Methods and compositions for therapeutic drug monitoring

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In certain embodiments, the present invention provides a method for therapeutic drug monitoring of an individual treated with a drug. The method involves constructing a pharmacokinetic profile of the drug for the individual using concentrations of drug in at least two samples obtained from the individual at time points suitable to construct a pharmacokinetic profile. The samples are collected at point-of-care or point of use by sampling or self-sampling on point-of-care devices or point of use devices, each capable of quantitating the drug, or on matrices suitable for storage of the at least two samples prior to quantitation of the drug by a laboratory. The pharmacokinetic profile includes pharmacokinetic parameters suitable for guiding dosing of the drug for the individual.

The samples are collected by at point-of-care or point of service, e.g., by self- sampling. Samples may be applied to a lateral flow device for quantitation of the drug, and the results transmitted to the physician or physician's agent for pharmacokinetic analysis. In other embodiments, the samples are collected at point- of-care or point of service, e.g., by self-sampling, on a suitable storage matrix, e.g., filter paper, prior to delivery of the samples to a laboratory for quantitation and analysis.

In certain embodiments, samples collected at various times from the individual through point-of-care or point-of-use by self-sampling are obtained by a laboratory. The laboratory then tests the samples to quantitate the drug of interest and, based on the results, constructs a pharmacokinetic profile. The results of the pharmacokinetic profile may be presented, optionally along with recommendations to increase the individual's dosage of the drug in order to enhance efficacy or to reduce the dosage in order to reduce risk of toxicity.

In another aspect it provides a kit for therapeutic drug monitoring of an individual treated with a drug using pharmacokinetic profiling. Advantageously, the kit may be used to perform the method of claim 1. The kit comprises a plurality of point-of-care device or a point of use device capable of quantitating the drug in the at least two samples, or matrices suitable for storage of the samples prior to quantitation by a laboratory.

The present invention relates to methods by which pharmacokinetic profiles of drugs may be constructed for individuals receiving a drug using samples obtained at various time points following dosing. Data for use in the construction of the pharmacokinetic profiles is obtained from samples collected at point-of-care or point of use. Advantageously, the samples may be obtained by self-sampling. In certain embodiments, the samples may be delivered to a point-of-care device to quantitate the drug, and the results thus obtained are reported to the physician or his agent. Alternatively, the samples are collected using a matrix or vessel suitable for collection and storage of the samples until receipt and analysis by a laboratory. Examples of matrices suitable for collection and storage of the samples include, but are not limited to commercially available biological sampling filter paper systems such as Whatman 3 MM, GF/CM30, GF/QA30, S&S 903, GB002, GB003, or GB004. Several categories of blotting materials for blood specimen collection are available, e.g., S&S 903 cellulose (wood or cotton derived) filter paper and Whatman glass fiber filter paper. The blood spot is placed in one or more designated areas of the filter paper, allowed to dry, and then mailed along with a test request form to the laboratory. This method of collection has the advantage of obviating the need for collection of samples at a doctor's office or clinic. Thus, multiple samples may be conveniently collected by the patient over a period of from 0 to 72 hours at considerable savings of cost and time. This has the advantages of increased efficiency and reduced delays in transmitting results of the analysis to the treating physician, who may use the information to adjust treatment as necessary, and contact the patient to convey the new treatment regimen.

Prior to the instant invention, the potential value of pharmacokinetic-guided dosing had not been exploited in part because collecting the samples needed for individual pharmacokinetic profiles was inconvenient and prohibitively expensive, in that collection of samples typically requires extended hospital stays of up to 72 hours. For a typical drug PK study, pharmacokinetic studies have been limited to phase I studies in which PK/PD on a few patients forms the basis for the use of the drug throughout the population. To compensate, a population PK study is usually performed during phase III of the drug development; however, due to the same limitations, these studies are performed under the sparse sampling procedure. Due to the imprecision associated with sparse sampling, only an approximation of population PK can be obtained. For full pharmacokinetic testing, at least 12 data points collected over a period of 48-72 hours are needed to adequately characterize the PK parameters for each particular patient. It is not possible to perform this for every patient enrolled in a phase III (or even for a phase II trial for that matter). Obtaining blood samples to assess drug levels immediately after drug administration for Cmax are not typically problematic. However, obtaining blood samples at subsequent time points to define "Clearance" and "Concentration at Steady State" are difficult as the inflection points are 4-24 hours after treatment. It is often inconvenient or burdensome for patients to return to the hospital for more blood work, and keeping the patient overnight would be expensive both in terms of cost and services.

A phase 3, multicenter, randomized study (N=208) in which 5-FU dosing was optimized at steady state levels by LC/MS demonstrates the benefits of pharmacokinetic-guided dosing for 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 (BSA). The other half were initially dosed based on BSA, with subsequent cycle doses adjusted based on blood tests that measured the actual concentration of chemotherapy in the patients' blood plasma. The primary endpoint was tumor response; the secondary endpoint was treatment tolerance. The study concluded that: 1 ) Response rates were nearly doubled in the dose-adjusted group versus the BSA group (33.6 percent versus 18.3 percent) with statistical significance; 2) Overall survival at two years among patients with personalized 5-FU dose management improved by 48 percent with an improved median survival of 22 months versus 16 months in the BSA arm. The survival data was leaning towards significance; 3) Grade lll/IV 5-FU related toxicities were found to be significantly lower in patients with personalized dose adjustment; 4) Fifty eight percent of patients were found to be under-dosed (sub-therapeutic and less effective drug levels) and had their doses adjusted upwards; and 5) Seventeen percent were found to be over-dosed (increasing the risk of severe side effects) and had their doses adjusted downward. However, most intravenously administered drugs are not dosed to achieve steady state with prolonged infusion of 24 hours Instead, they are dosed as single short infusions (30 min- 3 hours) not allowing for long sustained steady state drug concentrations in the blood.