Oliver, Lawrence K.

Abstract Background: Antiretroviral therapy for HIV-1 infection has become increasingly complex. The availability of new and potent drugs and progress in understanding the pathogenesis of HIV-1 infection have led to the establishment of new treatment paradigms. The varying dosing regimens, associated toxicities, and the potential for drug-drug and food-drug interactions further complicate treatment. This complexity contributes to patient nonadherence. Because clinicians have no tools to monitor adherence or drug-drug interactions and because response requires that therapy exceed the known inhibiting concentration, serum monitoring of antiretroviral therapy may play a role in improving treatment of HIV-1 infection. We report methods to quantify serum concentrations of antiretroviral drugs used to treat HIV-1 infection, precision and interference studies of these methods, and results observed in a pilot evaluation of blood serum concentrations from 12 human subjects. Methods: HPLC offers adequate sensitivity to measure peak or trough serum concentrations of delavirdine, lamivudine, nevirapine, indinavir, nelfinavir, ritonavir, and saquinavir and peak serum concentrations of stavudine, zidovudine, and didanosine with reasonable precision. Results: Peak indinavir serum concentrations in most patients were in the range of 1–10 mg/L, and trough concentrations were in the range of 0.1–0.5 mg/L. Peak stavudine concentrations were in the range of 0.3–1.3 mg/L, and trough concentrations were in the range of 0.1–0.5 mg/L. Peak zidovudine concentrations were in the range of 0.1–1.1 mg/L. Conclusions: Because this was a blood serum concentration-seeking pilot study to evaluate analytic performance, we do not report on the correlation of drug response to blood concentration. However, the concentrations observed in patients are generally consistent with blood concentrations reported from studies of monotherapy.

Abstract Well-founded pharmacokinetic information is one of the cornerstones of a New Drug Application (NDA) to the Food and Drug Administration (FDA) required to introduce a new drug or a generic equivalent (ANDA) to the marketplace. The service that laboratories engaged in therapeutic drug monitoring provide to support clinical activities is also needed by the pharmaceutical industry during the evaluation and introduction of drugs to the marketplace. In considering this alternative service activity, one must be aware of and compliant with rules established by the FDA for performance of such studies. As specified in CFR 21, Parts 58, 211, and 320, good clinical and laboratory practice indicates that the laboratory should employ a Lab Study Director, who is responsible for the validation of all procedures implemented to support a study protocol, ensures that the laboratory carries out the study following these defined procedures, and personally reviews the results of all testing. The laboratory must validate each procedure by demonstrating and documenting that the procedure does what it is designed to do while meeting the analytical performance specifications required by the study. Laboratory records of all activities must be maintained and available for inspection by the FDA on request. The FDA has authority over all activities related to NDA and ANDA submissions and can bring criminal charges if results of a study are changed because a laboratory deviates from standard procedure. Competent drug monitoring laboratories are fully capable of participating in clinical trials testing activities. Laboratory staff should be fully versed in the FDA rules governing these activities, validate all procedures, and establish systems to verify the procedures are carried out as specified.