Variability in drug response as a factor in drug design.
Variability in drug response can reside within the pharmacokinetic (PK) or the pharmacodynamic phase (PD) of the classical PK/PD model. Some reasons for variability in the pharmacokinetic phase are additive and therefore should be targets for drug design. For instance, poor absorption can be overcome by correct physicochemical properties. Excessive variability in clearance can be limited by avoiding metabolism by polymorphic cytochrome P450s, such as CYP2D6 and CYP2C19. However, clearance will always remain a large source of variability and has to be addressed by having sufficient selectivity for the target to avoid side-effects. There are also polymorphisms at the level of the drug target, such as in the beta(2)- adrenoceptor, which can add to the variability in the drugs response, making the desired selectivity sometimes difficult to attain. However, patient compliance is one of the most notable reasons for variability in drug response. This can be factored into drug design by targeting medicines that have convenient twice- or once-a-day dosage regimens, that are not complicated by food effects or by concomitant administration with other drugs.
Smith
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Department of Drug Metabolism, Pfizer Central Research, Kent, CT13 9NJ, UK. Dennis_Smith@sandwich.pfizer.com
Jones
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B