Patients carrying CYP2C8*3 have shorter systemic paclitaxel exposure

Aim:First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05M [T-c >0.05]). Second, screen additional pharmacogenes for associations with T-c >0.05.Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with T-c >0.05 (n=58). Results: Patients with predicted low-activity CYP2C8 had shorter T-c >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, =5.47, p=0.02). This association was attributed to CYP2C8*3 (p=0.006), not CYP2C8*4 (p=0.58). Patients with predicted low-activity SLCO1B1 had longer T-c >0.05 (12.12 vs 10.15hrs, =0.85, p=0.012). Conclusion: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability.