Effect of coadministration of statins on neutropenia in a phase I genotype-directed dose-escalation study of irinotecan.

Abstract

3020 Background: Irinotecan is a prodrug for SN-38, a topoisomerase I inhibitor. Homozygozity for UGT1A1*28 increases the risk for severe neutropenia, the most common dose-limiting toxicity (DLT). However, its occurrence remains fairly unpredictable. We are conducting a phase I dose-escalation study in advanced solid tumor patients where dosing is given according to the UGT1A1*28 genotype (Innocenti, ASCO 2007). In the context of this study, we aimed to evaluate whether the occurrence of neutropenia might be due to hitherto undiscovered drug-drug interactions. Methods: Patients (n=33, 26 males) were treated with 700-850 mg (flat dosing) of q3w irinotecan. DLT at cycle 1 was defined as grade (G)4 neutropenia lasting ≥4 days, G≥3 neutropenia on a scheduled treatment day, G≥3 febrile neutropenia, G4 anemia or thrombocytopenia, or G≥3 nonhematological toxicity. Patient charts were reviewed to obtain concurrent medications. Pharmacokinetic analysis of irinotecan and SN-38 was performed at cycle 1. Results: Seven patients had neutropenic DLTs. Irinotecan and SN-38 were associated with decreased log10 ANC nadir (r2=0.39, p<0.001 and r2=0.14, p=0.02, respectively). Review of concomitant medications indicated that patients treated with statins (atorvastatin, lovastatin, rosuvastatin, and simvastatin) tended to have more DLTs, lower ANC nadirs, and higher irinotecan and SN-38 AUCs (Table). The statin effects on ANC nadir (p=0.001), irinotecan AUC (p<0.0001) and SN-38 AUC (p=0.005) remained significant after adjusting for dose in multiple regression. Conclusions: The neutropenic effect of irinotecan may be increased by concomitant administration of statins, possibly through their inhibitory effects on liver uptake by SLCO1B1 and on irinotecan inactivation by CYP3A. If confirmed in larger studies, the irinotecan label should be revised to withhold statins during irinotecan dosing. Statins (n=7) No statins (n=26) P, test UGT1A1*28 heterozygote 3/7 (43%) 16/26 (62%) 0.8, chi-square DLT 4/7 (57%) 5/26 (24%) 0.045, chi-square Log10 ANC nadir (log10 1/μ L) 1.85 3.04 0.0003, t test Irinotecan AUC0-24h (h*μ g/ml) 52.7 33.0 <0.0001, t test SN-38 AUC0-24h (h*ng/ml) 820 464 0.008, t test Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University of Chicago