The effect of OCT-2 inhibitor Daclatasvir on Metformin pharmacokinetics and pharmacodynamics at two dose levels: A Bayesian approach using Markov-Chain Monte Carlo simulations

Abstract

Renal Organic Cation Transporter 2 (OCT2) plays a major role in metformin elimination. Daclatasvir, a Direct-Acting Antiviral (DAA), is an OCT2 inhibitor. Our study aimed to assess the potential interaction of daclatasvir with metformin pharmacokinetics and pharmacodynamics at two metformin doses. Twenty subjects were randomized in a two-period crossover study. The subjects received metformin 500 mg twice daily either alone (R1) or with daclatasvir 60 mg once daily (T1), followed by 1000 mg metformin twice daily either alone (R2) or with daclatasvir 60 mg once daily (T2). Metformin Cmax was higher in T1 and T2 than in R1 and R2 by 12% and 11%, respectively, with a geometric mean ratio (GMR) of 1.12 (90% CI: 0.98-1.26) and 1.12 (90% CI: 0.86-1.36), respectively. Renal clearance (Clr) was lower in T1and T2 compared to R1 and R2 by 15% and 11%, with a GMR of 0.85 (0.68-1.02) and 0.89 (0.69-1.09), respectively. The differences from baseline glucose level (ΔG %) and the area under the Δ G%-time curve (Δ AUG %) were higher for the 500 mg dose of metformin with daclatasvir (p < 0.05). Daclatasvir slightly altered the pharmacokinetics of metformin with a minor alteration of pharmacodynamics of the 500 mg dose.

Keywords

• metformin
• daclatasvir
• oct2
• pharmacokinetics
• pharmacodynamics
• mcmc