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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • (R,S)‐ketamine is a phencyclidine derivative that was initially developed as an anaesthetic agent and which is currently being studied in the treatment of pain and depression. After administration, the drug is extensively N‐demethylated to (R,S)‐norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub‐anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)‐dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated. WHAT THIS STUDY ADDS • The current study expands the characterization of the disposition kinetics of (R,S)‐ketamine and (R,S)‐norketamine and presents a population pharmacokinetic analysis of (R)‐ketamine, (S)‐ketamine, (R)‐norketamine, (S)‐norketamine, (R)‐dehydronorketamine, (S)‐ dehydronorketamine and (2S,6S;2R,6R)‐hydroxynorketamine and the serum concentration–time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40 min infusion of a sub‐anaesthetic dose of the drug. The data demonstrate that while norketamine is an initial metabolite, it is not the major circulating metabolite and suggest that the determination of the downstream metabolites of ketamine may play a role in the pharmacological effects of the drug. 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)‐n...

Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function

“…The present results demonstrate that low micromolar concentrations of ketamine, similar to those likely achieved in brain during ketamine infusions for the treatment of depression or induction of psychosis (Zhao et al, 2012; Hartvig et al, 1995; Doyle et al, 2013), have significant effects on CA1 hippocampal function in juvenile rats, resulting in changes in dendrosomatic processing and negatively modulating LTD and LTP, two forms of synaptic plasticity thought to underlie memory. LTD inhibition and enhancement of somatic EPSPs are observed shortly following ketamine administration, while modulation of LTP develops more slowly, being absent immediately and one hour post-ketamine, but present two hours or more after exposure.…”

“…The latter symptoms usually abate over several hours as antidepressant effects emerge. Subanesthetic blood levels of ketamine associated with psychotomimetic and antidepressant effects are in the range of 0.3–0.5 µM (80–150 ng/ml) (Zhao et al, 2012), resulting in brain concentrations of 1–10 µM (Cohen et al, 1973; Hartvig et al, 1995; Doyle et al, 2013). …”

Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor

“…These include the major N-demethylated metabolite norketamine, two diastereomeric hydroxyketamines, and a series of diastereomeric hydroxynorketamines, including hydroxynorketamine, and dehydronorketamine (Cohen et al, 1973;Adams, Jr. et al, 1981;Woolf and Adams, 1987). The rapid and extensive metabolic transformation of M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT ketamine was reported in studies using human microsomal preparations (Desta et al, 2012) and in clinical studies (Zarate, Jr. et al, 2012;Zhao et al, 2012).…”

The distribution and clearance of (2S,6S)‐hydroxynorketamine, an active ketamine metabolite, in Wistar rats

“…2012; Zhao et al. 2012; Hirota and Lambert, 2011). The initial pharmacodynamic studies of (R,S)-Ket were conducted using Wistar rats and examined the anesthetic effects of the parent compound and its two principle metabolites (R,S)-norketamine, (R,S)-norKet, and (2S,6S;2R,6R)-hydroxynorketamine, (2S,6S;2R,6R)-HNK, Scheme 3, Pathway A (Leung and Baillie 1986).…”