Differential pharmacokinetic drug-drug interaction potential of eletriptan between oral and subcutaneous routes

1. Pharmacokinetic drug-drug interaction (DDI) data is important from a label claim either in combination drug usage or in polypharmacy situation. 2. Eletriptan undergoes first pass related metabolism through CYP3A4 enzyme to form pharmacologically active N-desmethyl metabolite. 3. Differential DDI interaction of the concomitant oral dosing of ketoconazole (20.1 mg/kg), a CYP3A4 inhibitor, with oral (4.2 mg/kg) or subcutaneous dose (2.1 mg/kg) of eletriptan was evaluated in male Sprague Dawley rats. Serial pharmacokinetic samples were collected and simultaneously analysed for eletriptan/N-desmethyl eletriptan using validated assay. Non-compartmentally derived pharmacokinetic parameters for various treatments were analysed statistically. 4. After oral eletriptan in presence of ketoconazole, C_max (40 vs. 32 ng/mL alone) and AUC_inf (81 vs. 24 ng.h/mL alone) of eletriptan increased; the formation of N-desmethyl eletriptan decreased (C_max=1.1 ng/mL, 3.9%) with ketoconazole as compared to without treatment (C_max=3.7 ng/mL, 11.2%). After subcutaneous eletriptan in presence of ketoconazole, there was no change in C_max (153 vs.152 ng/mL) or AUC_inf (267 vs. 266 ng.h/mL) of eletriptan. Formation of N-desmethyl eletriptan after the subcutaneous dose was determined at few intermittent time points with/without ketoconazole. 5. Preclinical data support differential DDI of eletriptan when dosed oral vs. subcutaneous, which need to be evaluated in a clinical setting.