EP3151823A1 - Fixed dose combination for pain relief without edema - Google Patents

Abstract

Methods for individualized therapy of pain using a non-steroidal anti-inflammatory drug (NSAID) without inducing intolerable edema. Said methods comprise basing NSAID dose on each patient's pharmacokinetic response to said NSAID. Provided is a composition for treating pain without inducing edema comprising a NSAID and an anti-hypertensive, wherein the composition is administered in a fixed-dose combination.

Description

FIXED DOSE COMBINATION FOR PAIN RELIEF WITHOUT EDEMA

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Applications Nos. 62/009,300, filed June 8, 2014, and 62/023,962, filed July 14, 2014, which are both incorporated by reference. This application also claims the benfit of PCT Application PCT/US2015/01 1 148, filed January 13, 2015, which is incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] It is well appreciated that non-steroidal anti-inflammatory drugs ("NSAID") are highly active as pain relievers. However, NSAIDs also have major and minor side effects. One of these side effects is drug induced edema.

[0003] "Edema" is an abnormal accumulation of fluid in the tissue spaces, cavities, or joint capsules of the body, causing swelling of the area. Edema can occur in the tissues or body spaces such as the plural cavities or the peritoneal space. Clinically, edema has variable consequences depending on the site and severity of the edema. For example, subdermal edema may only manifest as mild swelling manifest by tight shoes. In contrast, chronic, severe subdermal edema can cause skin break down, ulceration and serious infection.

Similarly, While a pleural effusion may spontaneously resolve, ascites (edema in the paritoneal space) can be complicated by difficulty to treat bacterial peritonitis. See, e.g., Harrison's Internal Medicine, 16^th edition, p.213-214.

[0004] Pathophysiologically, edema occurs when there is an elevation in capillary hydraulic pressure, and/or an increase in capillary permeability or when the interstitial oncotic pressure exceeds the plasma oncotic pressure. Such changes can result from a variety of conditions and diseases. For example, in congestive heart failure the activation of the renin-angiotensin system causes volume overload which results in increased capillary hydraulic pressure. The kidneys control extracellular fluid volume by adjusting sodium and water excretion. When renal function is impaired, edema can result. In cirrhosis the reduced production of serum proteins such as albumin result in a decrease in the plasma oncotic pressure relative to interstitial onccotic pressure resulting fluid shifts into the intersitum. Venous insufficiency is a common cause of edema of the lower extremities from an increase in capillary hydraulic pressure. Harrison's Internal Medicine, 1 6 ¹ edition, p.213-214 ; O'Brian et al.. Treatment of Edema, American Family Physician, 71 (1 1). 21 1 1 -17.

[0005] Many drugs can cause edema including steroid hormones, vasodilators such as hydralazine, estrogens, NSAIDs, immunomodulators such as interleukin 2, and calcium channel blockers. The pathophysiology of drug induced edema is similarly wide ranging. Such mechanisms include, drug induced vasodilation (e.g. hydralazine), drug effects on the kidneys' sodium excretion (e.g., steroids), and capillary damage (e.g., interleukin 2). Drug induced edema is usually dose-dependent and its severity increases over time. Harrison's Internal Medicine, 16^th edition, p.213-214; O'Brian et al., Treatment of Edema, American Family Physician, 71 (1 1). 21 1 1 -17.

Many NSAIDs can cause edema. The mechanism for NSAID induced edema has been postulated to be from renal vasoconstriction. Harrison's Internal Medicine, 16th edition, p.213-214. NSAIDs inhibit cyclogenases (COX), the enzymes that catalyzes formation of various prostaglandins. The two principle COX isoforms are COX-1 and COX-2. Studies have shown that both therapeutic and side effects of NSAIDs are dependent on

cyclooxygenase inhibition. In general, selective inhibitors of COX-2 have therapeutic effects that are as strong as conventional NSAIDs but with fewer side effects. Nevertheless, selective COX-2 inhibitors still can cause edema. Siileyman et al., Anti-inflammatory and side effects of cyclooxygenase inhibitors, Pharma. Reports, 2007 59:247-258.

[0006] Celebrex (celecoxib) is a prototypic selective COX-2 inhibitor and the first page of the Celebrex (celecoxib) Package Insert lists edema as an "adverse reaction." Table 1 of this Package Insert discloses that 2.1% of patients treated with celecoxib develop edema, as compared to 1.1%, 2.1 %, 1.0%,, and 3.5 % for placebo, naproxen, diclofenac, and ibuprofen, respectively. Moore et al.'s review of the tolerability and rate of adverse events in clinical trials of celecoxib found that the incidence of edema at any site was usually about 3%, but in two trials the incidence of edema much higher at 23%> and 38%. Arthritis Res. & Therapy, 2005, 7(6), R644-R664, R658-59.

[0007] In view of the persistent problem of drug induced edema and, in particular, edema induced by drugs with known efficacy for the treatment of pain, there remains a need for better approaches to preventing and treating drug induced edema. BRIEF SUMMARY OF THE INVENTION

[0008] Provided is a composition for treating pain without inducing edema comprising a NSAID and an anti-hypertensive, wherein the composition is administered in a fixed-dose combination.

[0009] Additionally, provided is a method for individualized therapy of pain using a NSAID, wherein the NSAID is a COX-2 inhibitor, preferably the NSAID is celecoxib, said method comprising:

a. administering a first NSAID formulation comprising a first dose of a combination with an anti-hypertensive in specific amounts, to a first patient suffering from pain;

b. determining the NSAID and anti-hypertensive concentration in the first patient's blood at a plurality of time points after the first NSAID formulation was administered to the first patient;

c. transforming the first patient's NSAID and anti-hypertensive

concentration/time data points in to one or more pharmacokinetic (PK) parameters; d. comparing the first patient's values for said PK parameters to a predetermined ranges of values for each PK parameter and if one or more of the first patient's PK parameters fall outside of a predetermined range, designing a new NSAID formulation, wherein the dose of said NSAID inhibitor, the anti-hypertensive, or both is different from that of the first NSAID formulation;

e. administering the new NSAID formulation to the first patient;

f. repeating steps b-e until all the PK parameters used in step d are within said predetermined ranges, and

g. if pain control is adequate, toxicity is tolerable, and the patient is not experiencing edema, maintaining the first patient on the NSAID formulation at frequency of administration that satisfied the comparison in step d.

[0010] Related compositions and methods for individualizing therapy of arthritic pain are disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a scatterplot graph displaying the relationship between LPS-stimulated plasma PGE2 ex vivo, an index of NSAID activity, and log plasma concentrations of celecoxib 2, 4, 6, and 24 hours after dosing. PGE2 is expressed as a percentage of predosing values. A steep but variable dose-response is evident. (P , 0.01 vs. placebo) (from McAdam et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. PNAS. 1999; 96:272-7.)

[0012] FIG. 2 depicts the pharmacokinetic parameters produced by different doses of celecoxib.

[0013] FIG. 3 displays the result of a meta-analysis of the one dose AUC from patients in different age groups.

[0014] FIG. 4 displays the result of a meta-analysis of the celecoxib dose dependence of edema.

[0015] FIG. 5 displays the result of a regression analysis of the celecoxib dose dependence of edema.

[0016] FIGS. 6-1 1 display the incidence of edema for celecoxid given alone or with other drugs. HCTZ, hydrochlorothiazide; CCB, calcium channel blocker; ARB, angiotensin receptor blocker; ACE, angiotensin converting enzyme inhibitor; non-thiazide diuretic; beta blocker; Any, any other drug.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The invention provides compositions and methods for individualized therapy of pain, including but not limited to arthritic pain, using a NSAID, preferably a COX-2 inhibitor, and an anti-hypertensive (e.g., lisinopril). The high patient to patient variability in response to a dose of any NSAID and/or anti-hypertensive makes the mere clinical monitoring of patients an inadequate way to treat patients with this class of drugs. Even the measurement of "blood levels" (i.e., the ocasional measurement of the drug's concentration in the plasma) is unlikely to lead to effective nontoxic regimens. Given the complexity of NSAIDs' dose response relationships both alone and in combination with one or more antihypertensive , a more comprehensive set of metrics must employed in each patient. The methods claimed herein take advantage of a pharmacokinetic ("PK") analysis for each patient. As such, the claimed methods go beyond the measurement of a single blood level at a single time point. Instead, the claimed methods make use of data on the plasma drug concentraion from several time points (at least 2, peferably at least 12 over 72 hours) and take advantage of the full scope of PK parameters to generate a PK Profile of a patient for a particular drug. There is no known method of predicting individual PK profile for celecoxib due to the complexity of human pharmacokinetics. As such there is no natural law known that can explain human pharmacokinetics; or if there are, the multitude of potential determining factors make defining such law impractical. Therefore, the claimed method seeks to determined the individual's PK profile directly.

[0018] As used herein the phrase "individualized therapy" refers to a specific treatment regimen for a patient comprising the administration of one or more drugs, which is the result of analyzing pharmacokinetic and/or pharmacodynamic parameters of the subject to maximize drug efficacy at the lowest dosage of the drug(s) possible.

[0019] As used herein "pain" refers to physical suffering or discomfort caused by an illness or injury, e.g., arthritis.

[0020] As used herein "osteoarthritic pain" refers to pain resulting from osteoarthritis.

[0021] As used herein, "formulation" or "a formulation" refers to a combination of active ingredients and pharmaceutically acceptable carriers wherein each is present in a dosage form at fixed ratios to one another (i.e., fixed percentages of each ingredient in the dosage form.)

[0022] As used herein, "first COX-2 inhibitor formulation" is the NSAID formulation comprising a first dose of a NSAID combined with a dose of anti-hypertensive and, optionally, pharmaceutically acceptable carriers in specific amounts that is administered to the patient to begin the process by which PK parameters are determined . The "new COX-2 inhibitor formulation" is the formulation designed based on the PK parameters produced by the first COX-2 inhibitor formulation. As such, the "new COX-2 inhibitor formulation" may have a change in the dose of the COX-2 inhibitor, the dose of the anti-hypertensive or the compostion of the carrier. Alternatively, the compostion of the carrier may be changed while the doses of the COX-2 inhibitor and the anti-hypertensive remain the same. To evaluate the PK parameters produced by the new COX-2 inhibitor formulation it replaces the "first COX- 2 inhibitor formulation" and the process is repeated. The new COX-2 inhibitor formulation comprising a first dose of a NSAID combined with an anti-hypertensive in specific amounts formulation may be a second formulation.

[0023] As used herein the phrases "first formulation under a first regimen" and "first formulation" refer to the dosage of a NSAID or COX-2 inhibitor formulation that an individual initially receives prior to performing one or more steps of the claimed invention. For example, the first formulation under a first regimen, can be the standard 100 mg or 200 mg dosages of celecoxib prescribed to patients over 60 kg, twice daily for osteoarthritis combined with a standard dose of anti-hypertensive. [0024] As used herein, the phrase "NSAID and anti-hypertensive concentration/time data points" refers to the NSAID and anti-hypertensive concentration in a unit of volume (e.g., 1 ml) of plasma from a subject at a given point in time before or after administration of the NSAID and anti-hypertensive .

[0025] As used herein, the phrase "transforming" the patient's NSAID and antihypertensive concentration/time data points" refers to the application of mathematical operations, formulas, theories, and/or principles to the NSAID or anti-hypertensive concentrations/time data points of an individual to derive PK parameters (e.g., a formula for calculating AUC).

[0026] As used herein, the phrase "predetermined range of values" refers to a range of PK parameters associated with desirable drug efficacy with minimal toxicity determined by a statistical analysis the PK profiles of patients of known outcomes for the formulation administered. The predetermined range of values can readily be compared to a patient's values and used to adjust dosages.

[0027] As used herein, "Significant adverse drug reactions" refer to ADRs that the patient finds intolerable, impair physiologic functions, and/or put the patient at risk for immobility and/or death or combinations thereof.

[0028] As used herein "Significant side effects" refer to side effects that the patient finds intolerable, impair physiologic functions, and/or put the patient at risk for immobility and/or death or combinations thereof.

[0029] As used herein, the phrase "predetermined range of values" refers to a range of PK parameters associated with desirable drug efficacy with minimal toxicity determined by a statistical analysis the PK profiles of patients of known outcomes for the formulation administered. The identification of said predetermined ranges of values can be accomplished with the aid of data reduction (e.g., factor analysis or principal components analysis) and clustering computer protocols (e.g., K-means or SOMs) (See U.S. Patent Nos. 7,412,333; 8,660,370; 8,990, 135; 9,002,658; 9,026,536; and 9,043,321 .)

[0028] As used herein, "designing" refers to changes in the active agent's dose, formulation and/or regiment based on the patient data, using logic and the experience of one of ordinary skill in the art. Said designing may be done in accordance with the invention aided by statistical and data-mining techniques known to those of ordinary skill in the relevant art that can identify the pharmacokinetic parameters and formulation components of greatest importance. It will be appreciated by those of ordinary skill that iterative process claimed herein will lead to steady state PK profiles for the NSAID and the diuretic within 4 - 6 cycles of dose changes and single dose and steady state predetermined ranges will be used as appropriate.

[0029] Complete pharmacokinetic profiles may result in such a large number of variable parameters that there would be too many pairwise correlations between the variables to reasonably consider. In particular, with so many parameters graphical display, usually a powerful way to begin data analysis, may not be useful. Surprisingly, with 12 variables, there will be more than 200 three-dimensional scatterplots. To put the such complex data in a more useful form, it is necessary to reduce the number of variables to a few, interpretable linear combinations which account for most of the variability in the data.

[0030] "Factor Analysis" offers a way to reduce the data to a few critical parameters. In every factor analysis, there are the same number of factors as there are variables. Each factor captures a certain amount of the overall variance and the factors are always listed in the results in the order of how much of the overall variance they explain, (see US Patent No. 8,660,370.)

[0031] "Principal components analysis is another data reduction method. Suppose that there are a dozen variables, principal components analysis can reduce these to a few (2-3) principal components. Principal components analysis, like factor analysis, can be performed on raw data or on a correlation or a covariance matrix, (see US Patent No. 7,412,333.)

[0030] As used herein, "determining the level of efficacy" refers to the use of objective (e.g., pharmacokinetic) and subjective tests (e.g., pharmacodynamic), signs and symptoms to characterize, quantify or evaluate how well symptoms (e.g., pain) are controlled by the administration of the active ingredient (e.g., celecoxib and a anti-hypertensive).

[0031] As used herein, "determining the level of toxicity" refers to the use of objective and subjective tests, signs and symptoms to characterize, quantify or evaluate the significance of any side effects produced by the administration of the active ingredient.

[0032] As used herein, "pain control is adequate" refers to a level of pain the patient is willing to live with and which does not significantly impair the patient's functioning in society or the patient's physiologic functions.

[0033] As used herein, "toxicity is acceptable" refers to the absence of significant side effects and a level of toxicity that the patient is willing to live with and does not significantly impair the patient's functioning in society or the patient's physiologic functions. [0034] As used herein, "trace edema" is edema that is just above the threshold for detection on physical exam (inconsistently pitting) and does not significantly impair the patient's functioning in society or the patient's physiologic functions.

[0035] As used herein, "NSAID" or "non-steroidal anti-inflammatory drug" refers to a class of drugs which provide pain-reducing and fever reducing effects as well as antiinflammatory effects in a subject, e.g., a human patient. NSAIDs include both COX- 1 and COX-2 inhibitors.

[0036] As used herein, a "COX-1 inhibitor" refers to a non-steroidal anti-inflammatory drug that is capable of directly targeting the COX-1 enzyme in a subject and inhibits at least some COX-1 activity, e.g., aspirin.

[0037] As used herein, a "COX-2 inhibitor" refers to a non-steroidal anti-inflammatory drug that is capable of directly targeting the COX-2 enzyme in a subject and inhibits at least some COX-1 activity, e.g., celecoxib. As used herein, a "mixed COX-1 and COX-2 inhibitor" refers to a non-steroidal anti-inflammatory drug that is capable of directly targeting both the COX-1 and COX-2 enzymes in a subject and inhibits at least some COX-1 and COX-2 activity, e.g., ibuprofen.

[0038] As used herein the term "anti-hypertensive " refers to any substance that promotes the reduction of blood pressure. Suitable anti-hypertensives for use in the compositions and methods disclosed herein include but are not limited to azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, and

combinations thereof.

[0039] As used herein "controlled release" refers to the delivery of the NSAID, the antihypertensive, or both in response to in vivo stimuli. For example, pH changes in the digestive tract . As used herein "delayed release" refers to prolonged dissolution time, e.g., increase dissolution time by 2, 4 or 6 hours, (see e..g., US Patent No. 8,992,979)

[0040] As used herein "enteric coated" refers to a dosage form with polymer barrier which is resistant to dissolution at gastric pH levels but dissolves at the higher pH levels typical of in the intestine, applied to the composition comprising a NSAID and an antihypertensive.

[0041] As used here the combination can also include a "fixed dose combination" (FDC) or simply dosing with multiple pills each of a single agent to achieve a desired effect. [0042] The invention provides compositions and methods for individualized therapy of pain, including but not limited to arthritic pain, using a non-steroidal anti-inflammatory drug (NSAID), preferably celecoxib in combination with an anti-hypertensive, prefereably an angiotensin receptor blocker ("ARB") or an angiotensin converting enzyme inhibitor ("ACE") inhibitor. In addition, the invention provides methods for predicting the outcome of the therapy of pain with a composition comprising NSAID, preferably celecoxib, and an antihypertensive, preferably ARB or ACE inhibitor. Further, the invention provides methods of using a NSAID, preferably celecoxib, and an anti-hypertensive, preferably ARB or ACE inhibitor, in the manufacture of medicament for the treatment of pain.

[0043] The invention provides endpoints (i.e., an individualized drug therapy) based on the achievement of predetermined PK results, as well as the clinical condition of the patient.

[0044] In one embodiment, provided is a composition for treating pain without inducing edema comprising a NSAID and a anti-hypertensive, wherein the composition is

administered in a fixed-dose combination. Any type of pain may be treated by the compostion, including arthritic and osteoarthritic pain.

[0045] The NSAID may be one or more of the following NSAIDs, but is not limited thereto: diclofenac, diflusnisal, etodolac, fenoprofen, flubiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, salicylate, sulindac, tolmetin, celecoxib, rofecoxib, etoricoxib, lumiracoxib, parecoxib , valdecoxib, chlorthalidone and combinations thereof. In a preferred

embodiment, the COX-2 inhibitor is celecoxib.

[0046] In a preferred embodiment, the anti-hypertensive is an ARB or an ACE inhibitor.

[0047] Angiotensin II Receptor blockers , include but are not limited to, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartanand combinations thereof.

[0048] ACE (Angiotensin Converting Enzyme) Inhibitors include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, and combinations thereof.

[0049] The composition may be in the form of a capsule, a pill, a syrup, a controlled release device, or an injectable solution, and the release of one or both of the NSAID and the anti-hypertensive may be controlled. The NSAID and the anti-hypertensive may be released substantially simultaneously, or one may be released before the other, in any order. The composition may be administered, for example, daily, twice a day, three times a day, four times a day, or every other day.

[0050] One or more pharmaceuteically acceptable carriers or excipients may be included in the composition. Any suitable pharmaceutical carrier can be used in accordance with the invention. Suitable pharmaceutical carriers include, without limitation, sterile water; saline, dextrose; dextrose in water or saline; hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, solvents , ethanol, isopropyl alcohol, methylene chloride or sugar, lactose, gelatin, starch, silicon dioxide, diethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid, propylene glycol, butyl phthalate, dibutyl sebacate, castor oil, diethyl phthalate, diethyl sebacate, lactose, dextrose, saccharose, cellulose, starch or calcium phosphate, olive oil or ethyl oleate silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; clays, gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose,

polyvinylpyrrolidone, alginic acid, sodium starch glycolate, polysorbates , laurylsulphates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations, lactose, dextrose, saccharose, cellulose, ethyl oleate, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, polysorbates and combinations thereof.

[0051] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention can include other suitable agents such as flavoring agents, preservatives and antioxidants. Such antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants known to those of skill in the art. In embodiments where the composition is in the form of a pill, the pill may be bilayered, enteric coated, or a combination thereof. The pill may be administered orally.

[0052] The composition may be administered in a fixed dose combination wherein the NSAID and an antihypertensive selected the ARBs or ACE inhibitors.

[0053] The composition may include any suitable NSAID and anti-hypertensive dosage. For example, the compostion may comprise 50 to 400 mg, 75 to 350 mg, 100 to 300 mg, 150 to 250 mg, 50 mg, 100 mg, 200 mg, or 400 mg of NSAID. The compostion may comprise 2.5 to 200 mg, 10 to 150 mg, 20 to l OO mg, 40 mg, 100 mg, 150 mg, or 200 mg of antihypertensive [0054] The composition may be administered to any suitable subject, including mammals. Suitable mammals include but are not limited to humans.

[0055] The PK parameter used is one or more of concentration, concentration time course, peak concentration, time after administration to peak concentration, terminal half-life, AUC, bioavailability, absorption, volume of distribution, metabolism, excretion,

biotransformation, clearance or a combination thereof.

[0056] Any suitable NSAID can be used in accordance with the invention, including without limitation, a COX- 1 -specific inhibitor, a COX-2-specific inhibitor, a mixed COX-1 and 2 inhibitor or a combination thereof. As such, the NSAID can be a salicylate, propionic acid derivative, acetic acid derivative, enolic acid (oxicam) derivative, anthranilic acid derivative (fenamatea ) or combinations thereof. Accordingly, the NSAID can be, aspirin (acetylsalicylic acid), ibuprofen, naproxen, indomethacin, sulindac, piroxicam, clonixin, preferably celecoxib or a combination thereof. In addition, the invention can be used with combinations of NSAIDs and other analgesic drugs such as lidocaine, opiates,

acetaminophen, tricylic antidepressants, anticonvulsants, carbamazepine, gabapentin, and pregabalin; other anti-inflammatory drugs such as steroids and immunosuppressants. Further, the invention can be used with combinations of NSAIDs and other therapies for arthritis, including but not limited to, methotrexate and gold-salts.

[0057] The composition comprising a NSAID and an anti-hypertensive can be administered in accordance with the invention via any suitable route including, without limiting, orally, rectally, by inhalation, trans-cutaneously, by injection, intra-venously or intra-arterially. The non-NSAID component of any combination therapy can be administered in accordance with the invention by any suitable route including, without limiting, orally, rectally, by inhalation, trans-cutaneously, by injection, intra-venously or intra-arterially. Any suitable regimen can be used in accordance with the invention to administer two or more drug components, including without limitation, simultaneously (within minutes of one another), substantially simultaneously (within an hour of one another) or at different times.

[0058] Other treatments for chronic diseases can be included such as treatments for diabetes, cardiovascular diseases, dementia, cholesterol, and hypertension. For example, fixed dose combination for pain relief without edema, may be practiced in conjunction with the administration of a prescribed cholesterol regulator, such as atorvastatin.

[0059] Any suitable PK parameter or parameters can be used in accordance with the invention, including without limiting concentration, concentration time course, peak concentration, and time after administration to peak concentration, terminal half-life, AUC, bioavailability, absorption, distribution, metabolism, excretion, biotransformation, or a combination thereof.

[0060] Any suitable pharmacodynamic parameter or parameters can be used in accordance with the invention, including without limiting the physiological changes of cells, tissues and ligaments of a patient, patient or physician reported pain level, the frequency of side effects, or a combination thereof.

[0061] Any suitable method for the assessment of pain known to those of ordinary skill in the art can be used in accordance with the invention, including, but not limited to, one- dimensional pain intensity scales, Wisconsin Brief Pain Questionnaire, Brief Pain Inventory, The McGill Pain Questionnaire and the short-form, McGill Pain Questionnaire (See Breivik et al.: Assessment of pain, British Journal of Anaesthesia 2008, 101 (1): 17-24).

[0062] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1

[0063] The approved prescribing information for Celebrex® as listed on its package insert for US/EU/ROW instructs that a physician should use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient. For four of the six approved indications the package insert includes a 100 mg BID regimen:

[0064] 1) Osteoarthritis (OA): 200 mg QD or 100 mg BID

[0065] 2) Rheumatoid Arthritis (RA): 100 mg BID or 200 mg BID

[0066] 3) Juvenile Rheumatoid Arthritis (JRA): 50 mg BID in patients 10-25 kg. 100 mg

BID in patients more than 25 kg

[0067] 4) Ankylosing Spondylitis (AS): 200 mg once daily single dose or 100 mg BID.

[0068] 5) Acute Pain (AP) and 5) Primary Dysmenorrhea (PD). 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg BID as needed

[0069] Unexpectedly, however, the inventor's analysis of the actual prescribing behavior using Evaluate Pharma/IMS database determined that the 200 mg is the predominant dose being prescribed by physicians by more than 10 to 1 . These data are consistent with data from a MEPS survey (Table 1) and Medicaid survey (Table 2). In view of predominance of the 200 mg dosage form sales and the evidence that the 100 mg and 200 mg doses produce overlapping PK and pharmacodynamic results, it is questionable that the package insert's admonition that "the lowest dose of Celebrex® should be sought for each patient" is followed. Instead, the data indicates that it is likely that there are numerous patients at risk for ADRs because their celecoxib dose is higher than it needs to be (i.e., e.g., 200 mg BID rather than 100 mg BID).

Table 1. MEPS Survey Data

Table 2. Prescribing information derived from Medicaid

EXAMPLE 2

[0070] The combined plots of published pharmacokinetic data including those from the Summary basis for approval are shown in FIG. 2. The variability of Celebrex®

pharmacokinetics were unexpectedly high. The PK results for the 200 mg dose shows a substantial overlap with that of the 100 mg dose. Accordingly, the dose proportionality may not be as is described by the package insert for Celebrex®. As a result of the failure to determine and pursue target PK ranges, in some instances patients receiving 100 mg patients may not get enough of the drug and the 200 mg patients may receive too much of the drug.

EXAMPLE 3

[0071] Applicant's meta analysis of the reported PK parameters in different populations demonstrates that the elderly show a higher variability than younger patients. For Example, when the applicant's meta analysis is presented in age-based subgroups, the elderly and younger patients demonstrate highly significant differences in drug exposure defined as AUC (FIG. 3). In other words, the most efficacious celecoxib dosage is not well defined for the elderly. The problem is more widespread than expected as elderly here is defined as patients greater than >40 or >50, not the usually definition of elderly (age greater >65). Previously, there has been reported impaired PK with elderly and the package insert issued warning on impaired PK in elderly but did not suggest dose reduction. Our finding suggests that the issue is more substantial and more widespread and includes middle aged groups also.

[0072] That the variability of PK results within groups and the C_max and AUC overlap between the 100 mg and 200 mg groups indicates that correctly dosing elderly patients to maximize celecoxib efficacy at the lowest doses possible depends on many individualized, unpredictable variables. Based on the wide range of AUC values, some patients receiving 100 mg may not get enough of the drug and the 200 mg patients may receive too much of the drug (FIG. 2).

EXAMPLE 4

[0073] Applicant's meta analysis of the reported edema rates in different osteoarthritic populations receiving doses of celecoxib ranging from 100 mg/day to 800 mg/day reveals that edema event rates are significantly higher in osteoarthritic populations receiving doses of celecoxib that are greater than 200 mg/day. For Example, both the upper limit of the edema event rate and the average edema event rate in osteoarthritic populations reiceiving a 400 mg/day dose of celecoxib can be more than twice as high as the upper limit edema event rate and the average edema event rate seen in osteoarthritic populations receiving a 100 or 200 mg/day dose of celecoxib (FIGS. 4-5). Additionally, Applicant's meta analysis of the reported edema rates in different osteoarthritic populations receiving doses of celecoxib ranging from 100 mg/day to 800 mg/day reveals that patients receiving a 100 or 200 mg/day dose of celecoxib experience remarkably similar edema event rates. This analysis indicates that a patient who is selected to receive a 200 mg/day dose of celecoxib based on, for example, their individual pharmacokinetic data using one or more of the methods described herein, will not be at a higher risk for an edema event than a patient receiving a 100 mg/day dose of celecoxib, and vice versa.

EXAMPLE 5

[0074] Applicant has also compared the edema in patient populations receiving celecoxib alone, celecoxib in combination with a variety of antihypertensives.To support this study a database was created which contains: 1) Claims data from Symphony pertaining to antihypertensives, Statins, COX-2 inhibitors, and NSAIDS. The data span the most recent 36 months and 2) registry data from the ACC reporting Blood Pressure (systolic/diastolic), peripheral edema flags (yes, no, missing), Heart rate, LDL, Glucose Level, Ejection fraction, GFR, Height, Weight, BMI, and the like.

[0075] Symphony dataset is True Patient Level data - All Data Sources be it RX or MX claims is tied back to individual patients which is tracked and then encrypted based on first name, last name, gender, DOB and zip code to give an accurate picture of patient level informatics year over year regardless of insurance changes. The source of Managed Markets Rx claims data comes from various providers, including Intelligent network services (Switch Data) as well as direct data feeds from pharmacies that do not use Switches so it does not create payer biases.

[0076] The definition of the Symphony database is as follow: 1 ) Takes Celebrex, Antihypertensive ("AH"), Statin or NSAID or have Osteoarthritis ("OA"), Rheumatoid arthritis ("RA") or some other form of Arthritis for 36 months, 2) Time Frame of Jan 1 , 2012 - Dec 31, 2014 (3 years), 3) Number of files: 201 , 4) File Size: 561 GB zipped (~ 2.5 TB), 5) Unique Patients: 162 million, 6) Patients on Celebrex: 4.3 million, 7) Patients that have OA 16.3 million (15.4 million only OA), 8) Patients that have RA :2.3 million (1 .4 million only RA).

[0077] The definition for the ACC registry is as follow: 1) Have 3+ BP readings, 2) Time Frame: Jan 1, 2012 - Dec 31 , 2014 (3 years), 3) Number of files : 2, 4) Size: 590 MB, 51 MB, 5) Unique Patients: 1.58 million, 6) Patients with BP readings: 1 .58 million, 7) Patients with Edema Flag True:870K.

[0078] The edema rate was then measured in the aforementioned database . The incidence of edema was higher for OA patients than RA, other Arthritis, or Arthritis free patients. The incidence of edema increased when patients was taken Celebrex for all groups except for RA and no Arthritis free patients. Overall OA seems to be susceptible to Celebrex induced edema. The results confirmed the meta analysis shown above.

[0079] Table 3. showing cases of Edema (%) among OA, RA,Other Arthritis, and No

Arthritis.

EXAMPLE 6

[0080] The same database used in Example 5 was used to determine whether a specific anti-hypertensive would more effectively block the development of edema by patients taking Celebrex. There was a steady increase in incidence of edema among patient taking Celebrex only (FIGs 6-10). This trend was exacerbated by the additional of other non-anti- hypertensive drugs (FIGs 6-10). The incidence of edema was lower for patients taking Celebrex and an anti-hypertensive drug (FIGs 6-10) . The order of effectiveness of the classes of anti-hypertendive drugs in preventing edema was ARB » ACE inhibitor = HCTZ (FIGs 6-10). The Beta blockers were ineffective (FIGs 6 & 9). The CCB (FIGs 6 & 1 1) and nonHCTZ thiazides (FIG. 1 1) aggravated the edema. [0081] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0082] The use of the terms "a" and "an" and "the" and "at least one" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" followed by a list of one or more items (for example, "at least one of A and B") is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0083] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS We claim the following:

1. A composition for treating pain without inducing edema comprising a NSAID and a anti-hypertensive , wherein the composition is administered in a fixed-dose combination.

2. The composition of claim 1 , wherein the NSAID is selected from the group consisting of aspirin, diclofenac, diflusnisal, etodolac, fenoprofen, flubiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, salicylate, sulindac, tolmetin, celecoxib, rofecoxib, etoricoxib, lumiracoxib, parecoxib , valdecoxib, chlorthalidone and combinations thereof and combinations thereof.

3. The composition of claim 2, wherein the NSAID is a COX-2 inhibitor.

4. The composition of claim 3, wherein the COX-2 inhibitor is celecoxib, etoricoxib, lumiracoxib, parecoxib, valdecoxib, chlorthalidone or a combination thereof.

5. The composition of claim 3, wherein the COX-2 inhibitor is celecoxib.

6. The composition of claim 1 , wherein the anti-hypertensive is azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan,or a combination thereof of ARBs.

7 The composition of claim of claim 6, wherein the anti-hypertensive is is, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril,or a combination thereof of ACEs.

8 The composition of any one of claims 1-7, wherein the pain is arthritic pain.

9. The composition of claim 8, wherein the arthritic pain is osteoarthritic pain.

10. The composition of any one of claims 1-7, wherein the composition is in the form of a capsule, a pill, a syrup, a controlled release device, or an injectable solution.

1 1. The composition of any one of claims 1-7, wherein the release of one or both of the NSAID and the anti-hypertensive is controlled.

12. The composition of claim 1 1, wherein the NSAID and the anti-hypertensive are released substantially simultaneously.

13. The composition of claim 1 1, wherein the NSAID is released prior to the antihypertensive.

14. The composition of claim 1 1, wherein the anti-hypertensive is released prior to the NSAID.

15. The composition of any one of claims 1-14, further comprising one or more pharmaceutically acceptable carriers.

16. The composition of claim 15, wherein the composition is in the form of pill.

17. The composition of claim 16, wherein the pill is a bilayered pill.

18. The composition of claim 16, wherein the pill is enteric coated.

19. The composition of any one of claims 1 - 18, wherein the fixed dose combination comprises NSAID and anti-hypertensive in a mg NSAID to mg anti-hypertensive ratio of from 20: 1 to 4: 1.

20. The composition of any one of claims 1-18, wherein the fixed dose combination comprises 50 to 400 mg of celecoxib.

21. The composition of any one of claims 1-18, wherein the fixed dose combination comprises 2.5 to 100 mg of an ARB or an ACE inhibitor.

22. A method for treating pain in a mammal comprising administering the composition of any one of claims 1-21 to a mammal.

23. The method of claim 22, wherein the arthritic pain is osteoarthritic pain.

24. The method of claim 21, wherein the composition is administered daily, two times a day, three times a day, or four times a day.

25. A method for individualized therapy of pain using a Cox-2 inhibitor, comprising: a. administering a first COX-2 inhibitor formulation comprising a first dose of a COX-2 inhibitor combined with a anti-hypertensive in specific amounts, to a first patient suffering from pain;

b. determining the COX-2 inhibitor and anti-hypertensive concentration in the first patient's blood at a plurality of time points after the first COX-2 inhibitor formulation was administered to the first patient;

c. transforming the first patient's COX-2 and anti-hypertensive

concentration/time data points in to one or more pharmacokinetic (PK) parameters; d. comparing the first patient's values for said PK parameters to a predetermined ranges of values for each PK parameter and if one or more of the first patient's PK parameters fall outside of a predetermined range, designing a new COX-2 inhibitor formulation, wherein the dose of said COX-2 inhibitor, the anti-hypertensive , or both is different from that of the first COX-2 inhibitor formulation;

e. administering the new COX-2 formulation to the first patient;

f. repeating steps b-e until all the PK parameters used in step d are within said predetermined ranges, and g. if pain control is adequate, toxicity is tolerable, and the patient is not experiencing tolerable edema, maintaining the first patient on the COX-2 inhibitor formulation at frequency of administration that satisfied the comparison in step d.

26. The method of claim 25, wherein the COX-2 inhibitor formulation is administered orally.

27. The method of claim 25, wherein said predetermined PK ranges are based the PK parameters of other patients suffering from pain who had been successfully treated with said COX-2 inhibitor formulation such that pain control is adequate, toxicity is acceptable and at most, only trace edema is present.

28. The method of claim 25, wherein the COX-2 inhibitor is celecoxib.

29. The method of claim 25, wherein the PK parameter used is one or more of concentration, concentration time course, peak concentration, time after administration to peak concentration, terminal half-life, AUC, bioavailability, absorption, volume of distribution, metabolism, excretion, biotransformation, clearnce or a combination thereof.

30. The method of claim 25, wherein the COX-2 inhibitor and the anti-hypertensive are administered in a fixed dose combination.

31. The method of claim 25, wherein the COX-2 inhibitor is celecoxib.

32. The method of claim 25, wherein the anti-hypertensive is ARB or ACE inhibitor.