Exposure to Oral S-ketamine Is Unaffected by Itraconazole but Greatly Increased by Ticlopidine

Abstract

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.

Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

“…Our results indicate that ticlopidine predosing can cause more than a twofold rise in S ‐ketamine AUC in humans, which is consistent with previous NCA analysis and in vitro results9 ( Table 3). Ticlopidine profoundly inhibited CYP2B6 activity and the final DDI model was used to simulate the effect of ticlopidine on the parameters describing the fractional inhibition of intrinsic hepatic clearance, the change in the intrinsic hepatic clearance during placebo and inhibitor phase, and the percentage of remaining CYP2B6 activity (%RA).…”

“…For our analysis, we pooled the data from placebo phases of S ‐ketamine administration. For the DDI model development, the complete dataset (i.e., placebo as well as inhibitor phase) was included from the study that investigated the DDI between S ‐ketamine and ticlopidine 9. A summarized description of these studies with the study designs, sampling schemes, and the drug analysis are described in Supplementary Information S1 .…”

“…The ncappc ‐package in PsN30 was used to compare model‐predicted maximum plasma concentration (C max ) and area under the curve (AUC) to the values from the NCA analysis from our previous report 9. Model‐based simulations were performed using the final parameter estimates for the fixed and random effects in 1,000 virtual subjects with NONMEM to assess the performance of the mechanism‐based and reversible components of the inhibition parameters in the mechanistic static model (MSM) model.…”

“…9. Itraconazole, a CYP3A enzyme inhibitor, had no significant effect on plasma concentrations of orally administered S ‐ketamine, indicating that the gut wall might not be a significant contributor in S ‐ketamine first‐pass metabolism.…”

“…The N‐oxidation to norketamine by hepatic cytochrome P450 (CYP)2B6 is the primary metabolic pathway of ketamine biotransformation,6 whereas CYP3A has also been reported to contribute to ketamine metabolism in humans 7. A recent in vitro study has shown that the fraction of ketamine metabolized by hepatic CYP2B6 is around 60%,8 and, hence, CYP2B6‐inhibition can lead to a significant increase in S ‐ketamine exposure 9…”