Prospective CYP2D6 genotyping as an exclusion criterion for enrollment of a phase III clinical trial

Abstract

A phase III study was performed to compare the efficacy and safety of lamotrigine (Lamictal), desipramine (Norpramin), and placebo in the treatment of unipolar depression. Desipramine is extensively metabolized by cytochrome P450 2D6 (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 monitor 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 randomization 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 used to identify poor metabolizers who may have been incorrectly identified as extensive metabolizers upon initial three-allele screening. Of 628 subjects screened for *3(A), *4(B), *5(D) alleles, 590 (93.9%) were classified as extensive metabolizers. The remaining 38 (6.1%) subjects were poor metabolizers and excluded. Subsequent *6(T) and *7(E) testing revealed that two poor metabolizers had been enrolled, and the follow-up genotyping provided an explanation for the high desipramine plasma concentrations in one subject. No differences in phenotypic or allelic frequencies were found between the study population and literature populations. However, the frequency of poor 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 the need to continuously monitor drug plasma concentrations.

Optimized Strategy for Rapid Cytochrome P450 2D6 Genotyping by Real-Time Long PCR

“…This could help in choosing the right drug with the right starting dose. It may also be the rationale for a modified, possibly intensified, monitoring strategy (19,20 ).…”

“…Thus, genotyping of Cyp2D6 may become an important future tool in individually optimized drug therapy as well as in phase III clinical trials of new therapeutics metabolized by Cyp2D6 (19,21 ). To be of use in a time-critical pretherapeutic screening program, genotyping methods have to be robust, reliable, and rapid and must include all relevant mutations reported for a specific ethnic population.…”

Pharmacogenomics and Drug Development

“…The drug was subtherapeutic (<7), therapeutic (7)(8)(9)(10)(11)(12), or toxic (>12). Overall distribution of drug response in a population with different genotypes.…”

“…Although in its infancy, pharmacogenomic testing was incorporated in the design of a clinical trial. Genotyping of CYP2D6 alleles was performed to exclude individuals who would have difficulty metabolizing the drug from enrolling in a phase III clinical trial [12]. Although there are regulatory, financial and other barriers to overcome before pharmacogenomic testing is more widely used in clinical practice; the technical infrastructure to reproducibly analyze DNA, RNA or protein in clinical samples has been established.…”

Principles of pharmacogenetics—implications for the anaesthetist

“…Phase I trials can thus be designed for representative populations of the principal metabolic patterns. 51 Alternatively, the genotype can be used a posteriori, as a stratification factor. It should also be recalled that ethnic origin has an effect on allelic polymorphism, and that trials conducted on Caucasians may not necessarily be extrapolated to other ethnic groups.…”