Era of Drug Interactions and PKPD Relationships

In 1991, a Workshop was held to discuss current thinking related to the rational integration of pharmacokinetics, pharmacodynamics, and toxicokinetics [35]. This was an important milestone along the path of closer relationships between clinical data and pharmacokinetic data.

In CDER, a reorganization establishing the Office of Clinical Pharmacology and Biopharmaceutics in conjunction with increased resources related to User Fees, promoted communication among medical reviewers and clinical pharmacology reviewers. Co-location of these reviewers provided for increased discussions, data sharing, and consultations.

The importance of the relationship of changes in pharmacokinetics to drug safety and efficacy is a continuing topic of much discussion. One related area is drug interactions, which sometimes are extremely important.

The interaction of fluorouracil and sorivudine, which caused a number of deaths in Japan [36] in the 1990s, served as an important reminder of the potential consequences of drug-drug interactions. Sorivudine was withdrawn in Japan after 15 patients who were prescribed both sorivudine and fluorouracil died. They had developed aplastic anemia, after taking sorivudine with fluorouracil. Knowing the situation that had occurred in Japan, sorivudine was not approved in the United States because of this potentially fatal drug interaction and the fact that alternative drugs to sorivudine were available, without the serious drug interaction potential.

Serious interactions between mibefridil and certain cholesterol lowering "statin" drugs resulted in the removal of mibefridil from the market. Mibefradil is a potent inhibitor of the metabolism of lovastatin and simvastatin and if either of these drugs is taken together with mibefridil, they can cause potentially life-threatening rhabdomyolysis related to much higher exposure to the statin drug due to inhibited metabolism caused by mibefridil [37].

In response to the significance of drug interactions, Guidances for the study of potential drug interactions, both in vitro [38] and in vivo [39], are available from FDA. Study continues on establishing in vitro/in vivo correlations for metabolically related drug interactions, in order to increase the predictability of in vitro drug interaction data.

An important new law went into effect in 1997. The Food and Drug Administration Modernization Act (FDAMA) [40] contained many new provisions including a section describing the number of required clinical investigations needed for approval. "If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence " The confirmatory evidence described can be obtained from earlier clinical trials, pharmacokinetic data, or other appropriate scientific data. This indicates further reliance on pharmacokinetic data in conjunction with clinical studies in the overall development of a new drug.

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