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

Abstract

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.

Keywords:

• Drug-drug interactions
• pharmacokinetics
• bioanalysis
• physiologically based pharmacokinetic
• eletriptan
• N-desmethyl eletriptan

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Disclosure statement

This research work has been contributed by all authors. All authors with exception of Nirmal Desai (ND) are employees of Cadila Healthcare Limited, Ahmedabad, India. ND is an employee of St Xavier’s College (Autonomous), Ahmedabad, India. Authors have no conflict of interest with the contents of the manuscript (ZRC communication no 577).

Table 2. Pharmacokientic parameter of eletriptan following single subcutaneous and oral administration of eletriptan with and without co-administration of ketoconazole in male rats.