Marije E. Otto (1), Kirsten R. Bergmann (1), Kasper Recourt (1,2), Gabriël E. Jacobs (1,3), Michiel J. van Esdonk (1)
(1) Centre for Human Drug Research, Leiden, The Netherlands (2) Leiden University Medical Centre, Leiden, The Netherlands (3) Department of psychiatry, Leiden University Medical Centre, Leiden, The Netherlands
Introduction: Ketamine’s rapid onset antidepressant effects are of increasing interest for patients with major depressive disorder (MDD)[1,2]. However, it is unclear what the exact mechanism of action of these effects is and how the specific enantiomers and metabolites contribute[3,4]. Still, most population pharmacokinetic (PK) models available in literature describe only (S)-(nor)ketamine[5-7], with a few exceptions[8,9]. Knowledge of enantiomer and metabolite PK is limited, with only minimal information available on possible interactions between enantiomers[9]. Therefore, the aim of this project was to validate existing PK-models of (S)-(nor)ketamine with in-house clinical trial data and to adapt and extend the most predictive model with the PK of the (R)-enantiomer after racemic intravenous ketamine administration.
Methods: Data of three clinical trials performed at the Centre for Human Drug Research were available. Two studies (n=21/31) infused 10 mg or 0.4-0.9 mg/kg (S)-ketamine in healthy volunteers for 0.5h or 2h respectively and measured (S)-(nor)ketamine until 10h or 5.5h after administration. The third study (n=16) administered 0.5 mg/kg racemic ketamine in patients with MDD for 40 min and total (nor)ketamine measurements were collected for 24h. The predictive capabilities of (S)-(nor)ketamine literature models were explored using visual predictive checks (VPC)[5-8]. The best model was further refined by structural modifications and re-estimation of inter-individual variability (IIV) if required. For parent-metabolite modelling, a sequential approach was chosen to avoid bias in the identification of the structural model. Addition of the (R)-(nor)ketamine PK to this model was based on racemic concentrations. It was assumed that (S)-ketamine clearance (CL) was inhibited by (R)-ketamine with a factor of 0.703[9]. To stratify enantiomer specific IIV from the total variability, parametric-bootstrapping of the individual (S)-profiles was performed. Final model parameters of (R)-(nor)ketamine were derived from the bootstrap using the models with successful minimization and covariance steps. Parameters were evaluated by their median estimates including the 95% confidence intervals. Models were numerically and visually evaluated by a significant drop in objective function value (p<0.01), goodness-of-fit (GOF) plots, relative standard error (RSE<50%) and confidence interval or prediction corrected VPC’s.
Results: Literature models varied considerably in model structure and parameter estimates. The VPC of the model by Fanta et al.[7] showed the best agreement of predicted and observed median and 10-90th percentiles of the data. IIV of (S)-ketamine was re-estimated and the model structure of (S)-norketamine was adapted because the maximum concentrations were underpredicted. This resulted in a final model of three compartments for (S)-ketamine, two compartments for (S)-norketamine and no transit compartments for parent-metabolite conversion. Based on the racemic concentrations, two compartments for (R)-ketamine and for (R)-norketamine were identified. IIV could be estimated for both enantiomers and metabolites on central CL and distribution volume whilst they were allometrically scaled with fixed exponents of 0.75 and 1.0 respectively. Medians of estimated parameters from the parametric-bootstrap did not differ significantly when estimated without bootstrapping, but did result in increased parameter accuracy. The quantified IIV for the (R)-enantiomer model parameters was approximately twice as high compared to (S). The model showed an adequate description of the data over time, confirmed by the GOF plots and VPCs.
Conclusions: On the basis of the model of Fanta et al.[7], a refined population PK model for enantiomer-specific (R,S)-(nor)ketamine was developed. During model development assumptions had to be made regarding the metabolized fraction of parent drug and the interaction between enantiomers. Parametric bootstrapping was used to identify separate IIV for the enantiomers from total concentrations. Although parameter accuracy improved, estimated IIV for the (R)-enantiomer was high, which could originate from the use of a different population. Still, the presented model was able to accurately predict the PK of (R,S)-(nor)ketamine after racemic or (S)-ketamine administration in healthy volunteers and MDD patients.
References:
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[8] Zhao, X. et al. Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression. Br. J. Clin. Pharmacol. 74, 304–314 (2012).
[9] Ihmsen, H., Geisslinger, G. & Schüttler, J. Stereoselective pharmacokinetics of ketamine: R(-)-ketamine inhibits the elimination of S(+)-ketamine. Clin. Pharmacol. Ther. 70, 431–438 (2001).
Reference: PAGE () Abstr 9430 [www.page-meeting.org/?abstract=9430]
Poster: Drug/Disease Modelling - CNS