and is particularly susceptible to the effects described herein.

As used herein, “ammonia scavengers” are defined to include all orally administered drugs of the class that contain or are metabolized to phenylacetate. Thus, the term includes at least phenylbutyrate, buphenyl (R) (sodium phenylbutyrate), ammonaps (R), butyroyloxymethyl-4-phenylbutyrate, glyceryl tri- [4-phenylbutyrate ] (HPN-100), its esters, ethers, and acceptable salts, acids, and derivatives. These drugs reduce high levels of endogenous ammonia by providing phenylacetic acid in vivo that is efficiently metabolized to form phenylacetylglutamine (PAGN). PAGN is efficiently excreted in the urine and converted to PAGN by removing 2 equivalents of nitrogen per mole of PAA. As used herein, the term sodium phenylbutyrate is understood to include a reference to the pharmaceutical buphenyl®, and buphenyl® is used herein when the test subject is treated with sodium phenylbutyrate. Used for the examples in the book. Therefore, the dosage of sodium PBA used in these examples generally refers to the dosage of Buphenyl®, and the amount of sodium phenylbutyrate in the examples should be interpreted accordingly. The terms “ammonia scavenger” and “nitrogen scavenger” are used interchangeably in the present invention, reflecting the fact that the drugs described herein lower blood ammonia by excretion of waste nitrogen in the form of PAGN. Note that you do.

  In some embodiments, the invention uses a prodrug that can be converted to PAA in the body. Sodium phenylbutyrate (sodium PBA) is one such drug that is converted by the body's mechanism of oxidation to PAA. HPN-100 is another such drug. This can be hydrolyzed to release PBA and then oxidized to form PAA. Therefore, HPN-100 is a prodrug of PBA and a prodrug of PAA. Clinical evidence demonstrates that HPN-100 is converted to PAA in the body as expected, and then PAA binds to one glutamine molecule and is converted to PAGN, which is excreted in urine as expected. . This process can be summarized as follows.

PAGN is mainly excreted in the urine of the subject and removes two molecules of ammonia per molecule of PAGN excreted. Since each HPN-100 molecule forms 3 PAA molecules, each HPN-100 molecule can promote the excretion of 6 ammonia molecules. Although clinical results suggest that the conversion of HPN-100 to PBA and PAA is effective and fairly fast, notably, HPN-100 (or PBA or PBA derived PAA) is in the systemic circulation. It is suggested that conversion of HPN to PAGN may occur before entering. As a result, systemic levels of PAA or PBA do not reliably correlate with the effectiveness of HPN-100 as an ammonia scavenger.

  In some embodiments, the present invention uses prodrugs of PBA, including HPN-100 and other esters of phenylbutyrate. Thus, PBA prodrugs are prodrugs of prodrugs. This is because PBA is considered a prodrug of PAA because it acts to scavenge ammonia and is subsequently converted to PAA. In some embodiments, the PBA prodrug is an ester of phenylbutyrate (such as the following) and the preferred PBA prodrug used in the present invention is HPN-100. These compounds can be made and used by the methods disclosed in US Pat. No. 5,968,979, which is incorporated herein by reference for a description of these compounds and their methods of administration.

  If an “equal molar” or “equimolar” amount of a second drug is used with or instead of a fixed amount of the first drug, the amount of each drug is calculated on a molar basis; The equimolar amount of the second drug is the amount that produces an equimolar amount of the active drug in vivo. When one of the drugs is a prodrug, the amount of prodrug typically refers to the molar amount of active species formed from the prodrug. This active species is usually PAA for the prodrugs described herein, and the molar amount of the prodrug is calculated from the amount of the prodrug, assuming complete conversion to PAA in vivo. It corresponds to the amount of PAA that is considered to be formed in the body. Thus, for example, one molecule of HPN-100 can be metabolized by ester hydrolysis and subsequent oxidation to form three molecules of PAA, so one mole of HPN-100 is equimolar with three molecules of PAA. Will be considered. Similarly, since HPN-100 is hydrolyzed to form 3 molecules of PBA (and 1 molecule of glycerin), an equimolar amount of HPN-100 will be 1/3 the molar amount of PBA.

  The table below lists the amount of HPN-100 corresponding to an equimolar amount of a related dose of Buphenyl® (sodium phenylbutyrate). Conversion of sodium PBA dose to HPN-100 dose is corrected for its different chemical form (ie HPN-100 consists of glycerol containing 3 molecules of PBA via an ester bond and does not contain sodium (PBA sodium [g ] × 0.95 = HPN-100 [g])) and HPN-100 specific gravity (which is 1.1 g / mL).

The present invention relates to a compound of formula (I):

(Where
R ₁ , R ₂ , and R ₃ are independently H,

And
n is 0 or an even number, m is an even number, and at least one of R ₁ , R ₂ , and R ₃ is not H). For each R ₁ , R ₂ , or R ₃ , n or m is independently selected so that the R ₁ , R ₂ , and R ₃ groups in the compound of formula I need not be the same. Preferred compounds are those in which R ₁ , R ₂ , and R ₃ are not all H, and frequently each n or m of a particular embodiment is the same (ie, R ₁ , R ₂ , and R ₃ are all all Compounds). Having such triesters for dosage reduction is advantageous over the prior art, and having all three acyl groups identical alleviates problems with isomer mixtures. In addition, the triol backbone liberated by ester hydrolysis is glycerol (a normal dietary triglyceride component that is non-toxic).

  The present invention also provides a compound of formula II:

(Where
R is _C 1 _{-C 10} alkyl group,
R ₄ is

And
n is 0 or an even number, and m is an even number) phenyl butyrate prodrug and phenyl acetate prodrug.

  In Formula II, R can be, for example, ethyl, propyl, isopropyl, n-butyl, and the like.

  The compounds of the present invention are phenyl alkanoic acid having an even number of carbon atoms in the alkanoic acid moiety and esters of the same of phenylalkenoic acid (phenylacetic acid ester which can be converted into phenylacetic acid in the body by an efficient β-oxidation process) And esters of phenylbutyric acid). Accordingly, the compounds of the present invention are prodrugs of phenylacetic acid. When n is 2 or 4, the ester is also a prodrug of phenylbutyric acid. Preferably, the alkylene carboxylate group or alkenylene carboxylate group contains no more than 24 carbon atoms, so n or m is less than 24. In some embodiments, n and m are 0, 2, 4, or 6, and in some preferred embodiments, n or m is 2.

  Certain preferred embodiments of the present invention include HPN-100 (Formula III):

Is used.

  The total daily dosage of a prodrug such as sodium PBA is often selected according to the amount necessary to obtain the appropriate amount of active species (if this amount is known or can be determined) it can. PBA is a prodrug of PAA. Thus, if the effective dosage of PAA is known, the initial dose of PBA can be selected in view of the proportion of PBA that is converted to PAA and ultimately converted to PAGN. If the subject was treated with PAA or a prodrug that forms PAA in the body, the previous drug usage that was effective provides a possible starting point for the selection of a new PAA prodrug dosage. It is done. In this same patient, after administering a new prodrug at a dose expected to be equivalent to PAA, the PAA level in the subject is monitored and the same plasma level of PAA that was effective using the previous treatment. The prodrug dose can be adjusted until is achieved. However, the present invention does not correlate well with plasma doses of PBA prodrug or ammonia excretion, where plasma PAA and PBA levels are administered, and the effectiveness of prodrugs for monitoring dose levels of PBA prodrugs These parameters for assessing are based in part on the observation that they should not be trusted. Without being bound by the underlying theory, this effect (ie, the inconsistent relationship between ammonia capture and blood PBA and / or PAA levels) is described herein.

The following table provides data from three clinical trial groups. These data show that in healthy volunteers, cirrhosis patients, and UCD patients, despite the fact that all groups showed similar ammonia scavenging activity based on urinary excretion of PAGN, as detailed below. Shows an inconsistent relationship between plasma PAA levels and plasma PBA levels. Overall, this provides a convenient way for urinary PAGN to monitor the ammonia elimination induced by the administered drug, which does not require drawing blood and plasma ammonia levels. It is directly related to the actual nitrogen exclusion provided by the administered nitrogen scavenger, without being affected by many other factors that can affect it.

C _max = maximum plasma concentration; T _max = maximum plasma concentration attainment time; AUC ₂₄ = 0 to ₂₄ hours of AUC; NC = not calculated.
^One study did not include the sodium phenylbutyrate comparator arm. Values indicate HPN-100 dosing only. The AUC value represents the AUC from time 0 to the last measurable plasma concentration.

  One embodiment of the present invention is a method for determining and / or adjusting the dose of an ammonia scavenger in a patient with UCD. Thereby, the dosage will be based on the amount of dietary protein consumed by the patient, the expected conversion rate of the drug to PAGN, and the patient's remaining ability to synthesize urea (if any). If necessary, dose adjustments are based on the observed urinary excretion of PAGN and / or total urinary nitrogen (TUN) (the difference between the two reflects the patient's endogenous waste nitrogen excretion capacity). Let's go. While this intrinsic ability cannot be present in certain patients with innate urea cycle disorders due to inborn errors of metabolism, patients with late-onset nitrogen accumulation are generally occasionally occasioned by their residual urea synthesis. Has some intrinsic ability called ability. Brusilow, PROGRESS IN LIVE DISEASES, Ch. 12, pp. 293-309 (1995). A subject's plasma ammonia level can also be determined. This level is an important parameter for tracking the effectiveness of the overall treatment program but reflects the influence of various factors (such as dietary protein and physiological stress) and the drugs used to promote nitrogen excretion To do.

  The patient's remaining endogenous waste nitrogen excretion is once determined as either the difference between PAGN and total nitrogen excretion, or total urinary nitrogen excretion in the absence of an ammonia scavenger And the acceptable amount of dietary protein for this patient can be calculated according to the dose of ammonia scavenger administered, or the dose of ammonia scavenger to offset the estimated protein intake Can be adjusted or calculated.

  Another embodiment is a method for determining and adjusting the dose of an ammonia scavenger to be administered to a patient having liver disease (including hepatic encephalopathy). Thereby, the starting dose will be based on the amount of dietary protein consumed by the patient, the expected conversion rate of the drug to PAGN, and the patient's remaining ability to synthesize urea (if any). While urea synthesis capacity in patients with liver disease is generally considered to be higher than in UCD patients, there is considerable inter-patient relationship in both groups depending on the severity of the patient's liver disease and the patient's genetic enzyme deficiency, respectively. Fluctuations will be expected. The dose based on the observed urinary excretion of PAGN and total waste nitrogen will be adjusted according to the characteristics of each of these patients.

  Another embodiment is a method of determining or adjusting acceptable dietary protein in the diet of a UCD or hepatic encephalopathy patient treated with an oral PAA-forming ammonia scavenger. Thereby, the amount of protein acceptable will be determined by the amount of PAGN and total nitrogen in the urine. The difference between the total waste nitrogen in the urine and the amount of PAGN excreted indicates the patient's ability to process endogenous waste nitrogen. Once the patient's endogenous nitrogen processing capacity is known, the patient's endogenous nitrogen processing capacity can be used to adjust dietary protein intake while administering a fixed dosage of an ammonia scavenger, The dosage of the ammonia scavenger can be determined according to the amount required to facilitate excretion of waste nitrogen from the patient's dietary protein. Dietary protein intake should be determined or adjusted according to the amount of nitrogen that the subject can excrete beyond the amount excreted as PAGN due to the administered PAA-forming ammonia scavenger. When making these calculations or adjustments, we assume that about 47% of the nitrogen in the protein is waste nitrogen that needs to be excreted in the urine (this amount is more ingested to support the body's growth) It may be less for a growing patient holding a part), and it is appropriate to assume that on average about 16% of the protein is nitrogen (see Brusilow 1991).

For such determinations, it is generally assumed that prodrugs are converted to PAGN with 100% efficiency for excretion (eg, Berry assumes that FIG. 1 assumes 100% conversion).
et al. , J .; Pediatrics 138 (1), S56-S61 (2001)); one report found that about 80-90% of PAA or PBA was excreted as PAGN from certain individuals (Brusilow, Pediatric
Research 29 (2), 147-150 (1991)). It has now been found that on average, HPN-100 and phenylbutyrate are both converted to urinary PAGN at about 60% to about 75% of the total conversion efficiency (eg, a conversion efficiency of about 60% is UCD). Found in patients and about 75% conversion was observed in cirrhotic patients). Thus, this efficiency factor can be used to more accurately calculate or determine the initial dosage level of these drugs or the dietary protein level acceptable to the patient using these drugs. Considering this conversion rate, 1 g of HPN-100 can facilitate excretion of waste nitrogen from about 1 gram (about 1.3 gram) dietary protein per day. Note that PAGN carries away two molecules of ammonia per molecule of PAGN. Examples of calculations based on these parameters are shown in Examples 9 and 10 herein.

  In one aspect, the present invention provides a method for transitioning phenylacetate or phenylbutyrate in a patient to HPN-100 or other esters or prodrugs of phenylbutyrate. The method involves administering an initial dosage of the prodrug selected based on the patient's current dosage of phenylacetate or phenylbutyrate and adjusted according to the excretion level of PAGN obtained when the prodrug is administered including.

  In some embodiments, the transition from phenylbutyrate can be initiated in more than a single step, allowing urinary excretion of PAGN and monitoring of ammonia captured during the transition by total nitrogen. (E.g., for clinically “fragile” patients who are prone to frequent hyperammonemia). If judged to be clinically wise, the method can use two steps, three steps, four steps, five steps, or more than five steps. In each step, a portion of the initial dosage of phenylbutyrate corresponding to the number of steps used for the transfer is an appropriate amount (ie, the amount required to deliver an equimolar amount of PBA) of HPN-100. Or substitute other prodrugs of phenylbutyrate (eg, if the transfer is carried out in 3 steps, about 1/3 of the phenylbutyrate will be substituted for the prodrug in each step).

  Another embodiment of the invention is based on the finding that delivery of PBA in the form of glyceryl triesters or other prodrugs provides sustained release that makes the dosing regimen more flexible. Sodium phenylbutyrate (sodium PBA), for example, is typically administered every 4-8 hours or even more frequently to maintain appropriate plasma PAA levels. This regimen reflects the rapid absorption of phenylbutyrate from the gastrointestinal tract and the rapid metabolic conversion to PAA. In contrast, HPN-100, a glyceryl triester of phenylbutyrate, is only absorbed at a rate of only 40% of sodium PBA and is administered three times a day with meals, and twice a day (such as morning and evening). It has been found that it is possible. This dosing flexibility is further enhanced by the fact that the pharmacokinetic (PK) and pharmacodynamic (PD) properties of HPN-100 are indistinguishable in the fed or fasted state. Therefore, it is not important to use the ester form of the PBA prodrug to maintain strict dosing frequency, the number of doses per day can be reduced for convenience and the dosage is recommended in the label for sodium PBA There is no need to relate to a meal plan as is done. In fact, when HPN-100 was taken with food or separately from food one day after fasting, the pharmacokinetics for HPN-100 utilization were very similar, so HPN-100 was taken with food or separately. be able to. This provides a more convenient treatment protocol and potentially higher patient compliance when using HPN-100 instead of phenylbutyrate or phenylacetate. Remarkably, HPN-100 is effective when administered less frequently than sodium PBA, even though HPN-100 and sodium PBA are both prodrugs of PAA. Typically, to maintain stable plasma ammonia levels, smaller doses of sodium PBA need to be administered 3-6 times per day, while only 2-3 doses of HPN-100 per day Similar results can be achieved with administration. In some embodiments discussed in more detail below, HPN-100 is administered twice daily (BID), and in some embodiments, three times daily (TID).

  Because of the sustained release of HPN-100, patients taking HPN-100 have a longer duration and often lower plasma PBA and PAA levels than patients taking sodium PBA itself. This is because of the greater flexibility in dosing, which is discussed in more detail elsewhere in this application (the plasma PBA levels rise and fall more rapidly after administration of sodium PBA than after administration of HPN-100. To match)

  Another aspect of the present invention is the ability of the body to convert sodium PBA or HPN-100 to urinary PAGN, a fractional dose range that is less than the currently recommended maximum dose of sodium PBA. (range) is related to the finding that it seems to be satisfied only over. This should allow the patient to take a higher dose of HPN-100 than an equimolar amount compared to the patient's dose of PBA. This suggests that higher doses of HPN-100 can be administered to patients than currently recommended doses of sodium PBA, which means that the highest indicated dose of sodium PBA is adequate for ammonia levels. It is particularly useful for patients who have not been adjusted. Such patients can take higher doses of HPN-100 than previously recommended sodium PBA dosages.

For example, the present invention provides the following items:
(Item 1)
A method for determining an effective dosage of HPN-100 for a patient in need of treatment of a nitrogen retention disorder comprising:
Monitoring the effect of an initial dosage of HPN-100, wherein the step of monitoring the effect consists essentially of determining the urinary phenylacetylglutamine (PAGN) excretion of the patient; and Determining from the urinary PAGN excretion whether to adjust and / or how to adjust the initial dosage of the HPN-100 to obtain the desired ammonia scavenging effect.
(Item 2)
The method according to Item 1, wherein the urinary PAGN excretion is determined as a concentration ratio of urinary PAGN to urinary creatinine.
(Item 3)
Item 2. The method according to Item 1, wherein the nitrogen storage disorder is chronic hepatic encephalopathy or urea circuit disorder.
(Item 4)
2. The method of item 1, wherein administering to the patient an effective dosage of HPN-100 results in normal plasma ammonia levels in the patient.
(Item 5)
A method for determining an effective dosage of HPN-100 for a patient in need of treatment of a nitrogen retention disorder comprising:
Monitoring the impact of the initial dosage of HPN-100, wherein the step of monitoring the impact is essentially from determining the urinary phenylacetylglutamine (PAGN) excretion and / or total urinary nitrogen of the patient. A method comprising the steps of:
(Item 6)
A method of determining a dosage of HPN-100 for a patient with nitrogen retention disorder, said HPN-based on a utilization efficiency of about 60% to about 75% for the conversion of HPN-100 to PAGN. Calculating the dosage of 100.
(Item 7)
Item 7. The method according to Item 6, wherein the HPN-100 dosage is calculated from the dietary protein intake of the patient.
(Item 8)
8. The method of item 7, wherein the HPN-100 dosage is reduced in view of the patient's ability to synthesize urea.
(Item 9)
A method of determining dosage of a PAA prodrug for a patient with ammonia retention disorder comprising:
a) determining the patient's ability to synthesize residual urea;
b) determining the dietary protein intake of the patient;
c) assessing the patient's target urinary PAGN excretion from a) and b);
d) determining the amount of the PAA prodrug required to obtain the target amount of urinary PAGN;
A method wherein about 60% to about 75% of the PAA prodrug is converted to urinary PAGN.
(Item 10)
Item 10. The method according to Item 9, wherein the PAA prodrug is phenylbutyric acid (PBA) or a pharmaceutically acceptable salt thereof.
(Item 11)
Item 10. The method according to Item 9, wherein the PAA prodrug is HPN-100.
(Item 12)
A method of treating a patient with impaired ammonia retention using an appropriate dosage of a PAA prodrug comprising:
a) determining the patient's ability to synthesize residual urea;
b) determining the dietary protein intake of the patient;
c) assessing the patient's target urinary PAGN excretion from a) and b);
d) determining the amount of the PAA prodrug required to mobilize the target amount of urinary PAGN based on the conversion of about 60% to about 75% of the PAA prodrug to urinary PAGN; And e) administering the appropriate dosage of the PAA prodrug to the patient.
(Item 13)
13. The method of item 12, wherein the PAA prodrug is phenylbutyrate or a pharmaceutically acceptable salt thereof, or HPN-100.
(Item 14)
Item 13. The item 12, wherein the PAA prodrug is HPN-100, the patient has clinically significant residual urea synthesis ability, and the HPN-100 is administered at two or three doses per day. Method.
(Item 15)
A method of transferring a patient treated with an initial amount of phenylacetate or phenylbutyrate to treatment with a final amount of HPN-100,
Determining a substitution amount of HPN-100 for substituting at least a part of the phenyl acetate or phenyl butyrate;
Using the replacement amount of the HPN-100 in place of the phenylacetate or phenylbutyrate, and monitoring the amount of urinary PAGN excreted by the patient to monitor the effectiveness of the replacement amount of the HPN-100 A method comprising the step of evaluating.
(Item 16)
Item 16. The method according to Item 15, wherein the increase in the urinary PAGN amount caused by the transition can decrease the amount of the HPN-100.
(Item 17)
A method of transferring a patient taking an initial daily dosage of phenylbutyrate from taking phenylbutyrate to taking HPN-100,
a) determining an appropriate amount of HPN-100 to replace at least a portion of said initial daily dosage of phenylbutyrate;
b) the appropriate amount of HPN-100 together with an amount of phenylbutyrate corresponding to the initial daily dosage of phenylbutyrate minus the amount corresponding to the portion substituted by HPN-100. Administering to the subject,
c) determining the excretion level of urinary PAGN for the subject; and d) repeating steps ac until all the phenylbutyrate is replaced with HPN-100.
(Item 18)
A method of initiating treatment with phenylacetate, phenylbutyrate, or HPN-100 in a stepwise fashion comprising:
a) assessing or measuring the patient's dietary nitrogen intake, and / or b) assessing the urinary waste nitrogen excretion required for the patient based on diet and urea synthesis capacity, and c) Taking into account the assessment that 60% -75% will convert to PAGN, administering a starting dose of said drug that has been assessed to obtain some of the required waste nitrogen clearance as urinary PAGN; and d) Appropriately increasing the dose of the drug and repeating the steps to reach the maintenance dose of the drug;
Including a method.
(Item 19)
A method of treating a UCD patient with a PBA prodrug, wherein the patient is administered the PBA prodrug as compared to the AUC and Cmax observed when equimolar amounts of PBA are administered to the patient. The prodrug produces an equivalent or better level of ammonia compared to PBA without increasing the patient's exposure to PBA, as determined by AUC and Cmax for Adjusted, the way.
(Item 20)
20. A method according to item 19, wherein the PBA prodrug is HPN-100.
(Item 21)
21. The method of item 20, wherein the AUC for PBA exposure is at least about 20% lower when using the prodrug than when using PBA.
(Item 22)
21. The method of item 20, wherein exposure to the PBA during treatment with the prodrug is at least about 30% lower compared to treatment with PBA.
(Item 23)
A method for determining an appropriate dietary protein level for a patient with a nitrogen retention disorder comprising:
Determining the patient's intrinsic nitrogen excretion ability;
Calculating from the endogenous nitrogen excretion capacity the amount of dietary protein that the patient can process without the aid of a nitrogen scavenger;
Then, considering the proteins needed for health and body growth, add the amount of protein that the patient should be able to process with the help of a selected dosage of nitrogen-scavenging drug and the selected Reaching the amount of dietary protein that the patient can have while being treated with different doses of nitrogen scavengers;
Including a method.
(Item 24)
24. The method of item 23, wherein the nitrogen scavenger is HPN-100.
(Item 25)
The selected dosage of the HPN-100 is up to about 19 g / day and the amount of the dietary protein that the patient should be able to process with the help of this amount of HPN-100 is 1 g HPN 25. The method of item 24, wherein there are about 1 g of protein per 100.
(Item 26)
A method of treating a patient with a PBA prodrug comprising administering a daily dose of HPN-100 greater than 19 g / day to a subject having HE or UCD.
(Item 27)
27. The method of item 26, wherein the daily dose of HPN-100 is between about 19 g and about 57 g.
(Item 28)
A method of treating a patient with nitrogen retention disorder using a PBA prodrug HPN-100, wherein the AUC for PBA when said PBA prodrug is administered is less than about 600 and the Cmax for PBA is about The method is less than 100.
(Item 29)
29. The method of item 28, wherein the subject's plasma ammonia levels are on average normal when treated with HPN-100.
Other aspects of the invention will be apparent from the following detailed description and the examples provided herein.

  For convenience, the dosage of PAA (phenylacetic acid), PBA (phenylbutyric acid), or HPN-100 to a subject discussed herein refers to the total daily dosage. Since these compounds are used in relatively large daily doses, the total daily dosage is administered twice, three, four times, five times, six times, or more than six times a day Different drugs can be administered on different schedules. Thus, the total daily dosage accurately describes a treatment regimen with one drug compared to treatment with a related drug.

FIG. 1 shows the disposal of waste nitrogen by the alternative pathway involved in PAGN through the urea circuit. FIG. 2 shows that in the case of phenylbutyrate, prodrug drugs that assume that systemic circulation must be reached in order for PBA and PAA to become active (ie, to convert to PAGN resulting in ammonia capture) Figure 2 shows a conventional model for explaining kinetic (PK) behavior. FIG. 3 is characterized by PBA, characterized by the findings described herein, indicating that HPA-100 metabolism results in lower plasma levels of PAA and PBA while providing equivalent pharmacological effects. A model is shown that fits the description of the PK behavior of sodium or other drugs that can be converted to PBA and PAA (such as HPN-100). Unlike conventional models, this model is capable of “pre-systemic” conversion of PBA / PAA to PAGN, between the blood levels of these metabolites and PAGN-mediated excretion of waste nitrogen. Explains contradictory relationships. FIG. 4 shows changes in plasma levels of PAA, PBA, and PAGN over time after a single dose of either PBA or HPN-100. The figure shows that the peak level of PAA is lower when PBA prodrug (HPN-100) is used and the PAA level is higher 24 hours after administration using the prodrug. Thus, prodrugs better maintain plasma PAA levels. FIG. 5 shows ammonia level data from the test of Example 3. FIG. 6 shows an anatomical explanation of the finding that prodrug (PBA) can be converted to PAGN before reaching systemic circulation (corresponding to the model shown in FIG. 3). FIG. 7 shows that PBA levels fluctuate relatively rapidly after administration in healthy adults, while PAA and PAGN levels reach a very stable state several days after treatment with sodium phenylbutyrate. FIG. 8 shows that PBA, PAA, and PAGN levels reach steady state at different times in healthy adults, and that PAA takes more time to reach steady state levels in cirrhotic patients. FIGS. 9a, 9b, and 9c show that there is little or no correlation between HPN-100 dose and plasma levels of either PBA or PAA in subjects treated with HPN-100. . However, the figure also shows that urinary excretion of PAGN correlates well with HPN-100 dosage. FIGS. 9a, 9b, and 9c show that there is little or no correlation between HPN-100 dose and plasma levels of either PBA or PAA in subjects treated with HPN-100. . However, the figure also shows that urinary excretion of PAGN correlates well with HPN-100 dosage. FIGS. 9a, 9b, and 9c show that there is little or no correlation between HPN-100 dose and plasma levels of either PBA or PAA in subjects treated with HPN-100. . However, the figure also shows that urinary excretion of PAGN correlates well with HPN-100 dosage. FIG. 10 shows day and night plasma ammonia levels (area under time normalization curve (ie, TN-AUC) or 10 UCD patients treated with either sodium PBA or equimolar doses of HPN-100 for 7 days or Area under the curve (AUC)), indicating that HPN-100 modulated ammonia levels better than PBA: AUC (area under curve) (which is an indicator of total ammonia exposure) and Cmax (peak concentration of ammonia) Were both lower in subjects receiving HPN-100 than in subjects receiving equimolar doses of PBA. FIG. 11 shows that HPN-100 performed better than PBA in managing overnight plasma nitrogen levels. FIG. 12 demonstrates that HPN-100 maintained control in patients whose ammonia levels were well regulated for sodium PBA. In contrast, improvements in HPN-100-derived ammonia regulation were shown to be most beneficial in patients whose ammonia levels were elevated despite treatment with sodium PBA. FIG. 13 summarizes the data of FIG. 12 and shows a statistical comparison of patient ammonia levels with sodium PBA and HPN-100. The figure also shows the normal range for each patient set.

Embodiments of the Invention In one aspect, the present invention provides practice in determining the dose, dosing regimen, and dose adjustment required to treat nitrogen retention conditions (including liver disease due to urea cycle disorders and hepatic encephalopathy). Reduce. The starting dose and plan are based on theoretical considerations, including an assessment of the rate of drug conversion to PAGN, the waste nitrogen due to the patient's dietary protein, and the proportion of drug that is converted and excreted as PAGN I will. After initiation of treatment, the dose will be further adjusted as necessary to adequately correlate parameters such as the actual measurement of urinary PAGN excretion or the ratio of total urinary ammonia or PAGN to creatinine.

  In another aspect, the invention relates to a phenylbutyrate or phenylacetate to phenylbutyrate (a prodrug of PAA) prodrug (such as HPN-100) or other ester or prodrug (herein) in a patient. To the compounds of formulas I and II shown in FIG. For several reasons, HPN-100 is considered a desirable drug over sodium PBA in many patients with high ammonia levels and requiring treatment with an ammonia scavenger. In particular, HPN-100 avoids the unpleasant taste associated with sodium PBA and reduces potentially harmful sodium intake. In the majority of patients (9 of 10 UCD patients who participated in the clinical trial described in Example 3), HPN-100 was preferred over sodium PBA in the clinical trial. Thus, it may be desirable for many patients being treated with phenylbutyrate as an ammonia scavenger to move from phenylbutyrate to HPN-100.

  Doctors can transfer patients from phenylbutyrate to phenylbutyrate prodrugs by calculating the amount of prodrug that is believed to give the amount of PBA corresponding to the dosage of phenylbutyrate previously administered to the patient Seems logical. This would be expected to yield plasma levels of approximately the same active ingredient (PBA). The effectiveness of the new treatment with the prodrug can then be assessed by monitoring blood phenylbutyrate levels to establish a level that is identical to that achieved when PBA is administered. However, as discussed below, this approach is not appropriate because, surprisingly, plasma PBA levels do not correlate well with HPN-100 dosage or HPN-100 or PBA sodium efficacy (PBA Note that sodium is the acid form of phenylbutyrate, the generic name for the drug Buphenyl (R), and is typically administered as Buphenyl (R), the sodium salt of PBA. References herein to treatment with PBA include administration of a neutral compound of phenylbutyrate or a salt of phenylbutyrate. Typically, in all of the examples herein, PBA is converted to As a trademark)).

  Alternatively, since PBA is a prodrug of PAA, the phenylbutyrate prodrug dosage can be calculated according to the theoretical PAA formation. Since one molecule of PBA is expected to give one molecule of PAA, this amount of formation should be the same as would be calculated from the dosage of PBA. The molecular weight of sodium PBA (registered drug form PBA (sodium salt of PBA)) is 186, the molecular weight of HPN-100 is 530, and of course, 3 equivalents of PBA per molecule can be obtained from HPN-100. Only one third molar amount of HPN-100 would be required to replace one molar amount of PBA or PAA. Thus, 1 g of sodium PBA can be replaced with 0.95 grams of HPN-100. Since HPN-100 is a liquid with a density of 1.1 g / mL, assuming that HPN-100 is used as an undiluted liquid, 1 g of sodium PBA will be replaced with 0.87 mL of HPN-100. This can be used to select the starting dosage of HPN-100 for patients transitioning from sodium PBA to HPN-100. Alternatively, the starting dose of HPN-100 in patients who have not yet received Buphenyl® (sodium phenylbutyrate) is incomplete conversion of PBA to urinary PAGN when administered as HPN-100 It will be necessary to consider the notable findings (see Examples 2 and 3), which are described in more detail below, that the average value is about 60-75%.

  Alternatively, the physician measures plasma levels of either PBA or PAA in a subject that has received an effective amount of PBA, and by administering sufficient prodrug to obtain the same plasma level as PBA or PAA, The dosage of the drug can be determined. The physician can then monitor the amount of either PBA or PAA in the blood to ensure that the proper amount of active drug occurs in the body. The phenylbutyrate prodrug may have a slightly lower plasma concentration of PAA or PBA than phenylbutyrate, and therefore the nitrogen scavenging effect can be expected to be lower. This is because the conversion efficiency of the prodrug to the active drug can be less than 100%. Thus, monitoring the plasma levels of PAA or PBA and increasing the prodrug dosage to a level up to that obtained by administration of phenylbutyrate provides the same physiological effect as the phenylbutyrate dosage. Can be expected. However, to achieve the same ammonia scavenging effect, it is not necessary to adapt the plasma levels of PAA or PBA observed upon administration of the phenylbutyrate prodrug to the level obtained with an effective amount of phenylbutyrate. It was found. Rather, the effectiveness of the prodrug HPN-100 correlates with urinary PAGN levels rather than plasma levels of PAA or PBA.

  Models have been developed to explain how ammonia scavengers or prodrugs are expected to behave in vivo. One model shown in FIG. 2 reflects a conventional approach to assess drug efficacy when applied to HPN-100 based on blood levels of PAA or PBA. Clinical trials have found that HPN-100 does not provide plasma levels of PAA and PBA that can be expected from this model. Nevertheless, HPN-100 is at least as effective as PBA on an equimolar basis for regulating blood ammonia levels and excretion of ammonia as PAGN via urine. Thus, conventional models cannot account for some important metabolic differences between PBA and HPN-100. When compared to sodium PBA, a higher proportion of HPN-100-derived PBA is converted to PAGN for excretion (or PAA or PBA derived from it) before entering the systemic circulation ("center image" in Figure 2). The hypothesis was “Central component”). This recognition of importance and unexpected differences forms the basis of certain aspects of the present invention.

An improved working model based on the findings described herein and outlined in this disclosure is shown in FIG. This model supports the conclusion that HPN-100 and PBA from sodium PBA can be converted to PAGN without entering the systemic circulation. Perhaps, HPN-100 or its initial metabolite _(e.g., show one or two phenyl butyryl group of R 1 to R _3, the remaining one or two H of R 1 to R ₃ The compound of formula I shown-an expected partial hydrolyzate of HPN-100) reaches the liver and can be converted to PAGN in the liver before reaching the systemic circulation. Furthermore, partial conversion of HPA-100-derived PBA is greater than that absorbed when PBA is administered as a salt (despite the equivalent or potentially better ammonia scavenging activity, sodium PBA Findings that lower blood PBA levels after HPN-100 administration). With this observation, plasma levels of PAA or PBA are not a reliable indicator of the effectiveness of PBA prodrugs such as HPN-100, but should be relied upon to set or adjust the dosage of such PBA prodrug compounds. Not recognized. The data presented herein (eg, summarized in FIG. 9) proves this effect. There is a need for alternative monitoring methods for subjects treated with HPN-100, and this is provided herein.

  Furthermore, PK / PD modeling (reflected and shown in FIGS. 3 and 6) demonstrates that HPN-100 rapidly absorbs only about 40% of PBA when administered orally. As a result, despite the slow broadcast effect from HPN-100, once absorbed, it appears to be rapidly metabolized to PBA. This provides considerable flexibility in administration, for example why HPN-100 administration can be achieved, for example, a day to obtain stable ammonia levels similar to those requiring 4 or more PBA administrations. Explains three times and even two times a day.

  In view of these findings of unexpected pharmacokinetic behavior, plasma PAA and PBA should not be used for the evaluation or monitoring of treatment of subjects with HPN-100 or sodium PBA. There is a need for alternative monitoring methods for subjects treated with HPN-100, and this is provided herein. As an example, it has been found that between 50% and 85% of HPN-100, typically about 60 to about 75% of HPN-100 is converted to urinary PAGN. This conversion efficiency of HPN-100 and PBA sodium in UCD patients is surprising considering previous literature where it is generally assumed that the conversion efficiency of sodium PBA is approximately 100%. Urinary PAGN has been shown to inversely correlate with blood waste nitrogen (eg, ammonia) levels, so the effectiveness of HPN-100 can be assessed by measuring urinary PAGN. It has been found that HPN-100 has little or no effect on creatinine levels. In addition, creatinine levels in healthy adults and patients with nitrogen storage are typically rather stable, so measuring urinary PAGN excretion over time, or measuring the ratio of PAGN to creatinine (spot test) Can be conveniently performed on) to provide a method for monitoring the effectiveness of HPN-100. Accordingly, in one aspect, the present invention provides a method of assessing the efficacy of treatment with HPN-100, comprising determining the ratio of PAGN to creatinine in a “spot urine” test. Clinical trials show that urinary excretion of PAGN and the ratio of urinary PAGN to creatinine correlate well with blood ammonia levels, and increased PAGN or increased PAGN / creatinine ratio correlates with decreased plasma ammonia levels . Thus, in one method, HPN-100 treated patients are monitored by measuring urinary PAGN excretion or by measuring the ratio of PAGN to creatinine in a spot urine test. The method can be used to monitor the treatment of untreated patients, patients transitioned from PBA to HPN-100, or patients treated with HPN-100. Whether the dosing regimen using HPN-100 or another PBA prodrug is promising for excretion of excess ammonia, either by increasing the level of urinary PAGN excretion or by increasing the ratio of PAGN to creatinine in the spot test Determine and compare the two treatment methods to determine which is more effective for a particular subject.

  While plasma ammonia levels are often used to assess disease modulation in UCD patients, it is often inconvenient to rely on plasma ammonia levels to optimize administration of HPN-100 outside clinical practice settings. It is. Furthermore, plasma ammonia levels are affected by a number of factors and can rise regardless of how well treatment with the drug works. This reflects the appropriateness of diet and other factors, and the drug dose used. Plasma ammonia varies a lot, even when relatively well controlled, based on meal timing, drug timing, and various other factors. Therefore, it is necessary to monitor plasma ammonia levels over time by repeated blood collection in order to reflect the effects of the drug meaningfully, which is impractical for routine monitoring of certain patients and is an ammonia scavenger There is no direct information about whether or not it works. On the other hand, measurement of urinary PAGN can be more conveniently performed as a routine monitoring method. This is because this measurement does not require medical assistance to obtain a test sample. In addition, while urinary PAGN specifically measures the waste nitrogen clearance obtained by the scavenger, many other factors that affect ammonia levels can lead to errors in the actual effect of the nitrogen scavenger due to errors. Can cause adjustment. Thus, although several different parameters can theoretically be measured to evaluate the effectiveness of HPN-100 dosage, only urinary PAGN-based measurements are effective for nitrogen scavenging drugs. Convenient and reliable as a direct measurement of

  Accordingly, in one embodiment, the present invention provides for the treatment of a UCD patient with HPN-100 consisting essentially of monitoring the patient's urinary PAGN excretion and optionally checking plasma ammonia levels. Provide a way to monitor effectiveness. Urinary PAGN levels comparable to those achieved using previous PBA dosing regimens are considered evidence that HPN-100 treatment was as effective as PBA treatments that replaced it Will. Alternatively, plasma ammonia levels below or above about 40 μmol / L and up to 35 μmol / L will indicate that the treatment was effective. In some embodiments, rather than measuring urinary PAGN excretion over time, the ratio of urinary PAGN to creatinine in a spot test can be used.

  In another aspect, the present invention provides a utilization efficiency factor of about 60% to about 75% HPN-100 or sodium PBA. This factor can be used to more accurately determine the starting dose of either drug and / or correlate dietary protein intake with the predicted urinary PAGN.

  In one aspect, the present invention provides a method for transferring a patient from phenylbutyrate to HPN-100 or other esters or prodrugs of phenylbutyrate. The method comprises administering an initial dosage of the prodrug selected based on the patient's current phenylbutyrate dosage. For example, the required amount of HPN-100 to obtain an equimolar amount of PBA will be calculated (equal molar amount) and this equimolar amount will be administered to the patient. Monitor urinary excretion of PAGN or plasma ammonia levels as needed to establish PAGN excretion levels approximately the same as those obtained with an effective amount of phenylbutyrate or another nitrogen scavenger previously used Will increase or decrease the dosage of HPN. Typically, subjects transitioning from PAA or another PAA prodrug to HPN-100 for use in the present method are tested for urinary PAGN excretion before and after the transition and prior PAA prodrug treatment is effective. Assuming that it was considered, the HPN-100 dosage may be adjusted as necessary to match the urinary PAGN excretion from this patient when treated with a previous PAA drug or prodrug. I will. This allows a safer and more effective transfer to a new prodrug than methods that rely on the use of that amount without monitoring the in vivo effect of an equimolar amount of the new drug. This monitors PAA or PBA and attempts to adjust the dosage of the prodrug (ie HPN-100) to match the PAA or PBA level to the corresponding level obtained by administration of sodium phenylbutyrate itself. The risk of inaccurate administration and potential overtreatment that could be obtained if

  In some embodiments, the transition from phenylbutyrate can be performed in more than one step, and it will be possible to monitor ammonia capture during the transition by urinary excretion of PAGN and total nitrogen. In some embodiments, a patient receiving an initial dosage of phenylbutyrate is transferred from a phenylbutyrate to a phenylbutyrate prodrug in multiple steps. The method can use two steps, three steps, four steps, five steps, or more than five steps. In each step, a portion of the initial dosage of phenylbutyrate corresponding to the number of steps used for transfer is replaced with an appropriate amount of HPN-100 or other prodrug of phenylbutyrate. An appropriate amount for each step may be approximately sufficient to obtain an equimolar amount of PBA, assuming that the prodrug is quantitatively converted to PBA. Note also that Buphenyl® (sodium phenylbutyrate) contains about 6% inactive ingredients and is therefore suitable for calculations based on the PBA content of the drug rather than the weight of the prescription drug. The patient is then monitored to determine the amount at which an ammonia scavenging effect has been obtained. The amount of HPN-100 (or prodrug) is then adjusted to give approximately the same ammonia excretion in the form of excretion PAGN achieved by the initial dosage of phenylbutyrate when the patient is well regulated. Can be obtained.

  Physicians who switch patients from PBA to HPN-100 or another ester of phenylbutyrate have PAA or PBA levels as high as those observed when sodium phenylbutyrate is administered with an effective amount of HPN-100. You should be aware that this is not always possible. PAA has been reported to be somewhat toxic at high plasma concentrations. Thibault, et al. , Cancer Research, 54 (7): 1690-94 (1994) and Cancer, 75 (12): 2932-38 (1005). Given this and the inherent properties of HPN-100 described above, it is particularly important that physicians do not use plasma levels of PAA or PBA to measure the effects of HPN-100. If HPN-100 is administered in an amount sufficient to meet plasma PBA or PAA levels obtained by administration of phenylbutyrate, for example, the dose of HPN-100 may be unnecessarily high.

  Untreated patients are those who are not currently receiving treatment with an ammonia scavenger for nitrogen level management. While there are often recommended dosage levels for nitrogen scavengers, the exact dosage for untreated patients may be narrower than that range (eg, generally lower), while this dosage is Can exceed equimolar amounts when compared to the recommended dosage for sodium PBA. The initial dosage of PAA or PAA prodrug is calculated by methods known in the art once the patient's dietary protein intake is known, assuming that the patient has relatively normal liver function. be able to. Saul W Brusilow, “Phenylacetylglutamine May Replacing urea as a vehicle for waste nitrogen excretion,” Pediatric Research 29: 147-150, (1991). Methods for measuring total urinary nitrogen excretion are also known, and in the case of a subject who has taken a drug that acts by supplying PAA, the total waste nitrogen will include excreted PAGN.

  It is estimated that about 47% of the consumed protein is converted to waste nitrogen, and on average about 16% of the protein is nitrogen. Using these figures and assuming that HPN-100 is efficiently converted to PAGN, the daily dosage is about 19 g of HPN-100 and about 43 g of dietary protein-derived waste nitrogen Would provide a vehicle for excretion. Thus, 1 g of HPN-100 will be able to remove waste nitrogen from about 2 g of dietary protein. In addition, when it is estimated that the utilization efficiency of HPN-100 in various individual patients is between about 50% and 85% (as disclosed herein, an average of about 60-75% HPN-100 was found to be converted to urinary PAGN (consistent with clinical findings to date), these factors were used to determine the dietary habits for a given subject The relationship between protein intake and HPN-100 dosage levels can be further improved. Using this improvement, 1 g of HPN-100 will assist in the removal of about 1 gram (about 1.3 gram) of dietary protein waste nitrogen. This factor can be used to calculate an appropriate dosage of HPN-100 if dietary protein intake is known or adjusted, and tolerable diet for subjects receiving HPN-100 Protein intake can be calculated.

  Using this method, determination of the patient's ability to excrete nitrogen, calculation of the amount of dietary protein that the patient can process without the aid of a nitrogen scavenger, and the patient handles it on their own Patient's recommended daily diet by addition to the amount of dietary protein that can be processed (the amount of protein that a patient would be able to handle when using a specific dosage of PBA or a PBA prodrug such as HPN-100) Protein intake can also be established. Using HPN-100 as an example, with a maximum daily dosage of about 19 grams of HPN-100 used with an estimated efficacy of 60%, the treated patient is a waste equivalent to about 40 g of dietary protein. It will be able to excrete nitrogen. Thus, the present invention provides a method of establishing dietary protein levels appropriate for patients with urea cycle disorders or HE by adding this amount of protein to an amount that can be addressed by the patient's ability to excrete nitrogen.

  In some embodiments, it is also useful for measuring PAGN excretion, which accounts for some of the total excreted waste nitrogen when PAA or PAA prodrug acts. Total excreted waste nitrogen minus PAGN excretion indicates the patient's endogenous excretion of nitrogen waste via the urea cycle or other mechanism, which can be managed by the patient at a given dosage. It helps in determining the protein intake that can be made and also helps understand if the patient needs very close monitoring. The intrinsic ability to excrete nitrogen waste is very patient specific. HPN-100 dosage is then determined by determining the subject's intrinsic ability to excrete waste nitrogen, subtracting the amount of dietary protein corresponding to the subject's endogenous nitrogen excretion capability, and the subject's dietary protein It can be established by obtaining a dosage of HPN-100 sufficient for a subject to address the balance of waste nitrogen based on intake.

  In addition to measuring urinary PAGN, plasma or blood levels of ammonia are optionally determined to assess the effectiveness of all drugs and diet for a particular patient. If ammonia regulation is inadequate, it may be necessary to increase the dosage of the nitrogen scavenger when it is feasible, or the patient's dietary protein intake can be reduced when it is feasible.

In some instances, adjusted to the fact that 1 mole of HPN-100 can produce 3 moles of phenylbutyrate, the dosage of HPN-100 does not exceed the recommended dosage level of phenylbutyrate The amount can be limited. The label for the use of sodium PBA for long-term treatment of UCD recommends that the daily dosage not exceed 20 g; depending on the size of the subject, it is 9 for subjects whose body weight exceeds 20 kg. Daily dosages in the range of 9.9 to 13.0 g / m ² are set, and for subjects weighing 20 kg or less, dosages in the range of 450 to 600 mg / kg are shown. While lower doses of HPN-100 can provide ammonia capture comparable to PBA on a molar equivalent basis, certain subjects select higher dosages of HPN-100 to achieve proper ammonia regulation It may be appropriate. Typically, this dose does not exceed the recommended dosage range of phenylbutyrate for a given indication. Thus, HPN-100 at a daily dosage (corrected for the fact that three molecules of PBA can be obtained from HPN-100) does not exceed the amount of HPN-100 corresponding to the above molar amount of phenylbutyrate. May be appropriate. For subjects weighing over 20 kg, the dosage range of HPN-100 will be between 8.6 mL / m ² and 11.2 mL / m ² . For subjects weighing less than 20 kg, a dosage range of about 390-520 μL / kg / day of HPN-100 will be appropriate based on the use of equimolar amounts compared to the recommended dose of HPN-100. There is no evidence to suggest that HPN-100 produces adverse effects in proportions exceeding those derived from equimolar amounts of sodium PBA, so the recommended daily upper limit of 20 g / day of PBA sodium causes PBA sodium It is suggested that the daily dose limit of HPN-100 based on the recommended amount corresponds to an equimolar amount of HPN-100 (about 19 g or 17.4 mL).

  Accordingly, in one embodiment, the present invention comprises the step of monitoring or essentially consisting of monitoring a patient's urinary PAGN excretion and / or plasma ammonia level of a UCD patient with HPN-100. Provide a way to monitor effectiveness. Urinary PAGN levels comparable to those achieved using previous PBA dosing regimens would be considered evidence that HPN-100 treatment is equally effective as the PBA treatment it replaced . Alternatively, plasma ammonia levels that were normal (eg, levels below about 40 μmol / L or at most 35 μmol / L) would indicate that the treatment was effective. In some embodiments, rather than the use of urinary PAGN excretion measured over time, the ratio of urinary PAGN to creatinine in a spot test can be used.

  However, HPN-100 does not show toxicity at an equimolar dose when compared to an approved PBA dosage of 20 g / day, and blood results in AE by administration 2-3 times the dose equivalent to 20 grams of PBA. It has also been found that it is unlikely to reach medium PAA levels. Furthermore, tolerance from HPN-100 intake is much higher than PBA, and a linear relationship has been observed between HPN-100 dose and PAGN excretion up to a dose of 17.4 mL. In some patients or clinical practice settings, for example, UCD patients who show recurrent hyperammonemia despite the highest dose of sodium PBA, UCD patients who need increased dietary protein to support physical demands In patients with, or other nitrogen retention conditions, HPN-100 doses well above the approved PBA dosage are expected to be advantageous.

  Thus, in another embodiment, the present invention has HE or UCD using a dosage of HPN-100 corresponding to between 100% and 300% of equimolar amounts of the recommended highest PBA dose A method of treating a subject is provided. In some embodiments, a suitable dosage is between about 120% and 180% of the highest recommended PBA dose. In other embodiments, 120-140%, 140-160%, or 160-180% of an equimolar amount of the highest recommended PBA dosage. According to this embodiment, the daily dosage of HPN-100 can be as much as 57 g, up to about 38 g, up to about 33 g, up to about 30 g, or up to about 25 g.

In one aspect, the present invention identifies a starting dose or dose range of a nitrogen scavenger that includes PAA or a PAA prodrug (including HPN-100) used for the management of naïve patients, Or a method of adjusting the dose range individually,
a) taking into account the expected conversion efficiency to PAGN and administering an initial dosage of the drug evaluated according to the dietary protein load of the patient;
b) measuring total waste nitrogen excretion after administration of a nitrogen scavenger comprising PAA or a PAA prodrug;
c) measuring blood ammonia to determine whether an increase in urinary excretion of total waste nitrogen is sufficient to regulate blood ammonia levels; and d) adjusting the initial dosage to adjust ammonia. Obtaining a adjusted dosage of a nitrogen scavenger comprising a PAA or PAA prodrug based on dietary protein and total waste nitrogen excretion by the patient, or waste PAGN excretion is provided. Any or each of these parameters can be monitored to assess the dosage of HPN-100 or other nitrogen scavenging drug administered. Optionally, the method also includes determining the subject's ability to excrete nitrogen (residual urea synthesis capacity) to further assist in determining the initial dose of HPN-100.

  The initial dosage of HPN-100 for an untreated patient can be calculated as the amount of waste nitrogen that needs to be excreted based on the patient's dietary protein intake. Using the patient's endogenous waste nitrogen excretion capability, which can be measured as described herein, this amount can be reduced by an amount equivalent to the waste nitrogen that the patient can excrete. . By assessing the dietary protein intake required to manage an appropriate starting dose of HPN-100 via a nitrogen scavenger and taking into account the expected conversion rate of administered PBA to urinary PAGN Can be calculated by providing a drug dose equal to about 1 g of HPN-100 per 1-2 grams of dietary protein that exceeds the amount that can be addressed by the patient's endogenous nitrogen excretion capacity. . The method optionally further comprises assessing urinary PAGN excretion to investigate whether urinary PAGN excretion accounts for the expected amount of waste nitrogen, and optionally acceptable Measuring the subject's plasma ammonia level to ensure that the ammonia level has been achieved can be included. A check of the patient's plasma ammonia level provides a measure of the effectiveness of the entire treatment program, including diet and drug administration.

  The table below shows that HPN-100 doses below the dose equivalent to the recommended sodium PBA dosage (dose 1), within dose (dose 2), and above dose (dose 3) are “covered” (ie, The amount of dietary protein expected to mediate the waste nitrogen excretion obtained) is summarized. This takes into account the following assumptions: 1 gram of PAA mediates about 0.18 grams of waste nitrogen excretion when fully converted to PAGN; PBA pro released from HPN-100 60% PAA delivered as a drug is converted to PAGN; 47% dietary protein is excreted as waste nitrogen; and 16% dietary protein consists of nitrogen (Brusilow 1991; Callaway 1971) ). These factors can be used for the purposes of the present invention when associated with dietary protein intake, medication, and waste nitrogen excretion.

As used herein, plasma ammonia levels are tolerated when they are at or below what is considered normal for a subject, generally this means that plasma ammonia levels are less than about 40 μmol / L. Will do. In certain clinical trials described herein, the upper normal limit for subjects was between 26 μmol / L and 35 μmol / L. This is recognized in the art to vary depending strictly on how normal ammonia levels are measured. Thus, as used herein to describe ammonia levels, “about” means an approximate value, typically within ± 10% of the indicated numerical value.

In another aspect, the present invention identifies a suitable starting dose or dose range for UCD or HE patients and starts a new nitrogen scavenging drug used for the management of patients who have already been previously treated with nitrogen scavenging drugs. A method of individually adjusting doses or dose ranges,
a) Initial dosage of new nitrogen scavenger (evaluated according to patient dietary protein load and / or dose of new drug expected to yield urinary PAGN excretion identical to previously used nitrogen scavengers) Can be administered),
b) measuring the amount of total waste nitrogen and / or PAGN excreted after administration of the new drug;
c) optionally measuring blood ammonia to determine whether the initial dosage is sufficient to regulate blood ammonia levels or to establish an appropriate average ammonia level; And d) adjusting the initial dosage of the new drug as needed to provide an adjusted dosage based on the amount of ammonia regulation, dietary protein, and total waste nitrogen excreted by the patient. Provide a way. The initial dosage is adjusted based on the amount of PAGN in the urine without depending on the plasma level of PAA, PBA, or PAGN, and preferably not on the plasma ammonia level.

  If the patient has been previously treated with PAA or a PAA prodrug, the attending physician will either complete the previous treatment or set a new PAA or PBA prodrug dosage to be administered to the same patient. Can depend in part. If the previous drug was reasonably effective in managing the patient's condition, the physician would assume that each prodrug would be completely converted to PAA and that the new dose would yield the same dosage as PAA. The dosage of the new PAA or PBA prodrug can be set with reference to the previous drug so that the drug is administered to the patient.

  Also, as discussed above, it is sometimes desirable to measure excreted PAGN in addition to the excreted total waste nitrogen. Subtracting PAGN excretion from total excreted waste nitrogen indicates the patient's endogenous excretion of nitrogen waste via the urea cycle or other mechanism, which can be managed by the patient at a given dosage It helps in determining protein intake and helps understand if patients need very close monitoring. The intrinsic ability to excrete nitrogen waste is very specific to the patient.

In another aspect, the invention provides safe ingestion by a subject having a nitrogen accumulation disorder, including hepatic encephalopathy and UCD, the patient is taking an ammonia scavenger containing PAA or a PAA prodrug. A method for identifying the amount of dietary protein that can be achieved, comprising:
a) measuring the total waste nitrogen excretion after drug administration;
b) determining the amount of dietary protein calculated so as to obtain an amount of waste nitrogen less than or equal to urinary waste nitrogen, and c) appropriately adjusting the dietary protein and the dietary protein based on measurement of blood ammonia and total waste nitrogen excretion A method comprising the step of adjusting the drug dosage is provided.

  If the subject is treated with a nitrogen scavenger, the patient's dietary protein intake may need to be reassessed periodically. This is because a number of factors affect the balance between nitrogen intake, nitrogen excretion, and nitrogen scavenger dosage. The present invention provides a method for determining the amount of dietary protein that a patient can address based on measurement of the patient's nitrogen excretion level. The present invention may further be useful in measuring the patient's PAGN levels discussed above to assist in determining the patient's endogenous excretion capacity of nitrogen waste via the urea cycle or other mechanism.

  In the above method, the patient may be a patient with a urea cycle disorder or other nitrogen accumulation disorder. In many embodiments, the method is applicable to patients with urea cycle disorders but relatively normal liver function.

  The above method can be carried out using various prodrugs of PAA or PBA. In some embodiments, HPN-100 is a generally preferred PBA prodrug for these methods.

In another aspect, the invention provides a method for transferring a patient from treatment with an initial amount of phenylacetate or phenylbutyrate to treatment with a final amount of PBA prodrug comprising:
a) determining a replacement amount of a PBA prodrug to replace at least a portion of phenylacetate or phenylbutyrate;
b) using a substituted amount of a prodrug in place of phenylacetate or phenylbutyrate, and c) monitoring the amount of PAGN excreted by the patient to assess the effectiveness of the substituted amount of prodrug. A method comprising:

  Optionally, the method comprises the steps of adjusting the amount of the prodrug and administering the adjusted amount of the prodrug, then further monitoring PAGN excretion to assess the effectiveness of the adjusted amount of the prodrug. Including. The amount of substitution of the PBA prodrug can be approximately equimolar with the amount of PBA to be substituted.

  For reasons discussed extensively herein, relying on PAA levels can lead to errors when transferring patients to PAA or PBA prodrugs (or new prodrugs). The availability of a liver-based mechanism of rapid conversion of prodrug to PAGN without necessarily entering the systemic system makes PAA and PBA plasma levels insufficient as a predictor of efficacy and should be administered to patients For the assessment and monitoring of treatment with PAA or PBA prodrugs, the method relies on excreted PAGN.

  In many cases, it is possible to transfer patients directly in, for example, phenylbutyrate to HPN-100 or another PBA prodrug, rather than a gradual process. Thus, all previously used PAA or PAA prodrugs can be replaced with an appropriate replacement amount of a new drug (PBA prodrug). However, in some situations (eg, “vulnerable patients”, patients taking PAA or PAA prodrugs at or near recommended limits, and very limited endogenous nitrogen waste excretion It may be preferable to move from an initial drug to a new PBA prodrug such as HPN-100 in two or more stages or steps) in patients who have the ability or where the patient is uncertain of the ability to metabolize or excrete the drug. unknown. Thus, it can be transferred in two steps, three steps, four steps, or five steps, and in each step, a portion of the original drug (e.g., about half for the two-step transition and about 1 / three for the three-step transition). 3) is replaced with the new PBA prodrug to be administered. This approach is known to be susceptible to repeated episodes of hyperammonemia while receiving treatments that promote nitrogen excretion or taking large amounts of drugs that promote nitrogen excretion. May be appropriate for UCD patients.

Accordingly, in another aspect, the present invention is a method of transferring a UCD patient from treatment with an initial amount of phenylacetate or phenylbutyrate to treatment with a final amount of PBA prodrug, comprising:
a) determining the amount of substitution of the PBA prodrug to replace at least a portion of phenylacetate or phenylbutyrate;
b) using a substituted amount of a prodrug in place of phenylacetate or phenylbutyrate; and c) monitoring plasma ammonia levels in the patient to assess the effectiveness of the substituted amount of prodrug. provide.

  In some embodiments, the amount of prodrug substitution is equimolar compared to the amount of PBA substituted.

  During the monitoring process, the patient is treated with a mixture of phenyl acetate or phenyl butyrate and the new prodrug. The ratio depends on which transition process the patient is in. The physician can also use information regarding the impact of the first step in setting the replacement amount of prodrug to be used in subsequent steps. Therefore, if the prodrug is significantly more effective than would be expected when the evaluation amount used as the substitution amount was administered in the first step, the substitution amount used in the next transition step should be proportionally reduced. Can do.

In another aspect, the present invention provides a “fragile patient” (a UCD patient with a history of frequent symptomatic hyperammonemia and / or a history of neonatal-onset disease that probably has no ability to synthesize urea, or Initiate treatment with phenylacetate, phenylbutyrate, or PBA prodrugs in a stepwise fashion so that it may be appropriate for patients with severe impairments in liver function whose ability to metabolize drugs may be uncertain Provide a method. This process can be more complex because prodrugs depend on activated and functioning liver function. Thus, the method preferably comprises:
a) assessing or measuring the patient's dietary nitrogen intake; and / or b) assessing the patient's need for urinary waste nitrogen excretion;
c) administering a starting dose of drug evaluated to obtain part of the waste nitrogen clearance required for PAGN excretion; and d) appropriately increasing the dose of drug and repeating the above steps to maintain the maintenance dose. Performed in a step-wise manner exemplified by the process of reaching the drug.

  The method also optionally includes measuring total urinary nitrogen and urinary PAGN at least three days after drug administration (at which time steady state is achieved). The method can also include calculating the amount of drug converted to PAGN (which would be expected to be at least 50%) to determine if the drug has the desired effect. The appropriate dosage of the drug will be identified as the dosage at which PAGN excretion is sufficient to clear the amount of waste nitrogen expected from the dietary intake of protein. This dosage can be adjusted to account for the patient's endogenous nitrogen excretion capacity.

  The portion of the nitrogen waste to be cleared in a single step can be selected for the severity of the patient's condition (nitrogen accumulation disorder). In some embodiments, it is appropriate to target about 50% removal of waste nitrogen that requires clearance assistance. In some embodiments, the method is aimed at removing about 100% of the waste nitrogen.

In another aspect, the invention provides a method for transitioning from phenylbutyrate to HPN-100 in a patient who has received an initial daily dosage of phenylbutyrate, comprising:
a) determining an appropriate amount of HPN-100 to replace at least a portion of the initial daily dosage of phenylbutyrate;
b) Subject with an appropriate amount of HPN-100, with an amount of phenylbutyrate equivalent to the initial daily dosage of phenylbutyrate minus the amount corresponding to the portion displaced by the HPN-100. Administering to
c) determining the subject's level of PAGN excretion and confirming that the excretion level has not decreased; and d) repeating steps a through c until all phenylbutyrate is replaced with HPN-100. A method comprising the steps is provided.

  If PAGN excretion is found to be reduced, additional HPN-100 or additional PBA is administered to re-establish appropriate PAGN excretion levels to the patient, and then all PBA is replaced with HPN-100. The replacement process will continue until

  Here again, the portion of phenylbutyrate to be substituted in the first step is 100%, about 1/2, about 1/3, or about 1/4, or some value in between obtain. During the phased process, if less than all phenylbutyrate is replaced in the first step, the patient is administered both HPN-100 and phenylbutyrate. As demonstrated herein, a suitable method for determining the appropriate dose of HPN-100 is more than based solely on unreliable criteria for the evaluation of orally delivered PBA prodrugs. Rather, consider excreted PAGN.

  In another embodiment, the invention includes determining a subject's PAGN excretion rate after administration of at least one phenylbutyrate prodrug and selecting or adjusting a dosage regimen based on the PAGN excretion rate. Provided is a method of administering a phenylbutyrate prodrug to a patient. The compound can be a compound of formula I, formula II, or formula III as described above. Advantageously, the compounds used herein as prodrugs of PBA achieve sustained release that achieves nitrogen capture comparable to PBA but provides more stable ammonia levels in the treated subject. A kinetic profile is shown. In some embodiments, the methods of the present invention provide modulation of ammonia levels comparable to the modulation of ammonia levels achieved by PBA, but at a dosage at which subject exposure to systemic PBA is very low. Administering to the subject a prodrug as described herein. In some embodiments, the subject is lower to PBA while maintaining plasma ammonia levels comparable to or greater than those obtained by treatment with a dosage of PBA within the normal dosage range. Experience the pharmacokinetic parameters of PBA (including lower AUC and Cmax for PBA) that demonstrate exposure. When HPN-100 and PBA were administered to UCD patients at equimolar dosages, patients receiving HPN-100 overall had lower plasma ammonia levels and lower PBA exposure.

While larger data sets are needed to prove statistical significance, the amount of data available is limited due in part to the rarity of these conditions. Nevertheless, the data showed that PBA treatment was less effective at modulating ammonia levels and exposure to PBA was greater, while the PBA prodrug HPN-100 was more effective with equimolar doses. It shows that the ammonia level was well controlled and the PBA exposure level was also lower. Accordingly, in one aspect, the present invention provides a method of treating a UCD patient with a PBA prodrug. Here, as determined by AUC and Cmax for PBA, the prodrug provides better ammonia levels than PBA without increasing patient exposure to PBA when compared to treatment with equimolar amounts of PBA. Adjusted. In some embodiments, the treatment uses HPN-100 as a prodrug, and in some embodiments, the AUC for PBA exposure is at least about 20% lower using a prodrug than using PBA. Or, exposure to PBA during treatment with a prodrug is at least about 30% lower compared to treatment with PBA, or both of these conditions correspond to demonstrating a reduction in PBA exposure. . In some embodiments, when a prodrug is administered, the AUC for PBA is less than about 600 and the Cmax for PBA is less than about 100. Preferably, the prodrug provides plasma ammonia levels that average less than about 40 μmol / L, or at most 35 μmol / L.

  The advantageous sustained release kinetic profile of the compounds used herein as prodrugs for PBA allows for less frequent and more flexible administration in selected patients compared to sodium PBA . All patients who have UCD and tend to have high ammonia levels should in principle be able to benefit from the ammonia scavenging activity of HPN-100 while Urea synthesizing ability remains substantially (Eg, UCD whose first signs occur at ages of several years or more, ie patients who do not develop in the neonatal period) 3 times a day with a PBA prodrug (such as HPN-100) or twice a day It would be the best candidate for administration. Cirrhosis patients and HE patients may also be candidates for infrequent administration, as even patients with severe liver disease remain significantly capable of urea synthesis (Rudman et al., J. Clin. Invest. 1973). ).

  Specific embodiments of the invention include the following.

  A. A method of determining an effective dosage of HPN-100 for a patient in need of treatment of a nitrogen retention disorder, comprising the step of monitoring the effect of an initial dosage of HPN-100, wherein the monitoring of the effect comprises A method consisting essentially of determining urinary phenylacetylglutamine (PAGN) excretion.

  In this method, the initial dose of untreated patients will take into account the expected conversion rate of administered PBA to urinary PAGN. And creatinine (its daily excretion tends to be constant for a given individual) can be used as a reference to normalize urine parameter measurements while correcting for changes in urine volume Has been proven by others, urinary PAGN excretion can be determined as the ratio of urinary PAGN to urinary creatinine. In these methods, the nitrogen retention disorder can be chronic hepatic encephalopathy or urea cycle disorder. Plasma ammonia levels can be monitored to adjust overall treatment program and dietary protein intake, but as discussed above, urinary PAGN is preferred for assessing the role of drug waste nitrogen excretion A method is obtained.

  B. A method of determining an effective dosage of HPN-100 for a patient in need of treatment of a nitrogen retention disorder, comprising monitoring the effect of an initial dosage of HPN-100, the initial dose for an untreated patient Taking into account the expected conversion rate of administered PBA to urinary PAGN, monitoring the impact of the initial dosage of HPN-100 may result in the patient's urinary phenylacetylglutamine (PAGN) excretion and / or A method consisting essentially of determining total urinary nitrogen. In these methods, administration of an effective dosage of HPN-100 to a patient preferably results in normal patient plasma ammonia levels. This can be at a level of about 35 or about 40 μmol / L.

  C. A method of determining a starting dosage of HPN-100 for a patient having a nitrogen retention disorder, comprising calculating a dosage of HPN-100 based on utilization efficiency of about 60% to about 75%. In such methods, the dosage of HPN-100 can be calculated from the patient's dietary protein intake or can be estimated from the patient's weight and approximate growth rate. In such methods, the patient's ability to synthesize residual urea is clarified from time to time by adjusting the amount of HPN-100 to reflect the required amount of ammonia trapping taking into account the patient's endogenous nitrogen excretion ability. Reduce the dosage of 100.

D. A method for determining a dosage of a PAA prodrug for a patient having a nitrogen retention disorder comprising:
a) determining the patient's ability to synthesize residual urea;
b) determining the dietary protein intake of the patient;
c) assessing the patient's target urinary PAGN output from a) and b);
d) determining the amount of PAA prodrug required to mobilize a target amount of urinary PAGN based on about 60% to about 75% conversion of the PAA prodrug to urinary PAGN.

  In these methods, the PAA prodrug can be phenylbutyric acid (PBA) or a pharmaceutically acceptable salt thereof, or it can be HPN-100.

E. A method of treating a patient with impaired ammonia retention using an appropriate dosage of a PAA prodrug comprising:
a) determining the patient's ability to synthesize residual urea;
b) determining the dietary protein intake of the patient;
c) assessing the patient's target urinary PAGN output from a) and b);
d) determining the amount of PAA prodrug required to mobilize the target amount of urinary PAGN based on about 60% to about 75% conversion of the PAA prodrug to urinary PAGN; and e) appropriate dosing Administering an amount of PAA prodrug to the patient.

  In these methods, the PAA prodrug is often phenylbutyrate or a pharmaceutically acceptable salt thereof, or HPN-100.

G. A method of transferring treatment to a patient from an initial amount of phenylacetate or phenylbutyrate using a final amount of HPN-100,
a) determining a substitution amount of HPN-100 for substituting at least a portion of phenylacetate or phenylbutyrate;
b) using a replacement amount of HPN-100 in place of phenylacetate or phenylbutyrate; and c) monitoring the amount of urinary PAGN excreted by the patient to determine the effectiveness of the replacement amount of HPN-100. A method comprising the step of evaluating.

  In these methods, increasing urinary PAGN levels can indicate that HPN-100 levels can be decreased. A decrease in urinary PAGN may indicate that the amount of HPN-100 needs to be increased.

H. A method of transitioning from phenylbutyrate to HPN-100 for patients who have taken an initial daily dosage of phenylbutyrate, comprising:
a) determining an appropriate amount of HPN-100 to replace at least a portion of the initial daily dosage of phenylbutyrate;
b) Subject with an appropriate amount of HPN-100, with an amount of phenylbutyrate equivalent to the initial daily dosage of phenylbutyrate minus the amount corresponding to the portion displaced by the HPN-100. Administering to
c) determining the excretion level of urinary PAGN for the subject; and d) repeating steps ac until all phenylbutyrate is replaced with HPN-100.

I. A method of initiating treatment with phenylacetate, phenylbutyrate, or HPN-100 in a stepwise fashion comprising:
a) assessing or measuring dietary nitrogen intake for the patient, and / or b) assessing urinary waste nitrogen excretion required by the patient based on diet and urea synthesis capacity, and c) administered PBA Taking into account the expected conversion rate of urinary PAGN to urinary PAGN, administering as a urinary PAGN the starting dose of drug evaluated to provide some of the necessary waste nitrogen clearance, and d) as appropriate Repeating the above steps to increase the dose of the drug and reach the maintenance dose of the drug;
Including a method.

  J. et al. A method of treating a UCD patient using a PBA prodrug, wherein the patient is administered an equimolar amount of PBA as determined by the AUC and Cmax for PBA when the patient is administered the PBA prodrug A prodrug, when compared to the AUC and Cmax observed in Example 1, provides greater than equivalent modulation of ammonia levels compared to PBA without increasing patient exposure to PBA.

  In these methods, the PBA prodrug is often HPN-100.

  The method uses a PBA prodrug HPN-100 to treat a patient with impaired nitrogen retention, and the AUC for PBA exposure uses the prodrug compared to treatment using PBA. Including a method that may be at least about 20% or at least about 30% lower than when using PBA. This is believed to be related to the slow absorption or uptake properties of HPN-100, which results in more stable PBA exposure levels when compared to sodium phenylbutyrate and is effective at lower frequency administration The unexpected advantage of HPN-100 is obtained.

K. A method for determining an appropriate dietary protein level for a patient with a nitrogen retention disorder comprising:
a) determining the patient's endogenous nitrogen excretion ability;
b) calculating from the endogenous nitrogen excretion ability the amount of dietary protein that the patient can process without the aid of a nitrogen scavenger;
c) Then, taking into account the amount of protein needed for health and body growth, add the amount of protein that the patient should be able to process with the help of the selected dose of nitrogen scavenger and select Reaching the amount of dietary protein that a patient can have while being treated with a given dose of a nitrogen scavenger;
Including a method.

  In this method, the nitrogen scavenger can be HPN-100. In general, the selected dosage of HPN-100 is at most about 19 grams / day, and the amount of dietary protein that a patient should be able to process with the help of this amount of HPN-100 is about 1 g HPN-100. One gram (about 1.3 g) of protein.

  L. A method of treating a patient using a PBA prodrug comprising administering a daily dose of HPN-100 of greater than 19 g / day to a subject having HE or UCD. Optionally, the daily dose of HPN-100 is between about 20 g and about 57 g.

  M.M. Of patients who retain substantially the ability to synthesize urea (which may apply to most patients with cirrhosis and HE or most UCD patients who do not show symptoms within the first 2 years of life) A method of determining a dosing schedule for a PBA prodrug.

  In the above methods using HPN-100, exposure to PBA during treatment with the prodrug HPN-100 is at least about 30% lower compared to treatment with PBA. Also, generally, when a prodrug is administered, the AUC for PBA is less than about 600 and the Cmax for PBA is less than about 100. Also, in the above methods, when a subject is treated with a prodrug (which may be HPN-100), the subject typically achieves and maintains normal plasma ammonia levels.

  The following examples are given by way of illustration and do not limit the invention.

  The following data from three human studies and one preclinical study show that conventional drug exposure and impact assessment approaches by measuring blood levels are assessed by urinary excretion of PAGN or reduction of plasma ammonia. Illustrates that it does not correlate with capture. These data remarkably indicate that the plasma levels of PBA or PAA observed using an effective amount of a prodrug are higher than the plasma levels of PBA or PAA observed using a similar effective amount of phenylbutyrate. Prove that it is much less likely. Furthermore, these data show incomplete conversion of sodium PBA or HPN-100 to PAGN in the choice of starting dosage, sustained release behavior and relevance for a regimen of PBA delivery as a triglyceride rather than a salt, As well as that necessary to allow administration of HPN-100 at doses exceeding those currently recommended for sodium PBA. These are followed by a biological explanation of the findings.

Example 1
Single dose safety and PK in healthy adults
To evaluate its pharmacokinetic (PK) and pharmacodynamic (PD) profiles, HPN-100 was administered as a single dose to 24 healthy adults. Pharmacokinetic samples were taken before administration, 15 and 30 minutes after administration, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after administration. As discussed below, the plasma levels of the main HPN-100 metabolites PBA, PAA, and PAGN were much lower after HPN-100 administration than after sodium PBA administration. In contrast, urinary excretion of PAGN was similar between the two groups (4905 +/− 1414 mg after PBA sodium and 4130 +/− 925 mg after HPN-100), and the observed difference interrupted urine collection at 24 hours It was judged that this was largely due to the incomplete recovery artifacts resulting from the failure (PAGN excretion after PBA sodium administration was almost complete at 24 hours, but 24 hours after administration of HPN-100. Note that it persisted beyond). Therefore, plasma metabolite concentrations did not accurately reflect the comparison of ammonia scavenging activity between sodium PBA and HPN-100.

Three healthy adult volunteers were treated using a single dose of either 3 g / m ² dosage of sodium PBA or HPN-100. Plasma levels of PAA, PBA, and PAGN were monitored periodically for 12-24 hours by known methods. The result is shown in FIG. This shows a curve for each subject (note the log scale).

In each panel, the curve represents a subject who received a dose of HPN-100 that was calculated to give an equivalent molar amount of PBA to that obtained with a 3 g / m ² dose of PBA sodium or PBA sodium dose. Shown are measurements of PBA, PAA, or PAGN levels. Three curves for each substance are curves for three subjects who received a specific dosage of sodium PBA or HPN-100.

  In the left panel, the upper curve of the three sets of lines shows the PBA level, the middle curve shows the PAA level, and the lower curve shows the PAGN level. In the right panel, the bottom three curves for 10-15 hours are all for PBA, and the top three curves for 15-25 hours indicate PAGN levels. PAA levels were not determined after approximately 12 hours and were generally close to the PAGN curve up to this time.

Example 2
Administration of HPN-100 to patients with liver disease To determine its pharmacokinetic (PK) and pharmacodynamic (PD) profiles in patients with liver disease, cirrhosis (Child Puscore A, B, or C) A single dose of HPN-100 (100 mg / kg / day on day 1) orally administered to a control group of healthy adults with normal liver function and sex and age who have normal liver function, A clinical trial was conducted in which oral administration was carried out twice daily for 7 consecutive days (200 mg / kg / day, 100 mg / kg / dose twice on days 8 to 14). On day 15, the subject received a single dose of HPN-100 (100 mg / kg). PK blood samples were administered before administration, 15 and 30 minutes after administration, 1, 1.5, 2, and 15 days after administration, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours, And 48 hours after administration on days 1 and 15. On days 9-14, blood samples were taken before morning administration and 2 hours after morning administration. Urine was collected 0-4, 4-8, 8-12, and 12-24 hours after administration on days 1, 8, and 15 and 24-48 hours after administration on days 1 and 15.

HPN-100 is metabolized through the main pathway in all subject groups, and alternative HPN-100 metabolites PAG (phenylacetylglycine), PBG (phenylbutyrylglycine), and PBGN (phenylbutyrylglutamine) ) Was below the limit of quantification of all plasma samples. Despite no significant differences in these variables on day 15, both PBA and PAA systemic exposure (AUC 0- _t ) and C _max range were both higher than those of Child Pew Group A or Healthy Volunteers Also tended to be higher in Child Pew Group B or C. As described below, plasma PAA levels correlated with child-pugh classification (ie, patients with more severe liver disease). However, the average conversion rate of HPN-100 to PAGN was about 75%, and no difference was observed between cirrhosis patients and normal healthy volunteers. This proved that liver damage did not affect the patient's ability to activate the PBA prodrug HPN-100 or use it for excretion of excess ammonia. Therefore, as summarized in more detail below, plasma metabolite levels do not correlate well with HPN-100 dosage, and only for healthy adults, plasma metabolite levels are accurate for HPN-100 nitrogen scavenging effects. Did not reflect on. Furthermore, the average conversion rate from PAA to PAGN administered averaged about 75% in this patient population.

AUC 0- _t , area under the plasma concentration curve from time 0 to the last measurable concentration; CI, confidence interval; C _max , highest observed plasma concentration; PAA, phenylacetic acid; PBA, phenylbutyric acid.

During multiple doses (days 8-15), PBA and PAA whole body in subjects with increased liver damage (Child Pew B or C) compared to Child Pew Group A and healthy volunteers The concentration tended to be higher. Unlike PBA, PAA accumulated significantly in plasma during multiple days of administration. The difference between single (day 8) and multiple doses (day 15: steady state) was significant for PAA AUC _0-12 and C _max in all combinations of subjects. (P <0.001), not significant with PBA. After administration on day 15, the PAA exposure range was significantly correlated with liver damage, but not with PBA.

  The clinical efficacy of HPN-100 depends on its ability to capture ammonia by forming PAGN by conjugation of glutamine with PAA. After daily administration, PAGN was the main metabolite excreted: 42-49% of the administered HPN-100 dose was excreted as PAGN on day 1 and 25-45% was excreted on day 8. 58-85% was excreted on the 15th day. Very small amounts of PBA and PAA were excreted in the urine (less than 0.05% of the total HPN-100 dose). There was no significant difference in PAGN excretion between any child pew group and healthy volunteers. Urinary PAGN excretion also demonstrates the ability of HPN-100 to capture ammonia, since 2 moles of ammonia is combined with 1 mole of PAA to produce PAGN. In this study, liver injury did not significantly affect the ability of HPN-100 to capture ammonia. There was no significant difference in PAGN excretion between any child pew group and healthy volunteers. In this study, liver damage did not significantly affect the ability of HPN-100 to capture ammonia, but the finding that it was related to PAA accumulation in plasma was more than the level of blood metabolites to guide drug effects. Rather, the importance of using the urinary PAGN, and of course, the importance of the present invention is emphasized. This is because the average conversion rate from administered PAA to urinary PAGN in the four treatment groups was about 75%.

  Urinary PAGN excretion after administration (0 to 48 hours) on day 15

In particular, there was no association between plasma levels of PBA and PAA (which showed a statistically insignificant change towards higher plasma levels in patients with liver disease than in healthy adults) and urinary excretion of PAGN It should be noted.

Example 3
Administration of HPN-100 to adults with UCD To further investigate its pharmacokinetic (PK) and pharmacodynamic (PD) profiles in clinical conditions associated with nitrogen retention, 10 adult UCD patients were Sodium PBA was replaced with equimolar PBA HPN-100. Subjects needed stable sodium PBA administration prior to enrollment. Upon enrollment, all subjects received 7 days of sodium PBA and were then admitted to the study unit for overnight observation, 24-hour PK and ammonia measurements, and urine collection (visit 2 -1). The subject was then converted to an equimolar dose of HPN-100 with PBA in either a single step or multiple steps depending on the total sodium PBA dose. Nine out of 10 patients were converted in a single step. Subjects were kept at a 100% HPN-100 dose for 1 week and then re-hospitalized in the study building for repeated PK (visit 11-1), ammonia, and urine collection.

  Findings from this study summarized in detail below show that, for healthy adults and patients with liver disease only, plasma metabolite levels reflect urinary PAGN excretion and are demonstrated by ammonia scavenging activity as demonstrated by plasma ammonia results. Prove that it does not correlate well. Furthermore, the observations demonstrate that the ratio of both sodium PBA and HPN-100 converted to urinary PAGN varies greatly between individuals.

Pharmacokinetic, ammonia, and safety analysis: As summarized in the table below, 7 days of HPN-100 administration produced similar PAA and plasma PAGN levels, but with PBA molar equivalents of PBA sodium dose and In comparison, the PBA level was slightly lower.

AUC _0-24 : Area under concentration from time 0 (before administration) to 24 hours, Cmax _ss : maximum plasma concentration at steady state, Cmin _ss : minimum plasma concentration at steady state, A _e : excretion over 24 hours
¹ mean (SD) sodium PBA dose = 12.6 (4.11) g; mean (SD) HPN-100 dose = 12.3 (3.91) g.

  Despite different blood PBA levels, total urinary excretion of PAGN for the two treatments was similar, as summarized in the table below. In contrast to the assumptions inherent in current treatment guidelines that all significant administered sodium PBA is converted to urinary PAGN, the average conversion rate of administered PAA to PAGN, which was approximately 60%, is very high among individuals. And was similar for both sodium PBA and HPN-100. In addition, urinary excretion of PAGN in patients treated with sodium PBA reached the highest level during the “afternoon” (6-12 o'clock urine collection), whereas the peak of PAGN in HPN-100 treated patients The 24-hour excretion pattern appeared to be different in that excretion occurred overnight (12-24 hour urine collection). This difference probably reflects the sustained release and longer duration of PAA for effective blood levels after administration of HPN-100, as compared to sodium PBA. HPN-100 was not detectable in all blood samples or was below the limit of quantification.

  Comparison of sodium PBA (sodium phenylbutyrate) vs. HPN-100 for mean PAGN excretion (μg)

As summarized in the table below, the mean time-normalized curve area (TN-AUC) value of venous ammonia after HPN-100 is more unidirectional (approximately about the value observed using sodium PBA. 31%) was low (26.1 vs. 38.4 μmol / L), but this difference was not statistically significant (FIG. 10). Similarly, peak venous ammonia concentrations after HPN-100 were unidirectionally lower (about 29%; not statistically significant) than those observed using sodium PBA (56.3 vs. each). 79.1 μmol / L).

  The normal upper limit of venous ammonia varied between 26-35 μmol / L between research institutions. Each patient's ammonia level (TN-AUC) study demonstrated that patients with higher ammonia levels relative to sodium PBA had a greater decrease in ammonia level after administration of HPN-100 (FIG. 12). ). Furthermore, while the average ammonia value (26.1 μmol / L) after HPN-100 was within the normal range, the upper limit of normality (ULN) after sodium PBA (sodium phenylbutyrate) was exceeded (38.4 μmol / L). (FIG. 13). Similarly, the average percentage of normal ammonia values increased from 58% after sodium PBA treatment to 83% after HPN-100 treatment.

As summarized in the table below and FIG. 11, this decrease in ammonia exposure among UCD patients reflects better overnight regulation among subjects who received HPN-100. This study showed that HPN-100 was used to decrease both AUC and Cmax for ammonia (indicating a decrease in total ammonia exposure), and HPN-100 showed a significantly stronger effect, especially at night. Although not statistically significant due to the small size of the population, this is because HPN-100 is at least effective on an equimolar basis on the basis of an important criterion (the ability to mobilize ammonia for urinary excretion), apparently Proves more effective than PBA. Based on preliminary results, HPN-100 also provides more stable ammonia levels, reducing the risk of hyperammonemia. In this study, 9 of 10 subjects who experienced both HPN-100 and sodium PBA preferred HPN-100.

  Furthermore, in this study, two subjects who received PBA experienced symptomatic hyperammonemia while no serious adverse effects (SAE) were observed in patients taking HPN-100, The total number of adverse effects (AEs) reported among subjects who took HPN-100 (5 subjects reported a total of 15 AEs) was the number of AEs between subjects who took PBA (7 Of subjects reported 21AE).

  The following table summarizes all comparative data for sodium PBA and HPN-100 administered at equimolar ratio (n = 10) (see above table and Figures 10-13 for further details).

Although the difference between sodium PBA and HPN-100 did not reach statistical significance due to the small sample size, HPN-100 showed a clear trend to be more effective at equimolar dosages and ammonia It was particularly effective at improving the level of overnight regulation.

  FIG. 9a shows that blood PBA levels do not correlate with the administered HPN-100 dosage. This figure plots the 24-hour AUC for PBA and the Cmax for PBA against the HPN-100 dosage (upper panel) while tracking the AUC and Cmax in each patient together, It shows no association with HPN-100 dose: both highest and lowest PBA exposure occurred in patients receiving high doses of HPN-100. FIG. 9b shows that the level of PAA is similarly uncorrelated with HPN dosage.

  FIG. 10 shows the trend in clinical trials that waste nitrogen was better regulated overall by HPN-100.

  FIG. 11 shows the improvement in nighttime regulation of excess ammonia achieved using HPN-100.

  FIG. 12 shows that patients with higher ammonia levels, especially when treated with sodium PBA (NaPBA), are better regulated by HPN-100 than sodium PBA while patients with lower ammonia levels (PBA sodium In patients considered to work well), HPN-100 shows that at least similar ammonia regulation is obtained. For patients with ammonia levels above about 40 μmol / L when treated with sodium PBA, equimolar dosages of HPN-100 provide better ammonia regulation and ammonia levels are consistently reduced to below about 40 μmol / L Please note that. Thus, it is expected that better ammonia regulation can be achieved using equimolar amounts of HPN-100 for patients with abnormal ammonia levels (eg, greater than about 40 μmol / L) when treated with sodium PBA. Is done. Based on this, the dosage of HPN-100 can be determined as described herein. FIG. 13 shows that ammonia levels are better regulated by HPN-100 than using sodium PBA in this test (eg, lower average ammonia levels) and tend to be below the normal upper limit.

Example 4
Relationship Between Ammonia Regulation and Urinary PAGN Excretion As part of the clinical study in UCD patients described in the above example (Example 3), the relationship between plasma ammonia levels and urinary excretion of PAGN was examined. Unlike blood levels of PAA or PBA, which did not show a consistent relationship with ammonia levels (ie, ammonia regulation), blood ammonia, evaluated as the area under the time normalization curve, has a curvilinearity opposite to urinary PAGN. The relationship was shown. That is, plasma ammonia decreased as urinary PAGN increased. Furthermore, the relationship between ammonia and urinary PAGN excretion was not different between PBA sodium and HPN-100. This suggested that this dose determination method was independent of product formation. FIG. 5 shows a plot of plasma ammonia versus urinary PAGN excretion (TN-AUC).

Example 5
Experiments using dosing schedules The results of single dose PK / PD modeling observed in the above examples suggested that HPN-100 exhibits sustained release compared to sodium PBA. This may increase administration flexibility, which was further investigated in the further clinical studies described above. In one of these, HPN-100 was administered twice daily in a fasted and fed state. On the other hand, HPN-100 was administered with meals three times a day. Similar doses of urinary PAGN excretion were obtained with both three times daily and twice daily administration, and three times daily administration was associated with effective ammonia regulation in adult UCD patients. Proven.

  In Example 2, several secondary statistical analyzes comparing PK variables after feeding HPN-100 versus fasting HPN-100 and after single HPN-100 versus multiple HPN-100 were also performed. . When HPN-100 was administered after fasting (Day 1) or at the time of feeding (Day 8), there was no difference in PK or PD. Thus, HPN-100 could be effectively administered without the need for a meal, but the label and package insert for PBA sodium (PBA sodium) should be taken when fed doing. In addition to no difference in PAA PK variables between the fasted state and the fed state (day 8 vs. day 1), the following table uses multiple doses (day 15 vs. day 8). The resulting plasma accumulation of PAA is also shown.

^* P = 0.64 (for group effect); † p = 0.72 (for group effect)
‡ On day 1, child Pew group B n = 2 and all other groups n = 0; on day 15, group A n = 4, group B 2, group C 1, and group D 3
AUC _0-12 , area under the plasma concentration curve from time 0 to 12 hours after administration; AUC 0- _t , area under the plasma concentration curve from time 0 to the last measurable concentration; C _max , highest observed plasma concentration; CV, coefficient of variation; geo. Mean, geometric mean; n, number of subjects; SD, standard deviation; _Tmax , time to highest observed plasma concentration; t1 _{/ 2} , half-life.

Example 6
PK / PD modeling results For most drugs, a portion of the orally administered dose that is removed and metabolized by the liver before reaching the systemic circulation (ie, the first-pass effect) is considered bioavailable. Not done. This is because this dose does not enter the systemic circulation and therefore cannot reach its target organ or receptor. However, this is not the case for the ammonia scavengers described in the present invention. Hepatocytes and possibly intestinal cells contain the enzymes necessary for PBA to PAA conversion and PAA to PAGN conversion, and glutamine is present in the viscera and systemic circulation before reaching systemic circulation (i.e. , "Pre-systemically") PBA can be converted to PAGN, which is likely to be sufficiently effective for ammonia capture (Figure 6) (ie, fully active). To verify this possibility, NONMEM VI against plasma and urine metabolite data from the above clinical trials (over 5000 data points), including healthy adults, subjects with cirrhosis, and UCD subjects. PK / PD modeling using (Icon, Elicot City, MD.) Was performed. The model shown in FIG. 3 was confirmed from the result of this PK / PD modeling. Furthermore, modeling verifies that HPN-100 exhibits sustained release compared to sodium PBA, explaining the low correlation between blood PBA / PAA levels and ammonia, and urinary PAGN Important for dose adjustment. The important conclusions resulting from PK / PD modeling are shown below.
1. PBA is absorbed more slowly from the intestine after administration of HPN-100 versus sodium PBA (rate of about 40%) (the absorption rate constant and absorption half-life of HPN-100 and sodium PBA are 0.544 h ⁻¹ pair, respectively) 1.34 h ⁻¹ and 1.27 hours vs. 0.52 hours).
2. The lower plasma levels of PBA after administration of HPN-100 compared to sodium PBA were partially higher in PBA (31% vs. 1%) after administration of HPN-100 than NaPBA (PAA and Reflects the result indicating conversion to (PAGN).
3. For datasets containing healthy individuals, cirrhosis individuals, and UCD individuals, the diagnosis was introduced as a covariation with respect to the bioavailability of HPN-100 evaluated, and in healthy adults compared to adult UCD patients, 32 % Of the lower rated PBA bioavailability was revealed. Cirrhosis patients and UCD patients had similar PBA bioavailability after HPN-100 treatment.

Example 7
ADME study in 3 cynomolgus monkeys (Cynomolgus monkey) To assess preclinical handling of ammonia scavengers, 3 doses of either 600 mg / kg of radiolabeled sodium PBA or radiolabeled HPN-100 were administered as a single dose It was administered to cynomolgus monkeys. Similar to humans (unlike most other species), these monkeys were chosen because they metabolize PAA to PAGN, thereby being a useful model for PAA prodrug testing. This study demonstrated the clinical findings summarized in Examples 1-3 and included the following: (a) Oral administration of sodium PBA or oral administration of HPN-100 to urinary PAGN 100% not converted, (b) plasma PBA and blood PAA levels did not consistently correlate with ammonia scavenging activity reflecting urinary PAGN excretion, and (c) HPN-100 and PBA sodium It showed sustained release compared.

  Radiolabeled PBA and PAA enter the systemic circulation more slowly after administration of radiolabeled HPN-100 (Cmax for PBA is achieved 1.5 hours after administration (52.2 μg / mL) and for PAA Cmax was achieved 8 hours after administration (114 μg / mL)), demonstrating the findings observed in humans (including PK / PD modeling), and HPN-100 is essential during systemic circulation and excretion Did not appear. About 90% of the radioactive material derived from HPN-100 excreted in urine was PAGN, accounting for 39% of the administered HPN-100. In contrast, when sodium PBA was administered orally, PAGN accounted for only 23% of the radiolabeled material and unchanged PBA accounted for 48% of the oral dose of sodium PBA. Therefore, oral PBA sodium was used less efficiently than HPN-100, and unexpectedly large amounts of PBA were excreted unchanged.

Example 8
Biological and Anatomical Considerations Unlike most drugs that act on target organs / cells / receptors (and so on) that are perfused by whole body blood, the types of ammonia scavengers targeted by the present invention act on target organs. Rather, PAA acts by combining with glutamine to form PAGN (FIG. 6). Because glutamine is present in the viscera and systemic circulation, the liver is a metabolically active organ that can catalyze the entire process involved in the conversion of HPN-100 or PBA to PAA and subsequent conversion to PAGN. Based on data accumulated to date (including PK / PD modeling) and anatomical considerations, PBA / PAA is not significantly removed from PBA / PAA before it reaches systemic circulation (eg, in the liver). A conclusion is drawn to form PAGN. This is especially true when HPN-100 is administered as a PBA prodrug. This explains the low correlation between plasma levels and the ammonia trapping effect and leads to the conclusion that administration and dose adjustment of these PBA prodrugs should be based on urinary excretion of PAGN and total urinary nitrogen. It is burned. FIG. 6 shows how this happens.

  For certain clinical trials, particularly for comparison between HPN-100 and PBA, HPN-100 is administered at a dose (equimolar) equivalent to the amount of sodium PBA that would be considered appropriate for a particular patient. The dosage can then be adjusted by the methods described herein. For example, the dose range of HPN-100 is comparable to the PBA mole equivalent to the approved dose range of sodium PBA (sodium phenylbutyrate) (NaPBA). HPN-100 will be administered three times a day (TID) with meals. Conversion of NaPBA dose to HPN-100 dose is corrected for its different chemical form (ie, HPN-100 consists of glycerol esterified with 3 molecules of PBA and does not contain sodium) (NaPBA (g) × 0 Note that it includes corrections for .95 = HPN-100 (g)) and HPN-100 specific gravity (which is 1.1 g / mL).

¹ PBA sodium 20g include phenyl butyrate about 17.6 g; 19 g of HPN-100 include phenyl butyrate about 17.6 g.

Example 9
Determination of starting dosage of HPN-100 and dose adjustment Patients with nitrogen retention conditions (eg, hereditary urea cycle disorder or cirrhosis) that are not currently treated with the ammonia scavengers described herein are It is clinically determined that such treatment is necessary. This clinical decision will be based on various factors such as signs and symptoms of HE and elevated blood ammonia levels in cirrhotic patients.

  The starting dosage is clinical considerations (evaluation of residual urea synthesis capacity (it is estimated that infants with UCD who developed hyperammonia in the first few days of life do not have significant urea synthesis capacity) ) And appropriate dietary protein intake (ie, infants with UCD need to increase dietary protein to support body growth, but long-term dietary protein restriction in cirrhotic patients is usually ineffective or Which is counterproductive) and based on the method outlined in the present invention. For example, adults with limited ability to synthesize residual urea were treated with an initial dosage of 19 g / day of HPN-100 and given a protein-restricted diet containing about 25 g protein per day. Monitor the patient's daily urinary output of PAGN. The daily intake of HPN-100 is 19 g of HPN-100 (0.0358 mol of HPN-100) with a molecular weight of about 530. Since 1 mole of HPN-100 can theoretically be converted to 3 moles of PAA and thus 3 moles of PAGN, 0.108 moles of PAGN can be converted in vivo from 19 g of daily dosage of HPN-100. Can be generated. When fully converted to PAGN, all PAGN will be excreted in the urine, and the theoretical amount of PAGN would be 28.4 g / day. Assuming that 16% of the dietary protein is nitrogen and about 47% of the dietary nitrogen is excreted as waste nitrogen (see Brusilow), this amount is due to about 41 grams of dietary protein. It will be sufficient to mediate waste nitrogen excretion.

  However, as demonstrated herein, HPN-100 is typically about 60% -75% efficient (typically about 60% conversion in UCD patients, cirrhotic patients About 75% conversion), the physician expects to see about 17 g of urinary PAGN excretion per day from this dosage of HPN-100. I will. This corresponds to about 25 grams of dietary protein-this amount is similar to the prescribed amount, but less than the theoretical amount (41 grams). This dosage of HPN-100 may have been expected to be considered theoretically. Therefore, efficiency adjustments of 60-75% have a profound effect on the overall treatment program, and by knowing the efficiency, the attending physician will have too much protein for the patient to manage with this dosage of HPN-100. It can be avoided to provide the patient with a meal.

  When monitoring a patient, if higher urinary PAGN excretion is observed than expected by the physician, HPN-100 dosage is reduced proportionally. Thus, if 21 g of urinary PAGN / day is observed, the physician reduces the HPN-100 dosage to (17/21) × 19 g = 15 g. Similarly, if the urinary PAGN excretion is lower than expected (such as 12 g / day), it will increase the amount of HPN-100: if 12 g is observed and expected to be 17, then the physician will The dose of −100 can be adjusted (17/12) × 19 g = 27 g HPN-100 / day (if this dose is within the range considered safe to administer to the patient). Either HPN-100 dosage or dietary protein intake can be adjusted to optimize the treatment regimen for this subject.

  Optionally, the urinary PAGN excretion can be determined as the ratio of the urinary PAGN concentration to the urinary creatinine concentration. Rather than determining total daily urinary PAGN, creatinine levels are typically given for a given urinary PAGN so that a physician can evaluate total daily urinary PAGN from testing a single urine sample. The individual is stable enough to obtain a normalization factor for urine volume.

  The physician can also monitor the patient's plasma ammonia level and dietary protein intake to see if the combination of the patient's dietary protein intake and drug treatment provides an appropriate therapeutic effect. Dietary protein intake or drug dosage or both can be adjusted to obtain normal or desired plasma ammonia levels (eg, levels below about 40 umol / L). However, as evidenced by the observations described herein, the physician will adjust the plasma level of PAA or PBA to adjust the HPN-100 dosage or otherwise guide the treatment. Will not use. Because these levels do not correlate well with the ammonia scavenging effect of administered HPN-100.

  If a dose of 19 g of HPN-100 is determined to be inappropriate (eg, the patient requires waste nitrogen excretion beyond the patient's ability to synthesize urea and an increase in dietary protein that is believed to result in PAGN excretion. ), Increasing the HPN-100 dose sufficiently to target the necessary dietary protein, and applying the same dose adjustment method based on urinary PAGN excretion to determine the dosage of HPN-100. I will.

  In subjects who have little or no ability to synthesize urea, where essentially all urinary nitrogen is believed to be explained by PAGN, the ammonia scavenging effect was measured by total urinary nitrogen (TUN) rather than direct measurement of urinary PAGN levels. ) Can be monitored.

  In some cases, TUN can be used as a urea synthesis capacity criterion by subtracting the amount of nitrogen present as PAGN.

Example 10
Determination of HPN-100 dosage for patients already administered sodium PBA UCD patients who should be transferred to HPN-100 already administered sodium PBA should undergo dietary protein assessment and measurement of urinary PAGN excretion. I will.

  If it is determined that the patient is properly adjusted with sodium PBA, the starting dose of HPN-100 will be that amount necessary to deliver the same amount of PAA (eg, 19 grams of HPN-100 is Will correspond to 20 grams of sodium PBA). Subsequent dose adjustments will be based on repeated urinary PAGN measurements and assessment of dietary protein and ammonia. However, as evidenced by the observations described herein, the physician may determine the initial dosage of HPN-100, adjust the dosage of HPN-100, or otherwise treat Will not use plasma levels of PAA or PBA. Because these levels do not correlate well with the ammonia scavenging effect of administered HPN-100.

  If it is determined that the patient is inappropriately adjusted with sodium PBA, the starting dose of HPN-100 is more than the sodium PBA dose, provided that such HPN-100 dosage is otherwise appropriate. A large amount of PAA will be selected to be delivered. Subsequent dose adjustments will be based on repeated urinary PAGN measurements and assessment of dietary protein and plasma ammonia. However, as evidenced by the observations described herein, the physician may determine the initial dosage of HPN-100, adjust the dosage of HPN-100, or otherwise treat Will not use plasma levels of PAA or PBA. Because these levels do not correlate well with the ammonia scavenging effect of administered HPN-100.

  In some cases, for example, in “fragile” UCD patients with a history of repeated episodes of hyperammonemia, PBA sodium can be converted to HPN-100 in more than one step, thereby The dose of sodium PBA will be reduced to an amount corresponding to the amount of PAA delivered by increasing doses of HPN-100.

  When it is determined that the dose of HPN-100 is inadequate (eg, the patient requires production of waste nitrogen that exceeds the patient's ability to synthesize urea and an increase in dietary protein that is thought to result in PAGN excretion) The HPN-100 dose will be increased sufficiently to target the necessary dietary protein and the same dose adjustment method based on urinary PAGN excretion will be applied.

  The examples described herein are for illustrative purposes only and should not be construed as limiting the invention.

Claims (1)

Invention described in this specification.