P.Milligan, M.Karlsson, D.Nichols
Pfizer Central Research, Sandwich. U.K. and Division of Biopharmaceutics and Pharmacokinetics, Uppsala University. Sweden
During the drug development process compounds that exhibit large (unexplained) interindividual variability in plasma concentrations may fail to be advanced because of the resultant inability to predict efficacy and/or side effects. One of the causes of pharmacokinetic variability will be the existence of genetic deficiencies in the metabolic enzymes responsible for the elimination of the compound being developed. In order to identify and quantify the nature and extent of an individuals capacity to metabolise a compound with known polymorphism, Pfizer has generated information on the level of expression of the enzyme of interest (in this instance CYP2D6) in all individualÃs (both volunteer and patient) recruited to date in the clinical studies of a new development candidate. The approaches used included phenotyping with debrisoquine and dextromethorphan and genotyping using PCR based assays. Discussion will be made of the level of concurrence in the results obtained from these different approaches.
Following identification of genotype/phenotype status, quantification of the extent to which these categorical covariates can be used to account for variability in pharmacokinetics and/or pharmacodynamics is possible. The approach adopted at Pfizer is to perform both formal (mixed effects modeling) and informal (exploratory graphical analysis) population analyses in order to ascertain the magnitude to which genetic polymorphism may impact on the ability to develop safe and efficacious compounds.
The application of this approach will be illustrated with a compound currently under development at Pfizer which exhibits moderate degrees of both inter and intra subject variability, some of which may be apportioned to CYP2D6 polymorphism.
Reference: PAGE 5 () Abstr 565 [www.page-meeting.org/?abstract=565]
Poster: poster