Effects of Imatinib on the Pharmacokinetics of Acetaminophen in Korean Patients with Chronic Myelogenous Leukemia (CML)

Abstract

Background: Drug-drug interactions between imatinib (IM) and drugs which are substrates of CYP2C9, CYP2D6- and CYP3A4/5 isozymes have been characterized in clinical studies as IM has demonstrated an inhibitory effect on these isozymes in vitro in human liver microsomes [Gleevec® Prescribing Information]. IM also exhibited a weak in vitro inhibitory effect on UGTs-mediated O-glucuronidation using acetaminophen as a probe substrate (Ki 58.5 μM). The present study evaluates the clinical significance of PK interactions between IM 400 mg/d and acetaminophen, an often used analgesic/antipyretic medicine, in CML patients.Methods: Newly diagnosed CML patients (n=12) treated at St Mary's Hospital, the Catholic University of Korea first received a single oral dose of acetaminophen 1000 mg on day 1 after an overnight fasting. On days 2–8, IM 400 mg was administered daily (qd). On day 8, another 1000 mg dose of acetaminophen was administered together with IM 400 mg. Blood and urine samples over 24 hours were collected following the morning dose on days 1 and 8 to determine the plasma PK and renal excretion of acetaminophen and its glucuronide (G) and sulfate (S) conjugate metabolites (two major metabolites of acetaminophen). Additional blood samples were collected on day 8 to measure the plasma exposure of IM and its major metabolite CGP74588 (CGP) in patients.Results: Preliminary results from 6 patients showed that the plasma Cmax and AUC values of acetaminophen and the AUC ratios of conjugate G and S to acetaminophen were all similar between day 1 (Control) and day 8 (with IM) (Table 1). The renal clearance values for acetaminophen and its two conjugate metabolites were also similar between days 1 and 8. Following 7 days treatment at IM 400 mg qd, the IM plasma Cmax and AUC values were 2040±477.7 ng/mL and 31.8±8.68 μg*hr/mL, respectively. The oral clearance of IM in these Korean patients, 13.4±3.6 L/hr, was comparable to that reported in Caucasian CML patients, 10–14 L/hr [Schmidli 2005]. PK samples from an additional six patients have been collected, and results will be available for reporting by December 2008.Acetaminophen (A)Cmax (μg/mL)AUC (μg*hr/mL)G/A AUC ratioS/A AUC ratioDay 1 (n=6)15.6±8.352.4±242.66±0.750.77±0.11Day 8 (n=6)12.0±5.049.0±19.62.70±0.960.85±0.17Day 8/Day 1 ratio0.92±0.420.95±0.081.0±0.111.1±0.15Imatinib (IM)Cmax (ng/mL)AUCt (μg*hr/mL)Cmin (ng/mL)CGP/IM AUC ratioDay 8 (n=6)2040±477.731.8±8.68947±3230.15±0.035Conclusion: Preliminary results showed that coadministration of imatinib 400 mg/d had no effect on the PK and metabolism of acetaminophen 1000 mg in newly diagnosed CML patients.