Barry Jones
In vitro Sciences, Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent CT13 9NJ, U.K.
The reasons for inter-subject variability in dose response can reside within the pharmacokinetic (PK) or the pharmacodynamic phase (PD) of the classical PK/PD model. Thus concentrating solely on pharmacokinetics may not result in markedly reduced variation in response. However, some reasons for variability in the pharmacokinetic phase are additive and therefore should be targets for drug design. For instance, absorption problems can be overcome by correct physiochemical properties. Most drugs are cleared from the systemic circulation by cytochrome P450 enzyme system. Knowledge about which of the P450 enzymes is metabolising a drug can be used in the discovery phase for instance to minimise metabolism by enzymes such as CYP2D6 and CYP2C19 which are known to be highly variable (polymorphic). In the development phase it allows the design of a clinical programme to rationally and efficiently explore these findings further, for example the effect of selective concomitant medications. Variability in the pharmacokinetic phase can arise from polymorphisms in the drug target such as those in the P2-adrenoceptor. However, patient compliance probably represents one of the largest reasons for variability in drug effect. Hence design has to focus on medicines that have convenient twice or once a day dosage regimens, that are not complicated by food effects or concomitant administration with other drugs.
Reference: PAGE 8 (1999) Abstr 651 [www.page-meeting.org/?abstract=651]
Poster: oral presentation