Pretreatment with diltiazem and nicardipine increased lapatinib maximum plasma concentration by 29.30% and 36.76% respectively, whereas verapamil reduced it by 30.44% in rat models.
Do calcium channel blockers alter the pharmacokinetics of lapatinib in preclinical models?
Preclinical models show that calcium channel blockers significantly alter the pharmacokinetics of lapatinib, suggesting potential drug-drug interactions that warrant clinical investigation.
p-value: p=<0.01
Lapatinib, an oral tyrosine kinase inhibitor used to treat breast cancer, is associated with cardiotoxicity. Therefore, cardioprotective agents, including calcium channel blockers, are often co-prescribed, creating a potential for pharmacokinetic drug-drug interactions that need to be evaluated. The current study assessed the effects of calcium channel blockers on P-glycoprotein-mediated efflux, CYP3A4 (cytochrome P450-3A4)-regulated metabolism, and the overall pharmacokinetics of lapatinib using an ex vivo everted gut sac model, in vitro metabolic stability assays, and in vivo pharmacokinetic interaction studies in rats. Calcium channel blockers such as verapamil and nicardipine increased the apparent permeability of lapatinib 1.92- and 1.68-fold, respectively. Furthermore, lapatinib’s metabolic clearance in human liver microsomes was decreased by 15.78- and 9.47-fold in the presence of nicardipine and diltiazem, respectively, at a concentration of 100 µM. In vivo, the Cmax (maximum plasma concentration) of lapatinib was increased by 29.30% on pretreatment with diltiazem (25 mg/kg) and 36.76% on pretreatment with nicardipine (4 mg/kg). However, verapamil (20 mg/kg) reduced its Cmax by 30.44%. Pretreatment with diltiazem and nicardipine increased lapatinib exposure, whereas pretreatment with verapamil reduced it. These findings from preclinical models suggest the potential for drug-drug interactions between lapatinib and calcium channel blockers, warranting further clinical investigation.
Desai et al. (Fri,) conducted a other in Pharmacokinetic drug-drug interactions (n=21). Calcium channel blockers (diltiazem, nicardipine, verapamil) vs. Vehicle control (lapatinib alone) was evaluated on Maximum plasma concentration (Cmax) of lapatinib (p=<0.01). Pretreatment with diltiazem and nicardipine increased lapatinib maximum plasma concentration by 29.30% and 36.76% respectively, whereas verapamil reduced it by 30.44% in rat models.