Prospective GYP2D6 genotyping as an exclusion criterion for enrollment of a phase III clinical trial

A phase III study was performed to compare the efficacy and safety of lamot rigine (Lamictal(R)), desipramine (Norpramin(R)), and placebo in the treatm ent of unipolar depression. Desipramine is extensively metabolized by cytoc hrome P450 206 (CYP2D6), and kinetics of this compound are altered in poor metabolizers. Genotyping was utilized to exclude poor metabolizers in order to increase subject safety and to eliminate the need to continuously monit or plasma desipramine levels. As part of screening, subjects were genotyped for the *3(A), *4(B), and *5(D) alleles, which identify approximately 95% of poor metabolizers, Extensive metabolizers were eligible for randomizatio n to the lamotrigine, desipramine, or placebo arm. Follow-up genotyping for the *6(T) and *7(E) alleles was performed after study enrollment and was u sed to identify poor metabolizers who may have been incorrectly identified as extensive metabolizers upon initial three-allele screening. Of 628 subje cts screened for *3(A), *4(B), *5(D) alleles, 590 (93.9%) were classified a s extensive metabolizers, The remaining 38 (6.1%) subjects were poor metabo lizers and excluded. Subsequent *6(T) and *7(E) testing revealed that two p oor metabolizers had been enrolled, and the follow-up genotyping provided a n explanation for the high desipramine plasma concentrations in one subject , No differences in phenotypic or allelic frequencies were found between th e study population and literature populations. However, the frequency of po or metabolizers varied among clinical sites (0-15%), For a compound that is extensively metabolized by CYP2D6, prescreening subjects for *3(A), *4(B), *5(D), *6(T) and *7(E) alleles can increase subject safety and eliminate t he need to continuously monitor drug plasma concentrations. Pharmacogenetic s 10:583-590 (C) 2000 Lippincott Williams & Wilkins.