Pharmacogenetic meta‐analysis suggests that atrasentan is an organic anion transport protein C substrate

Purpose To assess whether genetic polymorphisms of drug metabolizing enzymes or drug transporters correlate with atrasentan pharmacokinetics. Methods Pharmacogenetic meta-analyses of single dose pharmacokinetic parameters from 3 clinical studies (n=44) and steady-state pharmacokinetic parameters from 2 clinical studies (n=38) were performed. ANCOVA including genotype, study, age, weight, gender & ethnicity as factors was the primary analysis. Genotypes in CYP3A5, UGT1A1, UGT2B4, UGT2B15, ABCB1, SLC21A6 & SLC22A2 were each assessed. Results Following a single dose of atrasentan, exposure (AUC0–∞) and apparent volume of distribution were correlated with organic anion transport protein C (OATP-C) activity predicted by SLC21A6 genotype (p=0.0034 and p=0.03, respectively). Analogous relationships of SLC21A6 genotype to steady-state atrasentan exposure (AUC0-24, p=0.03) and maximum post-dose plasma concentration (p=0.0003) confirmed the single dose results. No other tested genotypes were consistently associated with atrasentan pharmacokinetics. Conclusions Pharmacogenetic analysis suggests a testable hypothesis that atrasentan is an OATP-C substrate. In the current study, genotype-predicted OATP-C activity is the most influential covariate for atrasentan pharmacokinetics. Our work shows how pharmacogenetics can be used to gain insight into the pharmacokinetics of a new molecular entity. Clinical Pharmacology & Therapeutics (2004) 75, P94–P94; doi: 10.1016/j.clpt.2003.11.357