JP2017207508A - Method and composition for curative medicine monitoring by point-of-care pharmacokinetic profile and dosage administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an improved method for adjusting an amount of dosage by using curative medicine monitoring.SOLUTION: A method for monitoring curative medicine for an individual treated by medicine is provided. A sample is collected by point-of-care or point-of-service. A pharmacokinetic profile is constructed by results of quantification of medicine in the sample. Further, a method for pharmacokinetic profiling that enables adjustment of an amount of dosage based on the pharmacokinetic profile and a kit are provided.SELECTED DRAWING: Figure 1

Description

(Cross-reference of related applications)
US Patent Provisional Application Nos. 61 / 491,268 (filed on May 30, 2011), 61 / 514,488 (filed on August 3, 2011), 61 / 526,950 (2011) No. 61 / 533,250 (filed Sep. 11, 2011), No. 61 / 577,008 (filed Jan. 3, 2012), No. 61 / 606,371 No. 61 / 615,312 (filed Mar. 25, 2012) and No. 61 / 635,730 (filed Apr. 19, 2012). Claims the benefit of priority over (incorporated herein by reference).

  When personalized medicine is applied to coordinate treatment of individual patients with therapeutic agents, pharmacokinetic (PK) components whose drug dosage is optimized for the patient, as well as treatment methods are adapted to the patient It has a pharmacodynamic (PD) component. Treatment methods require an understanding of the mechanism of action and the mechanism of resistance. The identification of PD biomarkers is the focus of considerable research effort, as evidenced by the tremendous development of prognostic, predictive and / or diagnostic biomarkers. However, PK components are often ignored. An incomplete understanding of PK here prevents the PD biomarker from reaching its full capacity.

  Therapeutic drug monitoring (TDM) has the potential to revolutionize therapies by improving drug delivery, as well as enabling the precise application of biomarker tests. It is widely believed that the identification of biomarkers that predict response allows targeted treatment only for responders and keeps those who do not respond to treatment. However, no matter how sensitive the disease is to a drug, an individual with the disease will not respond if the individual does not take enough drug. This is expected to allow TDM to complement and advance the latest efforts in biomarker discovery.

  However, individualized dose administration has typically been a successful method. With regard to patient dose administration, doctors only provide general guidance, and much of the dose adjustment is left to the patient's subjective observation. The physician desk reference book summarizes the experimentally determined rational drug dosage ranges found in the research literature. These ranges are broad and the same dose is specified for all patients. Scientific studies and publications seeking dose adjustment are not oriented to dose-matching individual patients. Rather, they provide a wide range of doses based on an average of the characteristics of the entire population at worst, or at best only the subpopulation of patients.

  Research has recognized the need to find new ways to account for interindividual differences in drug response. Studies over the last 20-30 years have identified a number of factors that affect the clinical effects of pharmaceuticals. Age, gender, ethnicity, weight, obesity, complications, diet and drug-drug interactions have all been found to affect both the pharmacokinetics and pharmacodynamics of the drug. Pediatric populations, women, ethnic minorities and older adults often require a different dosage regimen than their male white relatives.

  Because of the large number of potential interaction variables that affect individual responses to treatment, physicians faced with the task of minimizing side effects and maximizing drug performance are generally trial and error for a given individual. In order to improve the dosage prescribed for it. Subjective and objective methods are used to identify symptomatic symptoms and make necessary changes during the course of treatment. The general method of monitoring is clinical observation, which includes individual counseling and in-depth personal instruction by a physician observing the physiological signs and symptoms of the disease. This method is error prone, time consuming, expensive, very subjective, and excessively increases doctor-patient contact time. In addition, patients are at risk of unnecessary toxicity from exposure to high levels of drugs, or at suboptimal or ineffective levels of treatment with insufficient levels of drugs.

  Therefore, there is a need for improved methods of individual dose administration by using therapeutic drug monitoring.

  In certain embodiments, the present invention provides a method for therapeutic drug monitoring of an individual treated with a drug. The method includes constructing a pharmacokinetic profile of a drug for an individual using concentrations of the drug in at least two samples obtained from the individual at an appropriate time to construct the pharmacokinetic profile. Samples are suitable for storing at least two samples on point-of-care devices or point-of-use devices (each capable of quantifying drugs) or prior to quantification of drugs by the laboratory Collected at the point of care or at the point of use by sampling or self-sampling in the matrix. The pharmacokinetic profile includes pharmacokinetic parameters suitable for guidance of drug dosage administration for an individual.

  Samples are collected by point-of-care or point-of-service, for example by self-sampling. The sample can be applied to a lateral flow device due to the low amount of drug and the results are communicated to a physician or physician representative for pharmacokinetic analysis. In other embodiments, the sample may be point-of-care or point-of-care, such as by self-sampling, on a suitable storage matrix, such as filter paper, before delivering the sample to the laboratory for quantification and analysis. Collected by of service.

  In certain embodiments, samples collected at various times from an individual through point of care or point of use by self-sampling are obtained by a laboratory. The laboratory then tests the sample and quantifies the drug based on the results to build a pharmacokinetic profile. Pharmacokinetic profile results can be presented, optionally with recommendations to increase individual doses of the drug, to increase efficacy or reduce dose to reduce risk of toxicity .

  In another aspect, a kit for therapeutic drug monitoring of an individual treated with a drug using pharmacokinetic profiling is provided. Advantageously, the kit can be used for carrying out the method of claim 1. The kit is suitable for multiple point-of-care or point-of-use devices that can quantify drugs in at least two samples prior to laboratory quantification, or for storage of at least two samples Includes a matrix.

2 is a graph showing a PK profile from a bolus intravenous administration of a drug and a PK profile from an oral administration of a drug. FIG. 6 is a graph showing AUC as a function of dose for taxol administered over 3 or 24 hours. FIG. 6 is a graph showing AUC as a function of dose for two different formulations of paclitaxel. FIG. 6 is a graph showing AUC as a function of dose for two different formulations of paclitaxel. FIG. 6 is a graph showing AUC as a function of dose for two different formulations of paclitaxel. FIG. 5 is a graph showing average paclitaxel concentration as a function of time from 0 to 72 hours after infusion initiation for two different formulations of paclitaxel. FIG. 7 shows the variability of Abraxane pharmacokinetic parameters Vz (FIG. 7A), AUC _inf (FIG. 7B), C _max (FIG. 7C), CL (FIG. 7D) and T _1/2 (FIG. 7E) within the Abraxane-ingested population. It is a series of graph showing the test result which shows. FIG. 7 shows the variability of Abraxane pharmacokinetic parameters Vz (FIG. 7A), AUC _inf (FIG. 7B), C _max (FIG. 7C), CL (FIG. 7D) and T _1/2 (FIG. 7E) within the Abraxane-ingested population. It is a series of graph showing the test result which shows. FIG. 7 shows the variability of Abraxane pharmacokinetic parameters Vz (FIG. 7A), AUC _inf (FIG. 7B), C _max (FIG. 7C), CL (FIG. 7D) and T _1/2 (FIG. 7E) within the Abraxane-ingested population. It is a series of graph showing the test result which shows. FIG. 7 shows the variability of Abraxane pharmacokinetic parameters Vz (FIG. 7A), AUC _inf (FIG. 7B), C _max (FIG. 7C), CL (FIG. 7D) and T _1/2 (FIG. 7E) within the Abraxane-ingested population. It is a series of graph showing the test result which shows. FIG. 7 shows the variability of Abraxane pharmacokinetic parameters Vz (FIG. 7A), AUC _inf (FIG. 7B), C _max (FIG. 7C), CL (FIG. 7D) and T _1/2 (FIG. 7E) within the Abraxane-ingested population. It is a series of graph showing the test result which shows. FIG. 8 presents test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 8A), AUC (FIG. 8B), CL (FIG. 8C) and T _1/2 (FIG. 8D) within the 150 IU FSH ingested population. It is a series of graphs. FIG. 8 presents test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 8A), AUC (FIG. 8B), CL (FIG. 8C) and T _1/2 (FIG. 8D) within the 150 IU FSH ingested population. It is a series of graphs. FIG. 8 presents test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 8A), AUC (FIG. 8B), CL (FIG. 8C) and T _1/2 (FIG. 8D) within the 150 IU FSH ingested population. It is a series of graphs. FIG. 8 presents test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 8A), AUC (FIG. 8B), CL (FIG. 8C) and T _1/2 (FIG. 8D) within the 150 IU FSH ingested population. It is a series of graphs. FIG. 9 presents the test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 9A), AUC (FIG. 9B), CL (FIG. 9C) and T _1/2 (FIG. 9D) within the 300 IU FSH ingested population. It is a series of graphs. FIG. 9 presents the test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 9A), AUC (FIG. 9B), CL (FIG. 9C) and T _1/2 (FIG. 9D) within the 300 IU FSH ingested population. It is a series of graphs. FIG. 9 presents the test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 9A), AUC (FIG. 9B), CL (FIG. 9C) and T _1/2 (FIG. 9D) within the 300 IU FSH ingested population. It is a series of graphs. FIG. 9 presents the test results showing the variability of FSH pharmacokinetic parameters C _max (FIG. 9A), AUC (FIG. 9B), CL (FIG. 9C) and T _1/2 (FIG. 9D) within the 300 IU FSH ingested population. It is a series of graphs. A profile of a single exponential PK curve is shown (assuming bolus administration). Figure 2 shows a PK profile characterized by two exponential functions. Prototype paclitaxel lateral flow test is shown. Figure 3 shows quantitative lateral flow results for hCG using a confocal photometric scanner. FSH quantitative lateral flow using an image analysis program connected to the camera. Signal stability for nanogold quantitative FSH lateral flow. Quantitative point-of-care lateral flow assay for LH-luteinizing hormone. Urine LH assay (range = 5-1,700 IU / L); Serum / plasma LH assay (range = 1-1,700 IU / L); Blood LH assay (range = 5-1,700 IU / L). Quantitative point-of-care assay for FSH-follicle stimulating hormone. Urine FSH assay (range = 6-1,500 IU / L); Serum / plasma FSH assay (range = 5-10,000 IU / L); Blood FSH assay (range = 5-10,000 IU / L). Quantitative point-of-care assay for hCG-human chorionic gonadotropin. Urine hCG assay (range = 5-10,000 IU / L); serum hCG assay (range = 1-10,000 IU / L); blood hCG assay (range = 20-10,000 IU / L). Summary of estimated paclitaxel blood pharmacokinetic variables for Abraxane and Taxol (pharmacokinetic population).

  The present invention relates to a method by which a pharmacokinetic profile of a drug can be constructed for an individual taking the drug using samples obtained at various times after dose administration. Data for use in building pharmacokinetic profiles is obtained from samples collected at the point of care or point of use. Beneficially, the sample is obtained by self-sampling. In certain embodiments, the sample is delivered to a point-of-care device to quantify the drug, and the results thus obtained are reported to the physician or his representative. Alternatively, the sample is collected using a matrix or container suitable for sample collection and storage until receipt and analysis by the laboratory. Examples of matrices suitable for sample collection and storage include commercial biological sampling filter paper systems such as Whatman 3 MM, GF / CM30, GF / QA30, S & S 903, GB002, GB003 or GB004. However, it is not limited to these. Several classes of blotting material for blood specimen collection are available, such as S & S 903 cellulose (wood or cotton derived) filter paper and Whatman glass fiber filter paper. The blood spot is placed on one or more indicated areas of the filter paper, allowed to dry, and then mailed to the laboratory along with the test request. This collection method has the advantage of insolubilizing the need to collect samples in a doctor's office or clinic. Thus, a large number of samples can be conveniently collected by the patient over a period of 0 to 72 hours, saving considerable costs and time. This increases the efficiency and reduces delay in communicating the results of the analysis to the treating physician who can use the top to adjust the treatment as needed and communicate with the patient to communicate the new treatment regimen. Have advantages.

Prior to the present invention, the potential value of pharmacokinetic-inducing dose administration has never been developed, but it can partly collect samples required for individual pharmacokinetic profiles. Sample collection was typically inconvenient and cost prohibitive in that it required hospital stay extension up to 72 hours. For typical drug PK studies, pharmacokinetic studies have been limited to phase I studies where PK / PD for a small number of patients forms the basis for drug use across the population. To compensate, population PK tests are usually performed during phase III of drug development; however, due to the same limitations, these tests are performed under poor sampling techniques. Due to the inaccuracy associated with poor sampling, only an approximation of the population PK can be obtained. For a complete pharmacokinetic study, at least 12 data points collected over a 48-72 hour period are required to properly characterize the PK parameters for each particular patient. This cannot be done for all patients enrolled in Phase III (and, for that matter, even for Phase II). Taking a blood sample to assess drug levels immediately after drug administration for C _max is typically not a problem. However, it is difficult to collect a blood sample at a later time point and specify “clearance” and “steady state concentration” because the inflection point is 4-24 hours after treatment. It is often inconvenient or cumbersome for a patient to return to the hospital for more blood work, and holding the patient overnight is expensive both in terms of expense and care.

  A phase III multicenter randomized trial in which 5-FU dose administration was optimized by LC / MS at steady state (N = 208) demonstrates the benefits of pharmacokinetically induced dose administration in terms of both efficacy and toxicity ( Gamelin, E, Delva, R, Jacob, J, et al: \ "Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage:. Results of a multicenter randomized trial of patients with metastatic colorectal cancer \" J Clin Oncol 13: 2099-2105, 2008). Half of the patients were dosed with 5-FU based on body surface area. The other half was dosed initially based on BSA (body surface area), and then the cycle dose was adjusted based on a blood test that measured the actual concentration of chemotherapy in the patient's plasma. The first endpoint was tumor response; the second endpoint was treatment tolerability. The study concluded that: 1) The response rate was almost double in the dose-adjusted group compared to the BSA group (33.6% vs 18.3%); 2) Year 2 Overall survival was improved by 48% in the individualized 5FU dose-controlled patients, with an improved median survival of 22 months versus 16 months of BSA arm treatment. Survival data was skewing in a significant direction; 3) Grade 11 / IV 5-FU related toxicity was found to be significantly lower in individualized dose-adjusted patients; 4) 48% of patients were administered sub-dose (Sub-therapeutic and low effective drug levels) were found and the dose was adjusted upwards; and 5) 17% was found to be overdose (increased risk of severe side effects) The dose was adjusted downward. However, most intravenous drugs are not dosed to achieve steady state with a 24 hour infusion extension. Instead, it is dosed as a single short-term infusion (30 minutes to 3 hours) but does not sustain long-term steady state drug concentrations in the blood.

  Drug PK is characterized by the uptake of the drug into the various compartments of the body (generally across blood, tissue and then into the target organ). It is also characterized by clearance from the body due to the body's active metabolism, or by clearance by the liver and / or kidneys. The blood concentration versus time curve describes how the drug is handled by the individual. The generally accepted parameter describing drug exposure is the area under the curve (AUC) or the effective drug concentration over time or toxic drug concentration over time. It is generally acceptable that there is a single universal PK profile for each drug. However, it is not consistent with the fact that the inspection of the PK literature reveals a wide variation in the PK profile for any particular drug. This is probably due to individual variability in uptake and clearance. In fact, two completely different profiles can have similar AUC values. Therefore, in order to fully develop TDM-induced dose administration, dose optimization is performed and dose adjustments due to changes in the frequency or duration of dose administration are estimated using conventional PK programs such as Phoenix (WinNonlin) To obtain, for each patient a fully personalized PK profile must be created. The use of any one of the single PK parameters for dose adjustment neglects the large number of PK data available and is not valid. Thus, a sufficiently individualized PK profile is useful for inducing dose adjustment, allowing more precise dose adjustment than a single PK parameter such as AUC.

  In one embodiment, a solution to this problem is the development of a lateral flow test that can be performed with blood from a single finger stab. Ideally, the test involves the application of a single stab on the lateral flow device, which is then read and sent to the attending physician via WiFi / Internet. In certain embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 during a period of 0-24 hours, 0-36 hours, 0-48 or 0-72 hours. Significant PK data can be obtained by the patient testing for a specific point in time.

  There is a need for improved assays that can be used to more easily detect small molecule analytes and to detect low concentrations of analytes. Furthermore, improved measurements of analytes, including small molecules, are needed to tailor drug regimens to retain drug efficacy while reducing undesirable side effects in individual patients. In addition, methods and apparatus that can be used in point-of-care to measure biological and / or clinically relevant analytes to reduce salt between sample acquisition and assay result acquisition. is necessary.

  The agent to be monitored according to the invention described herein is any specific substance or component for which detection and / or measurement in chemical, physical, enzymatic or optical analysis is desired. Such analytes include, but are not limited to, therapeutic agents and / or pharmacological agents (eg, theophylline, anti-HIV agents, lithium, antidepressants, cyclosporine, chemotherapeutic agents). In preferred embodiments, the analyte is the physiological analyte or a chemical having a physiological effect, such as a drug or pharmacological agent. The terms drug and pharmacological agent are used interchangeably and may include any molecule having a therapeutic effect, such as small molecules and biologics.

  In certain embodiments, agents to be monitored include, but are not limited to, chemotherapeutic agents, ovulation inducers, antiviral agents, and antimicrobial agents.

  In certain preferred embodiments, the methods of the invention are used to monitor patients who would benefit from dose adjustment due to PK variability of the particular therapeutic agent they are taking.

  Chemotherapeutic agents that can be monitored using the methods of the present invention include, but are not limited to, paclitaxel, docetaxel, gemcitabine and 5-fluorouracil. The method can be used to monitor various formulations of paclitaxel, such as Abraxane, Taxol or Genexol or Nanoxel, or Geotag, or Tocosol or other formulations. Examples of these include albumin-bound paclitaxel, polymeric micelle paclitaxel, polymeric nanoparticle formulation of paclitaxel, vitamin E-based paclitaxel emulsion, polyglutamate paclitaxel, and a formulation currently under development or to be further developed Products such as, but not limited to, lipid dispersion paclitaxel, targeted paclitaxel nanoparticles (albumin-based and PEG-based) and porous paclitaxel nanoparticles.

  Examples of ovulation inducers that can be monitored include FSH, LH, hCG, GnRH agonist / antagonist, estradiol, and the like.

  Antiviral / microbial agents that can be monitored include protease inhibitors, reverse transcriptase inhibitors such as 2 ', 3'-dideoxythymidine (AZT), antifungal agents such as itraconazole (also used for anti-Leishmania chemotherapy) ) Or antimony agents (most commonly used anti-Leishmania drugs).

  Additionally, patients taking a class of therapeutics benefit from dose adjustment due to PK variability. Examples of these classes of therapeutic agents include oral drugs, intravenous drugs and intramuscular / intravaginal / orbital drugs.

The PK profile for oral drugs is generally characterized by slow absorption followed by regular reductions in blood levels. T _max and C _max are important parameters that describe the PK profile and bioavailability and steady state levels. These include antiviral drugs that are often administered orally, as well as targeted therapies for cancer, anti-high cholesterol plasma drugs, anti-hypertensive drugs, and the like.

For intravenous drugs, including small molecules and biologics, C _max is important as a limiting toxicity as well as an AUC. These include most chemotherapeutic drugs and antibody drug conjugates (ADC) used in cancer therapy. The PK profiles for this class are characterized by a rapid increase in C _max that reaches steady state during infusion, followed by a rapid decline after cessation of infusion, followed by a slow decline.

For agents administered by the intramuscular / intravaginal / orbital route, such as biologics and small molecules, steady state concentrations, absorption, terminal T _1/2 are important parameters. This class of drugs includes hormones used in pregnancy treatment and other biologics such as etanercept, rituximab, rosuvastatin, trastuzumab, insulin, factor VIII, tPA, up, antibody-drug conjugates, and the like. These agents exhibit a PK profile that is an intermediate between oral and intravenous drugs. Therapeutic agents include, for example, immunosuppressants such as cyclosporine, tacrolimus (FK-506), rapamycin and mycophenolate mofetil. Immunosuppressive drugs have a narrow therapeutic index and a high degree of inter- and intra-patient variability in bioavailability. In order to balance the level of immunosuppression required to prevent graft rejection while avoiding the adverse effects of hyperimmunosuppression, such as toxicity, infection and increased risk of speaking cancer, immunosuppressive drugs are used in patient samples. Requires careful and frequent monitoring. These include antiviral drugs such as anti-HIV. Examples include antiretroviral drugs such as proteinases or reverse transcriptase inhibitors such as 2 ′, 3′-dideoxyinosine (ddI), 2 ′, 3′-dideoxycytidine (ddC) or 3′-azido-2 ′. 3,3'-dideoxythymidine (AZT).

  Therapeutic drug monitoring is expected to be most effective for drugs with highly variable PKs such as paclitaxel. Paclitaxel has more than 10-fold variability in patient exposure (Evans, WE & Relling, M. V. Clinical pharmacokinetics-pharmacodynamics of anti-cancer drugs, Clin. Pharm. , G. et al. Pharmacokinetic studies in cancer chemotherapy: useful in clinical practice. Cancer Trea. Rev. 23, 153-169 (1997); pharmacokinetics (PK), such as organ function, metabolic enzyme expression and activity, drug resistance, physique, pharmacokinetics (PK), for example, chemotherapeutics: effect on outcomes. Gender, complications, and co-administration of other drugs may affect these factors, which may have clinical significance in chemotherapeutic dose determination Paclitaxel is eliminated in the feces by the liver (Sparreboom A , Script CD, Trieu V, Williams PJ, De T, Yang A, Bears B, Fig WD, Hawkins M, Desii N. Comparative preclinical. .. Cokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol) Clin Cancer Res 11, 4136-43 (2005); Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 7, 78-86 (1996)); therefore, liver dysfunction affects drug clearance from circulation and Known permeable glycoprotein (Pgp) state even resistance protein 1 (MDR1) affects reabsorption in drug clearance and intestine. Liver clearance is further influenced by CYP factors (Wall T. Assays of CYP2C8-and CYP3A4-mediated metabolism of taxo in vivo and in vitro. Methods Enzymol, 272- 195, 272). In addition, there are other factors that are specific to the use of body surface area (BSA) as a dose normalizing agent (Baker, SD et al. Role of body surface area in dosing of anticancer agents in 1991). -2001. J. Natl. Cancer Inst. 94, 1883-1888 (2002)). BSA itself is affected by weight; paclitaxel AUC increases with increasing weight due to the increased total dose in heavier patients. As a result, white races tend to have a higher AUC than Asian races. The effects of age (since most patients are elderly) have not been adequately analyzed.

  For paclitaxel, there is a large inter-individual variability in pharmacokinetics; for AUCinf, the average CV is in the range of 20-50% (Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, Beals B, Figg WD, Hawkins M, Desai N. Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res. 11, 136-43 (2005); Nyman DW, Campbell KJ, Hersh E, Long K, Richardson K, Trieu V, Desai N, Hawkins MJ, Von Hoff DD and Phase I. paclitaxel in patents with advanced nonhematological malaignies. J Clin Oncol. 23, 7785-93 (2005); Yamada K, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N, Yamamoto N. . Harmacokinetic study of ABI-007, albumin-bound paclitaxel, administered every 3 weeks in Japanese patients with solid tumors Jpn J ClinOncol 40:. 404-11 (2010); Gardner ER, Dahut WL, Scripture CD, Jones J, Aragon- Ching JB, Desai N, Hawkins MJ, Sparreboom A, Fig WD. Randomized crossover pharmacokinetic slaving-based paclitaxel paclitaxel. cer Res. 14: 4200-5 (2008); Stinchcombet TE, Socinski MA, Walko CM, O \ 'Neil BH, Collichio FA, Ivanova A, Mu H, H C, and Hawkins MJ, G. I and pharmacokinetic tribal of carbplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on the third treatment quotient in the tit. The cause of this great variability is not fully understood and therefore cannot be controlled. Liver dysfunction and obesity have been identified as contributing factors; however, other unknown factors remain unrestricted. Examining paclitaxel PK, patients who receive an approved dose are likely to be underdosed or overdosed (Mielke S. Individualized pharmacotherapy with paclitaxel. Curr Opin Oncol. 19, 586-9 2007)).

The highly variable paclitaxel PK dose has a significant impact on its therapeutic application. In two trials where a 100 mg / m ² paclitaxel dose was compared to a 125 mg / m ² paclitaxel dose, the high dose group was better than the low dose group (Blum JL, Savin MA, Edelman G, Pipepen JE, Robert) .. NJ, Geister BV, Kirby RL, Clawson A, O \ 'Shaughnessy JA Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes Clin Breast Cancer 7: 850-6 (2007); Von Hoff DD, Ramanathan RK, Borad MJ, Lahe ru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in Patents With Advanced Pancreas Cancer: A Phase 1 / ll Trial. J ClinOncol. 29: 4548-54 (2011)). Given the high variability of paclitaxel PK, it is very likely that identifying under-dosed patients as well as moving them to higher doses will result in a greater than 25% increase in drug exposure. In view of the above, paclitaxel TDM appears to be beneficial.

  The methods of the invention have applicability in monitoring diseases characterized by a relatively high frequency of resistance to treatments such as cancer and HIV. Treatment of these symptoms is enhanced by frequent monitoring of drug levels along with resistance testing. Accordingly, methods have been developed to monitor phenotypic changes in circulating populations of HIV virions in patients (eg, WO 97/27480). Other phenotypic tests include those described by Witflow (WO 01/57245), Virological (W097 / 27319) and Bioalliance (WO 02/38792). Antivirogram. RTM. (WO 97/27480) approximates the drug susceptibility of a viral population when compared to a “wild type” strain. In this test procedure, the drug concentration that inhibits virus growth by 50% (IC50) is determined in vitro. The IC50 ratio of virus in the blood sample of a patient above the IC50 of “wild type” virus is a fold change in the drug susceptibility of the virus in that patient.

  The minimum plasma concentration or trough concentration may be important during the treatment of diseases or conditions in which the drug target is subject to modulation to overcome drug action. Examples of this latter phenomenon are found in diseases such as viral infections such as HIV, bacterial infections and cancer. For example, the presence of a drug creates a mutational pressure on the HIV protease, escaping from drug therapy, and insufficient inhibitor concentrations facilitate such deviations. The determination of the drug level in the patient, as well as the use of this value to determine the trough level, can be important in obtaining a dosage that is high enough to produce a therapeutically effective concentration.

One aspect of the method of the invention is the determination of the pharmacological parameters of the drug in the individual, such as trough level (Ct), maximum concentration (C _max ), area under the curve (AUC), exclusion rate, and the like. These parameters can be entered into a population pharmacokinetic model and pharmacokinetic variables such as Ct, C _max and AUC can be calculated (WO 02/23186). These pharmacological variables can be used, for example, to approximate a dose of potential toxicity, exposure time to a drug (eg, in the case of radiochemistry), or minimum concentration.

  In order to obtain an effective treatment, an individual's exposure to a drug, for example as determined by trough levels or AUC, must exceed a certain level. This level is determined by the nature of the viral population. The rate of drug exposure (trough levels, AUC, etc.) above drug resistance (magnification resistance, IC50, IC90, etc.) is predictive of treatment success. This ratio can be expressed as IQ (suppression quotient) (IQ = Ct / IC50). This IQ value is further normalized (normalized IQ, NIQ) to obtain a value that is adjusted for protein binding. One approach to obtain this adjusted value is to determine the mean Ct for the population, as well as the IC50 for the active ingredient for the reference strain, ie the reference laboratory HIV strain. The quotient of these latter two values yields a (Ct / IC50) reference. The normalized IQ is provided by the quotient: [(Ct / IC50)] patient / [(Ct / IC50)] reference.

  According to the present invention, a “biological sample” encompasses any sample obtained from an organism, ie a human or animal, and optionally contains an active ingredient. Biological samples include, but are not limited to, blood, serum, plasma, saliva, cerebrospinal fluid, ejaculate, ductal lavage fluid and hair. In certain preferred embodiments, the sample is blood. Biological samples further include samples obtained from culture flasks, wells and other types of containers. A biological sample may contain one or more active ingredients.

  Active ingredients include any compound, such as chemicals, drugs, antibodies, ligands, antisense compounds, aptamers, ribozymes, peptides, non-natural peptides, proteins, PNA (peptide nucleic acids) and nucleic acids, or at least one compound A composition. Active ingredients further include the compounds as administered and their metabolites. Metabolites can be produced under physiological conditions. When used in the present invention, the level of active ingredient means the amount or concentration of the active ingredient in the sample. The active ingredient present in the biological sample can be different from the active ingredient in the reference. Under these circumstances, the inhibitory potential of the biological sample is equal to the amount or concentration of the active ingredient obtained from the reference standard curve. The amount can be expressed, for example, as g, ml, mol. The concentration can be expressed as, for example, ml / ml, g / l, M, etc.

A pharmacokinetic profile constructed using at least two data points is used to generate PK parameters that can be used to induce dose adjustment. Parameters include the following: AUCinf, T _max , C _max , time above threshold, T _1/2 , V _d , CL, Vss, Vz, T _max , lambda, index, tau and the like. These include parameters from non-compartment PK analysis and compartmental PK analysis (physiological based or not). These PK parameters are derivatives of the actual PK profile and may require one or more to allow proper dose adjustment. The determination of which parameters or how many should be determined practically during the clinical development of the drug. Based on the PK profile for the individual, the dose can be adjusted to reduce toxicity and / or enhance the efficacy of the administered drug. For example, neutropenia associated with paclitaxel treatment is associated with a time greater than 50 nM of paclitaxel. Thus, this parameter can be used to induce dose adjustment to reduce the risk of an individual developing neutropenia. Similarly, drug exposure measurements such as AUC can be used to guide dose adjustments to enhance efficacy. The complexity of PK parameters and PK profiles is established after clinical trials comparing responses to PK profiles and their parameters. Multivariate analysis, logistic regression, neural nets, and other suitable statistical analyzes can be used to obtain appropriate limited adjustment parameters to facilitate dose adjustment.

  Dose adjustments can be made within the expected median value for a particular drug. For example, the dosage can be adjusted to achieve a level that is within 5%, 10%, 15% or 20% of the desired target value. If the effective dose of the drug is known and also variable with respect to the patient, dose adjustment is performed as a therapeutic index to maintain sufficiently high therapeutic efficacy without approaching toxicity. In some cases this is not possible.

  Use of pharmacokinetic profiles to induce dose administration increases doses for under-dosage patients, reduces doses for over-dosage patients, reduces unpredictability of dose administration and increases efficacy And reduce toxicity. Underdose and overdose patients are limited by the PK profile and its associated parameters.

  Non-limiting examples of suitable devices or methods for testing drugs include a side for determination of the concentration of the analyte in the sample, including providing a lateral flow strip for use in measuring the analyte. A flow apparatus is mentioned. Examples of analytes that can be tested include therapeutic agents, drug metabolites, and hormones. Application of the sample to the lateral flow strip combines the fraction of the analyte in the sample with the components of the lateral flow strip such that a detectable signal is generated that is proportional to the concentration of the analyte in the sample.

Alternatively, any suitable assay, such as those widely known in the art, such as ELISA, liquid chromatography-mass spectrometry (LC-MS), thin layer chromatography (TLC), high performance liquid chromatography Quantitation can be performed on samples submitted to the laboratory by individuals by (HPLC) and mass spectrometry (MS) (but not limited to) or other traditions for drug monitoring in the central laboratory The manual test is well illustrated. The sample can be whole blood collected as a dry blood spot collected after a finger prick on a suitable matrix and shipped or otherwise delivered to the laboratory for testing. Sampling can be performed using capillaries and / or devices designed to deliver an accurate and small amount of blood to a dry blood spot card.
Example:

Example 1. The theoretical PK profile is shown in FIG. As shown in FIG. 1, the PK profile has two main components—the uptake portion of the curve immediately after administration and the decay / clearance portion of the curve after maximum blood concentration (C _max ). This topic changed from immediate C _max by bolus administration to delayed C _max by oral administration. Among these are intravenous injection, intranasal, intrabuccal, intramuscular, intraperitoneal, and the like. The three main attributes of the PK profile are as follows: C _max (maximum blood concentration), mean residence time (MRT) and AUC (area under the curve). AUC is commonly used to indicate blood exposure. However, two curves with similar AUC as shown in FIG. 1 can have very different profiles. Intravenous bolus dose administration shows a high initial blood concentration as defined by C = dose / blood volume. Oral dose administration exhibits a long residence time of the drug due to delayed absorption. Pharmaceutical development usually relies on experiments to limit the method of best delivering a drug for maximum activity and minimum toxicity. Surprisingly, therapeutic drug monitoring (TDM) only relies on single PK parameters or single blood concentration determinations. Suggests that the entire PK data (PK profiling) should be used for therapeutic drug monitoring because factors that affect drug absorption or drug clearance are unpredictable personal attributes It is the present invention that does this. Direct determination of the personal PK profile should be one tool for individualizing dose administration.

  Example 2 To demonstrate that simply changing drug intake changes the PK profile, published pharmacokinetic data for taxol was used to determine the dose of taxol dosed at a 3 hour infusion rate and a slower 24 hour infusion rate. was examined PK profile (Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y, Saijo N. (1995) Clinical pharmacokinetics and pharmacodynamics of paclitaxel:. a 3-hour infusion versus a 24-hour infusion Clin Cancer Res. 1: 599-606 .; Wiernik PH, Schwartz EL, E inzig A, Straumman JJ, Lipton RB, Dutcher JP. (1987) Phase I triar of Taxol give as a 24-hour infusion every 21 days: respons. , Sasaki Y, Eguchi K, Shinkai T, Ohe Y Nishio M, Kunikane H, Arioka H, Karato A, Omatsuu H, et al. (1994) Phase I and kine ph. . Usion Jpn J Cancer Res.85: 1057-62 .; Tamura T, Sasaki Y Nishiwaki Y Saijo N. (1995) Phase I study of paclitaxel by three-hour infusion: hypotension just after infusion is one of the major dose-limiting toxins. Jpn J Cancer Res. 86: 1203-9). Paclitaxel administered at the same dose and only with different infusion times produced completely different AUCs (FIG. 2). The 3 hour infusion resulted in higher AUC or drug exposure than the 24 hour infusion. Variation in ingestion efficiency—which acts on the curve as well as shortening the infusion time—shows a powerful effect on drug exposure as limited by PK profiling. This reinforces the concept that the PK profile is highly variable and depends on parameters that are known to vary between patients. These include absorption efficiency, rate of distribution from blood and into tissues, and protein binding characteristics. Single factors such as AUC cannot limit drug exposure.

  Example 3 FIG. To demonstrate that an increase in tissue distribution rate, and thus a decrease in blood drug accumulation rate, changes the PK profile, the Abraxane vs. Taxol PK profile was examined. As shown in FIG. 3, paclitaxel formulated as Abraxane (ABI-007) showed a lower AUC than paclitaxel formulated as taxol (Cremophor EL). No increase in AUC with faster uptake / infusion (Abraxane: 30 min infusion vs. Taxol: 3 hr infusion) was observed. Abraxane® (albumin-bound paclitaxel, Abraxis BioScience)-FDA approved in 2005 for metastatic breast cancer. It is known that Abraxane formulations resulted in faster tissue penetration-a property known to vary from individual to individual depending on the level of paclitaxel binding protein and the like. This further illustrated that PK profiling (overall use of PK data) is more suitable for therapeutic drug monitoring. With other cremophor free formulations such as genexol (FIG. 4) and nanoxel (FIG. 5) we found the same. Genexol-PM® (methoxy-PEG-poly (D, L-lactide) taxol; Samyang, Korea) was approved in Korea for stage II metastatic breast cancer and in the US for pancreatic cancer.

Example 4 Comparison of the Abraxane (ABI-007) and Taxol PK profiles clearly demonstrates the need for PK profiling to predict response and adjust dose. As noted above, the Abraxane PK profile is different from the Taxol PK profile, and AUC is higher for Taxol at the same dose. FIG. 6 shows the average paclitaxel concentration versus time (0-72 hours after the start of Abraxane or Taxol infusion). When Abraxane was dosed at 260 mg / m ² and Taxol was dosed at 175 mg / m ² , they showed nearly identical PK parameters (Table 1). The PK profiles for Abraxane and Taxol were very similar at this dose level (Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, Bears B, Fig WD, Hawk WD, Hawk. . 2005) Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol) Clin Cancer Res 11:. 4136-43); and further, ABI-007 is Standard Pakuri Showed significantly higher response rates compared to taxel (33% vs 19%, respectively; P = 0.001) and time to tumor progression was significantly longer (23.0 vs 16.9 weeks respectively; Hazard ratio = 0.75; P = 0.006) (Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O \ 'Shaughness J. (2005) Pharse pallet p -bound paclitaxel prepared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 23: 7794-803). This reinforces that the PK profile (or the entire PK data) needs to be used to assess drug dose efficacy.

  Table 1 (Figure 19) is a summary of estimated paclitaxel blood pharmacokinetic variables (pharmacokinetic population) for Abraxane and Taxol.

Example 5 FIG. To determine whether Abraxane PK has sufficient variability to benefit from therapeutic monitoring, PK analysis was performed using all published literature on Abraxane PK (FIG. 7) (Yamada K , Yamamoto N, Yamada Y, Mukohara T, Minami H, Tamura T. (2010) Phase I and pharmacokinetic study of ABI-007, albumin-bound paclitaxel, administered every 3 weeks in Japanese patients with solid tumors. Jpn J Clin Oncol. 40: 404-1; Gardner ER, Dahut WL, Scripture CD, Jones J, Arago .. N-Ching JB, Desai N, Hawkins MJ, Sparreboom A, Figg WD (2008) Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel Clin Cancer Res 14:. 4200-5; Nyman DW, Campbell KJ, Hersh E, Long K, Richardson K, Trieu V, Desai N, Hawkins MJ, Von Hoff a lin f ol p . With advanced nonhematologic malignancies J Clin Oncol 23:. 7785-93). The ranges for all variables were 209%, 142%, 458%, 200%, 69% of the average for Vz, AUC, _Cmax , CL and T1 _{/ 2} , respectively. In contrast, we calculated that 5-FU AUC showed a range of 3.9 to 16.41 and an average of 9.05, or 138% variability (Ychou M, Duffour J, Pinguet). F, Kramar A, Joulia JM, Topart D, Bressolle F. (1999) Individual 5-FU dose adaptation schedule using bimonthly pharmacokinetically-modulated LV5-FU2 regimen:. a feasibility study in patients with advanced colorectal cancer Anticancer Res 19:. 2229 -35). Because 5-FU has been proven to benefit from therapeutic drug monitoring dose adjustment (Gamelin, E, Delva, R, Jacob, J, et al: \ "Individual fluorouric dose adjustment on pharmacocolitic liquid- with conventional data: Results of a multi-centered random of patents with the use of the metallic collective collector. \ "J Clin Oncol. 13: 2008-P data. We did not)) our analysis Emissions dose administration, especially with PK profile for dosage adjustments benefit from therapeutic drug monitoring, strongly suggest that. Genexol-PM and nanoxel are expected to have the same PK variation. The wide variability of Abraxane was rather surprising. The role of therapeutic drug monitoring is to reduce this variability. The PK profiles for Abraxane and Taxol are similar, but there are differences. However, these differences are small and can be masked by large variations in the Abraxane / Taxol PK.

  Example 6 PK analysis was performed using published literature on FSH PK to determine the pharmaceuticals used for reproductive assistance, FSH (follicle stimulating hormone). Plots of FSH PK crossing several trials are shown below (Figures 8 and 9) (Duijkers IJ, Klipping C, Boerrigter PJ, Machielsen CS, De Biej JJ, Voortman G. (2002), Single Sing s ed single on foliar growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in Health pituitary-H. TB, Boschaert MA, Coelingh Bennnink HJ. (1996) A bioequivalence study of two-dimensional primary preparation. The variability was used as SD / mean to compare it with 5-FU data. AUC variability was calculated at 26.08% and 20.57% for IM foregon and metrogin, respectively; 17.72%, 18.42% and 17.69% for sc normegon, foregon and metrogin, respectively. Surprisingly, this variation is close to 34.42% of 5-FU variability (Ychou M, Duffour J, Pinguette F, Kramar A, Joulia JM, Topart D, Bressole F. (1999) Individual 5-Fu. adaptation schedule using bimodally-pharmacologically-modulated LV5-FU2 regimen: a feasibility study in patents with ARC. The analysis suggested that therapeutic drug monitoring for FSH could be as beneficial as therapeutic drug monitoring for 5-FU.

Example 7 Determine the minimum data points required for PK profiling.
For a single accessible pool model, after a bolus injection of quantity D into the pool, the general form shown by the following equation: C (t) = C0 ^{−t / τ1} +... + C0 ^{−t / τn} Pharmacokinetic data can be described by the sum of exponential equations.

  Thereby, once the index is limited, the PK variable can be quantified. It must be performed with clinical data from sufficient pharmacokinetic studies so that the index (τ) can be limited. Modeling to limit the index can be performed using any pharmacokinetic program that can perform compartmental modeling. They include programs such as WinNonlin, EquivTest, Kinetica, Phoenix / WinNonlin and PK Solutions. Once limited, the index can be used to generate a full PK profile using n + 1 seborrhea. As shown below (FIG. 10), for a single index, this is preferably early in the first quarter of the descent and late in the last quarter of the descent. , Which means two data points collected to handle the PK curve together. Usually a PK profile does not have at least two indices. Each additional index requires two additional data points. Data points must be placed in the first quarter of cure and the last quarter of descent and terminate at the intersection of the two components. This is necessary if the index can only be accurately modeled using two data points along its dominant segment. Since the second data point with index 1 overlaps with the first data point with index 2, only three data points are required (or n + 1). This is illustrated in FIG. For other modes of administration with IV infusion and absorption phase, bioavailability and absorption rate must be included in the equation in addition to these indices. They are also adjusted by the index and can be treated similarly.

  Typical profile of a single exponential PK curve (assuming bolus administration). Two data points are sufficient to establish a PK profile for a single index PK. Positioning the starting concentration at 100%, a slow decay PK with 100 tau is shown as the upper first curve with a gradual tau with respect to the subsequent curve. Exponential visualization allows proper placement of data points. The placement of the first and second data points is 75-100 and 0-25 blood drug concentrations.

  FIG. 11 shows a PK profile characterized by two indices. The early part (distribution period) of the curve is dominated by the index 1, and the latter part (clearance period) of the curve is dominated by the index 2. Exponential visualization allows proper placement of data points. The first / second data point placement for index 1 is 0-1 hours and 2-4 hours; the first / second data point placement for index 2 is 2-4 hours and 29-39 hours. is there.

  Example 8 FIG. Detection of paclitaxel in a prototype lateral flow assay for PK profiling. To enable PK profiling, we have developed a point-of-care assay for various analytes, one of which is paclitaxel. Paclitaxel is most commonly detected by LC / MS / MS with a detection level of 1-5 ng / ml. An ELISA using mAb against paclitaxel has also been developed with comparable detection levels. Although these ELISA assays are simpler than the LC / MS / MS method, they are still impractical for practical application, blood draw, blood separation into serum, and in clinical laboratories by skilled personnel Requires testing in microtiter plate format. Our newest innovation is the development of lateral flow samples that can be read with a reader that can accept finger scratched blood and can be deployed point-of-care (at home, in the examination room, or in a central laboratory). It is in. The ease of sampling and testing is compatible with multiple sampling during the course of treatment, so detailed pharmacokinetic data can be obtained.

  Cellulose absorbent pad (cellulose fiber sample pad 17 mm × 100 m CFSP001700 (Millipore, Bedford, Mass.)) And glass conjugate fiber (glass fiber conjugate pad 8 mm × 100 m GFCP000800 (Millipore, Bedford, Mass.)) Test strips were constructed by annealing on a Flow Plus 240 membrane card 60 m × 301 mm HF240MC100 (Millipore, Bedford, Mass.). The laminated card was cut with a guillotine cutter to obtain a 4 mm strip. An on-site guillotine cutter is Index Cutter II (A-Point Technologies Inc., Gibbstown, NJ, USA).

  An initial test of paclitaxel-BSA at a ratio of 20: 1, as well as 1 mg / ml mAb colloid conjugation with the pI of each mAb was performed to establish positive binding. The experiment shown in FIG. 12 shows that the paclitaxel-BSA / anti-paclitaxel mAb-colloidal gold conjugate pair produced sufficient signal. The signal was very strong, however, for the BSA-paclitaxel / anti-paclitaxel mAb-colloidal gold pair, the BSA-paclitaxel flowed throughout the membrane when the mAb was interspersed on the membrane (left panel, FIG. 12). As shown (right panel, FIG. 12), when anti-paclitaxel mAb was immobilized on a nitrocellulose membrane and the paclitaxel-gold conjugate flowed across the membrane, a very strong signal was detected. Paclitaxel was mixed with serum and the mixture was directly labeled with nanogold particles. A detection limit of 20 ng / ml of paclitaxel was possible.

  Example 9 Quantitative lateral flow assay using Qiagen lateral flow reader. This example shows how a lateral flow cassette can be converted to a quantitative point-of-care device using a suitable reader such as that manufactured by Qiagen.

  The calibration curve is embedded in a 2D barcode stamp cassette and the entire quantification process is uploaded onto the reader as practical, without the need for expert technical support at the point of care / point of use. Build a quantitative point-of-care side flow assay for hCG using a conventional hCG side flow cassette that is quantified using a Qiagen side flow reader modified so that quantitation occurs in the background did.

  FIG. 13 shows quantitative lateral flow TDM results for hCG. hCG is a hormone commonly used to induce ovulation in assisted reproduction. Sera spiked with increasing levels of hCG (top-bottom = 0-1694 ml U / mL) were tested with a quantitative lateral flow device for hCG (FIG. 13A). The device was scanned with a reader. The scan is shown in FIG. 13B. The ratio of peak areas for T and C was plotted against concentration to establish a calibration curve (FIG. 13C). Using a calibration device, unknown hCG levels were quantified to obtain excellent agreement between predictions and experiments (FIG. 13D). All of these data served as a two-dimensional barcode, which was read and acquired with one of the readers to establish parameters for the analysis of unknown samples.

  FIG. Quantitative lateral flow test using the ImagePro program connected to capture images with an Olympus SXX16 microscope equipped with an Evolution MP camera. This example demonstrates the use of any image analysis program such as ImagePro and any camera system such as a cell phone camera. As long as the image is of sufficient quality for comparison of test line versus control line intensity, it can be used for low volumes that can occur in the field or remotely. Develop side cassettes for FSH with increasing concentrations of FSH, analyze captured images with ImagePro, plot intensity vs. concentration using test intensity ratio over control, and provide good quantitative hardness showed that. The assay in its latest format suffered adhesion effects and resulted in signal reduction at excessive levels of FSH. Adhesion is very important and means to avoid it are under development.

  Example 11 The stability of the signal allows point-of-use / point-of-care or central to allow shipment to return the device to a centralized laboratory after point-of-care development Stabilization of the lateral flow device signal for later date quantification in the centralized laboratory.

  Upon completion of flow (ie, 15-20 minutes), quantification was performed and monitored for up to 72 hours to ensure signal stability. Signal stability is necessary to ship the cassette back to the central test laboratory. As will be shown below, all of the tested quantitative substances we have developed to date have shown stability of at least 72 hours. In most cases, stability was weeks and months. Appropriate cassette geometry, buffer conditions, sample volume size were used to ensure stability. Once the signal was stabilized, it turned out to be stable for at least several months.

  FIG. 15 illustrates the stability of the signal for the FSH quantitative nanogold side.

  Example 12 Construction of quantitative point-of-care assays for hCG, LH and FSH. IVF has a delivery rate per starting cycle of approximately 22% and has approximately 250,000 people (26% of pregnancies are twins and 2.5% are triplets). The IVF protocol (target: generation of 8-15 egg cells) is complex, time consuming and expensive, resulting in considerable discomfort to the patient and complications, particularly for ovarian hyperstimulation syndrome (OHSS). Increase opportunities. The most frequently used drug regimen for ovarian hyperstimulation promotes the development of multiple follicles, steroid contraceptive pretreatment to regulate the menstrual cycle, GnRH agonist analogs to suppress LH release in the prestimulation cycle Consisting of daily gonadotropin injections for approximately two weeks, as well as administration of a bolus dose of hCG to induce ovulation of mature egg cells. In many countries, the cost of pharmaceuticals and monitoring is heavier than the cost of the IVF procedure itself. Therefore, the shift of power points from mild stimulation to mild ovarian response is ongoing, and by developing more personalized treatment regimens based on initial patient characteristics such as age, weight and ovarian reserve characteristics Reduce both churn and excess response rate. Developed gonadotropin point-of-care therapeutics monitoring widely used in IVF-FSH, LH, and hCG to facilitate personalized treatment regimens that reduce over-medicine costs and risk of OHSS .

  Lateral flow assays were constructed using mAb pairs for LH, FSH and hCG. A reflected light measuring optical reader utilizing a confocal optical instrument with a low distance to target ratio was used. Serum, urine from prepubertal women, and blood from female donors were used as matrices to spike standards and thus create samples for these experiments. The product used was 40 uL / set. For the hCG blood assay, the volume was reduced to 30 ul / cassette. The following standards were used: LH reference standard from Genway, San Diego, CA (lot number A11072104), FSH reference standard from Genway, San Diego, CA (lot number 11-663-45941) and AbdSerotec, Raleigh, NC HCG reference standard from (lot number 120811). Data was plotted and analyzed using GraphPad Prism (San Diego, Calif.).

  The described embodiments are to be considered in all respects only as illustrative and not restrictive, and the invention is not limited to the foregoing description. Those skilled in the art will recognize that changes, substitutions, adaptations, and other modifications can be made without departing from the scope of the invention.

Claims (50)

A method for therapeutic drug monitoring of an individual treated with a drug using pharmacokinetic profiling comprising the following:
Constructing a pharmacokinetic profile of a drug for an individual using concentrations of the drug in the at least two samples obtained from the individual at an appropriate time to construct a pharmacokinetic profile, the at least two samples being points • In a matrix suitable for storing at least two samples at the care-of-care device or at the point-of-use device (each capable of quantifying the drug) or prior to quantification of the drug by the laboratory Collected at point-of-care or point-of-use by sampling or self-sampling, and the pharmacokinetic profile includes pharmacokinetic parameters suitable for guidance of drug dose administration for individuals how to.   The method of claim 1, wherein the at least two samples comprise 2 to 12 samples.   The method according to claim 1 or 2, wherein at least two samples are collected over a period of up to 8 hours, up to 24 hours, up to 48 hours or up to 72 hours. The pharmacokinetic parameters are AUC, AUC _inf , T _max , C _max , time above threshold, steady state concentration, absorption rate, clearance rate, distribution rate, terminal T _1/2 , or non-compartmental PK or compartmental PK analysis, 4. The method according to any of claims 1 to 3, comprising at least one parameter selected from the group consisting of, for example, a physiological model based compartment PK analysis.   5. A method according to any of claims 1 to 4, further comprising generating a report comprising a pharmacokinetic profile of the individual.   6. The method of claim 5, wherein the report includes recommendations regarding dosing based on the pharmacokinetic profile of the individual.   7. A method according to any of claims 1 to 6, wherein the reduction of drug dosage is directed to reduce the risk of toxicity based on one or more pharmacokinetic parameters.   One of the index, Vss, Vz, defining the drug concentration above which toxicity occurs or the AUC, AUCinf, MRT, PK profile is indicated based on the time the drug dose reduction exceeds a threshold 8. The method of claim 7, wherein the method is a combination of one or more or a group of PK variables to adequately describe the PK profile.   7. A method according to any of claims 1-6, wherein drug dose adjustment is indicated to increase efficacy based on one or more pharmacokinetic parameters.   The drug dose increase is an AUC, AUCinf, MRT, one or more of the indices defining the PK profile, Vss, Vz, or a group of PK variables to adequately describe the PK profile. 9. The method according to 9.   11. A method according to any of claims 7 to 10, wherein the dose is adjusted within 5 to 25% of the desired target value.   12. A method according to any preceding claim, wherein each of the at least two samples is applied to a point-of-care device or a point-of-use device to determine the concentration of a drug. Wherein application of one or more of the at least two samples to the lateral flow strip combines a fraction of the drug in the sample with one component of the lateral flow strip to provide the drug in the applied sample A method wherein the point-of-care or point-of-use device comprises a lateral flow strip having a structure and composition such that a detectable signal proportional to the concentration of the product is generated.   12. A method according to any one of the preceding claims, wherein at least two samples are applied to a matrix suitable for storage of at least two samples prior to laboratory quantification.   14. The method of claim 13, wherein at least two samples are stored as dry blood spots.   The method according to claim 13 or 14, wherein the drug concentration is measured by ELISA or LCMS.   The method according to any one of claims 1 to 15, wherein the agent is selected from a chemotherapeutic agent, an ovulation inducing agent and an antiviral agent.   The method of claim 16, wherein the agent is a chemotherapeutic agent.   The method of claim 17, wherein the agent is a taxane.   18. The method of claim 17, wherein the drug is a paclitaxel formulation.   20. The method of claim 19, wherein the paclitaxel formulation is selected from the group consisting of albumin-bound paclitaxel, polymeric micelle paclitaxel, paclitaxel polymeric nanoparticle formulation, vitamin E-based paclitaxel emulsion, polyglutamate paclitaxel.   The method according to claim 16, wherein the drug is an ovulation inducer.   The method according to claim 21, wherein the ovulation inducing agent is selected from the group consisting of FSH, LH and hCG.   The method of claim 16, wherein the agent is an antiviral agent.   24. The method of claim 23, wherein the agent is an anti-HIV drug.   The method according to claim 23 or 24, wherein the drug is an antiretroviral drug.   26. The method of claims 1-25, wherein the medicament is formulated for administration, and examples of claimed routes of administration include oral administration, intravenous administration, intramuscular administration, vaginal administration, buccal administration. Methods such as, but not limited to, intraorbital administration, intranasal administration, and transdermal administration. 27. The method of claim 26, wherein the agent is formulated for oral administration and the pharmacokinetic parameter comprises at least one of _Cmax and steady state level.   The drugs are from chemotherapeutic drugs, antihypercholesterolemic drugs, antihypertensive drugs, antimicrobial drugs, antifungal drugs, anti-nematode drugs, immunosuppressive drugs, antipsychotic drugs, sleeping pills, anesthetics, morphine-based analgesics 28. The method of claim 27, which is selected. 27. The method of claim 26, wherein the agent is a small molecule formulated for intravenous administration and the pharmacokinetic parameter comprises at least one of _Cmax and AUC. 27. The biological agent is formulated for intravenous administration or intramuscular injection, and the pharmacokinetic parameters comprise at least one of steady state concentration, absorption and terminal T1 _{/ 2.} The method described.   31. The method of claim 30, wherein the biological product is a hormone, antibody-drug conjugate or antibody or antibody derivative, biologically active protein or peptide.   13. The method of claim 12, wherein the agent in the sample competes with a detectably labeled molecule in a lateral flow strip for binding to an antibody or ligand.   13. The method of claim 12, wherein the agent competes with a molecule that is immobilized in a limited area of the lateral flow strip for binding to a detectably labeled antibody or ligand.   34. A method according to any of claims 12, 32 or 33, further comprising detecting a detectable signal in the lateral flow strip and correlating the signal with an analyte concentration in the sample.   34. A method according to any of claims 12, 13, 32 or 33, wherein the sample is whole blood.   34. A method according to any of claims 12, 32 or 33, wherein the lateral flow strip comprises two or more separate antibodies having different affinities for drugs.   37. A method according to any of claims 12, 32, 33 or 36, wherein the agent is a therapeutic agent selected from the group consisting of small molecules and biological agents.   38. The method of claim 37, wherein the analyte is a small molecule.   39. The method of claim 38, wherein the small molecule is a chemotherapeutic agent or an antiviral agent.   40. The method of claim 39, wherein the small molecule is a chemotherapeutic agent.   41. The method of claim 40, wherein the chemotherapeutic agent is paclitaxel.   40. The method of claim 39, wherein the small molecule is an antiviral agent.   43. The method of claim 42, wherein the small molecule is an antiretroviral drug.   38. The method of claim 36, wherein the biologic is a hormone or antibody.   45. The method of claim 44, wherein the hormone is selected from the group consisting of FSH, LH, hCG, prolactin, TSH and insulin.   46. The method of claim 45, wherein the hormone is a biologic comprising gonadotropin.   45. The method of claim 44, wherein the biologic further comprises a cytotoxic moiety.   38. The method of claim 37, wherein the biologic is an antibody conjugated to a therapeutic moiety. A kit for therapeutic drug monitoring of an individual treated with a drug using pharmacokinetic profiling for use in the method of claim 1, comprising:
Includes multiple point-of-care or point-of-use devices that can quantify drugs in at least two samples prior to laboratory quantification, or a matrix suitable for storing at least two samples Kit to do.   50. The kit of claim 49, further comprising instructions for collecting at least two samples.

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