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in nonclinical pharmacokinetic studies, with far greater emphasis on toxicokinetic studies. Toxicokinetic-toxicodynamic data are critical for the preclinical to clinical transition; pharmacokinetic-pharmacodynamic data generally are not. |
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The main objective during initial Phase I clinical pharmacology studies is to determine the safety of a new drug candidate in a small number of healthy individuals or, in the case of most anticancer agents and some other therapeutic classes, in selected patients. Compounds are routinely given as single rising doses and as multiple doses, and subjects are closely monitored for clinical signs and blood chemistry and also circulating levels of unchanged drug and/or metabolites. Other studies, for example, pilot bioavailability and food-drug interactions are also frequently conducted during clinical Phase 1. |
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These studies are routinely carried out by means of close collaboration between pharmacokinetics and clinical pharmacology scientists. The studies are data rich from both pharmacokinetic, pharmacodynamic, and safety perspectives and analysis is often conducted on the fly, particularly in the single rising dose studies, so that compound blood or plasma levels and safety or activity data can be assessed before proceeding to the next highest dose. Depending on divisional organization, these responsibilities may be shared between two or more departments, for example, Pharmacokinetics, Clinical Pharmacology, and Biometrics, each depending on the other for data generation and integration, and probably represents the most intensive period of interdepartmental interaction and collaboration during the entire clinical development program. Overall, clinical Phase 1 may last between 6 months and 2 years, or longer. |
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If a drug candidate is shown to be safe during Phase 1, it then proceeds into initial phase 2 and then into later Phase 2 and Phase 3 full-scale development. During Phase 2, the drug candidate is tested in small patient populations to further monitor safety and also to examine efficacy. Most Phase 2 clinical studies contain an extensive pharmacokinetic component. Such studies are summarized in Table 2. |
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The pharmacokinetics of a drug candidate are characterized after single and repeated doses in patients and additional information is obtained on dose proportionality, food effects, and possibly other interactions. Absolute systemic availability may be determined at this stage. Metabolism studies are initiated, together with mass balance. Thus extensive pharmacokinetic and metabolism characterization of the compound is obtained as it moves through |
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