Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression

Abstract

Aim: To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)-HNK) and hydroxyketamine (HK) in patients with treatment-resistant bipolar depression.

Method: Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)-Ket (0.5 mg kg⁻¹) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)-HNK, (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two-stage algorithm in ADAPT5.

Results: Ket, norKet, DHNK and (2S,6S;2R,6R)-HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml⁻¹) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter-patient variations in terminal half-lives and relative metabolite concentrations; at 230 min (R,S)-DHNK was the major metabolite in four out of nine patients, (R,S)-norKet in three out of nine patients and (2S,6S;2R,6R)-HNK in two out of nine patients. The final PK model included three compartments for (R,S)-Ket, two compartments for (R,S)-norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)-Ket and (R,S)-norKet were in agreement with prior estimates.

Conclusion: This represents the first PK analysis of (2S,6S;2R,6R)-HNK and (R,S)-DHNK. The results demonstrate that while norKet is the initial metabolite, it is not the main metabolite suggesting that future Ket studies should include the analysis of the major metabolites.

Figure 1

The metabolism of ketamine

Figure 2

Schematic of the final pharmacokinetic model of (R)- and (S)-ketamine and corresponding metabolites. Abbreviations and system equations are defined under Pharmacokinetic model in Methods

Figure 3

The chromatographic trace from the achiral analysis of a plasma sample obtained 230 min after administration of a 0.5 mg kg⁻¹ dose of (R,S)-Ket where: A = (2S,6S;2R,6R)-HNK; B = (2S,6R;2R,6S)-HNK; C = (2S,5S;2R,5R)-HNK; E = (2S,4R;2R,4S)-HNK; F = (2S,5R;2R,5S)-HNK

Figure 4

The chromatographic trace from the achiral analysis of a plasma sample obtained 1 day (day 1) after administration of a 0.5 mg kg⁻¹ dose of (R,S)-Ket where: A = (2S,6S;2R,6R)-HNK; F = (2S,5R;2R,5S)-HNK

Figure 5

The average plasma concentrations, presented as ng ml⁻¹, of the stereoisomers of (R,S)-Ket and its major metabolites in nine patients treated with a 0.5 mg kg⁻¹ dose of (R,S)-Ket. 40 min (); 80 min (); 110 min (); 230 min (); Day 1 (); Day 2 (); Day 3 ()

Figure 6

Pharmacokinetic profiles for ketamine and corresponding metabolites in a representative subject; (A) ketamine, (B) norketamine, (C) dehydronorketamine, and (D) (2S,6S)-/(2R,6R)-HNK. Red circles are measured (S)-enantiomer concentrations, blue circles are measured (R)-enantiomer concentrations and continuous lines are model fitted profiles