Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice

Background: Erlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. Objective: The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. Methods: The rabbits were divided into three groups: the rabbits receiving erlotinib (I-ER), the group receiving paracetamol (IIPR), and the rabbits receiving erlotinib + paracetamol (IIIER+PR). A single dose of erlotinib was administered orally (25 mg) and was administered intravenously (35 mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites - glucuronide and sulphate were measured with the validated method. Results: During paracetamol co-administration we observed increased erlotinib maximum concentration (C-max) and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC(0-proportional to) by 35.5% and C-max by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for C-max were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for C-max and AUC(0-infinity) were 37.1% and 57.1% lower in the IIPR group, when compared to the IIIER+PR group. Conclusions: Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed. (C) 2017 Published by Elsevier B.V.