Pharmacokinetics and pharmacodynamics of intravenous and oral (S)-ketamine: Investigating metabolite contribution to subjective effects.

Oral (S)-ketamine for treatment-resistant depression undergoes extensive first-pass metabolism, yielding low parent drug but high levels of active metabolites like (S)-norketamine. Using data from 17 healthy participants in a crossover trial, researchers developed a population PK model linking (S)-ketamine and (S)-norketamine concentrations to subjective 'Feeling High' scores. A significant relationship was found for (S)-norketamine alongside (S)-ketamine, though model variance was high. The analysis suggests that (S)-norketamine, not (S)-ketamine itself, primarily drives subjective effects after oral administration and may contribute to antidepressant effects in patients.

Study at a glance

Abstract

Oral administration of (S)-ketamine for treatment-resistant depression (TRD), as alternative to the registered intranasal or off-label intravenous administrations, has high potential. However, it is characterized by an extensive first-pass metabolism, resulting in low (S)-ketamine exposure and high levels of active metabolites, including (S)-norketamine and (S)-hydroxynorketamine. The relative contribution of the parent and metabolites to the resulting antidepressant effects remains unclear. Therefore, this study aimed to first characterize the pharmacokinetics (PK) of (S)-ketamine and its metabolites after oral and intravenous administration in healthy participants and secondly quantify the pharmacokinetic/pharmacodynamic (PKPD) relationship of (S)-ketamine and (S)-norketamine to the subjective effects measured on the visual analogue scale (VAS) 'Feeling High'. Data from a previously conducted clinical study was used, where 17 healthy participants received oral (0.20 and 0.45 mg/kg) and intravenous (0.4 mg/kg over 40 min) (S)-ketamine in a randomized, placebo-controlled, crossover clinical trial. A semi-physiological population PK model was developed to describe the first-pass metabolism and (S)-ketamine and subsequently (S)-norketamine concentrations were linked to the VAS 'Feeling High' using a bounded integer modelling approach. A significant (S)-norketamine PKPD relationship was determined alongside (S)-ketamine, but estimated variance of the bounded integer model was high warranting further investigation. Our analysis suggests that not (S)-ketamine, but its metabolite, is the main driver of subjective effects after oral administration, and as such may also contribute to antidepressant effects in TRD patients receiving oral (S)-ketamine.