Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis

Kamp, Jasper; Jonkman, Kelly; Velzen, Monique van; Aarts, Leon; Dahan, Albert; Olofsen, Erik

doi:10.1016/j.bja.2020.06.067

Cited by 39 publications

(40 citation statements)

References 20 publications

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“…2 of Kamp and colleagues. 10 In the second step, the empirical Bayesian estimates obtained from the pharmacokinetic analysis were used as input for the (cardiac output) pharmacodynamic model. Random effects were included in the model to account for interindividual variability and inter-occasion variability (IOV), as follows: q i ¼q Â exp (h i þh iov ), where q i is the parameter for individual i, q is the population parameter, h i is the random difference between the population and the individual parameter, and h iov is the difference between q i and q attributable to IOV.…”

Section: Methodsmentioning

confidence: 99%

“…This study is part of a large project on the ability of SNP to reduce RS - and S -ketamine-induced side-effects. Apart from the primary analysis, 9 three separate secondary analyses were pre-planned: (i) development of a population pharmacokinetic model of RS - and S -ketamine and metabolites 10 ; (ii) development of a pharmacodynamic model of the analgesic and schizotypical side-effects of RS - and S -ketamine; and finally, (iii) development of a population pharmacodynamic model that describes the changes induced by RS - and S -ketamine on cardiac output and effect of SNP. Here, we report the results of the last analysis.…”

Section: Methodsmentioning

confidence: 99%

“… 9 More recently, we published a pharmacokinetic model of ketamine and its metabolites, and concluded that the SNP effects were not induced by changes in ketamine pharmacokinetics. 10 Our current analysis is aimed at determining the separate effects of S - and R -ketamine isomers and related metabolites on cardiac output, and determining whether SNP has a mitigating effect on ketamine-induced cardiovascular excitatory effects.…”

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confidence: 99%

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Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers

Kamp

Velzen

Aarts

et al. 2021

British Journal of Anaesthesia

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Background: Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine. Methods: Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites. Results: A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output. Conclusions: S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to Sketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner. Clinical trial registration: Dutch Cochrane Center 5359.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers

Kamp

Velzen

Aarts

et al. 2021

British Journal of Anaesthesia

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“…The available population PK models on ketamine are diverse in terms of administered and measured compound, being either racemic, (S)-ketamine or (R)-ketamine, but also in whether the PK of metabolites such as norketamine is described as well [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. An important limitation in the cross-application of these PK models is the assumption that enantiomer-specific PK remains similar when administered as racemate or separate compounds.…”

Section: Introductionmentioning

confidence: 99%

“…Their study suggested that the presence of (R)-ketamine inhibits (S)-ketamine clearance after racemic administration because of competition for metabolism. However, when Kamp et al tested the infusion of racemic or (S)-ketamine as a covariate during the development of their population PK model, no significant differences were found [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers

Otto

Bergmann

Jacobs

et al. 2021

Eur J Clin Pharmacol

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Purpose The recent repurposing of ketamine as treatment for pain and depression has increased the need for accurate population pharmacokinetic (PK) models to inform the design of new clinical trials. Therefore, the objectives of this study were to externally validate available PK models on (S)-(nor)ketamine concentrations with in-house data and to improve the best performing model when necessary. Methods Based on predefined criteria, five models were selected from literature. Data of two previously performed clinical trials on (S)-ketamine administration in healthy volunteers were available for validation. The predictive performances of the selected models were compared through visual predictive checks (VPCs) and calculation of the (root) mean (square) prediction errors (ME and RMSE). The available data was used to adapt the best performing model through alterations to the model structure and re-estimation of inter-individual variability (IIV). Results The model developed by Fanta et al. (Eur J Clin Pharmacol 71:441–447, 2015) performed best at predicting the (S)-ketamine concentration over time, but failed to capture the (S)-norketamine Cmax correctly. Other models with similar population demographics and study designs had estimated relatively small distribution volumes of (S)-ketamine and thus overpredicted concentrations after start of infusion, most likely due to the influence of circulatory dynamics and sampling methodology. Model predictions were improved through a reduction in complexity of the (S)-(nor)ketamine model and re-estimation of IIV. Conclusion The modified model resulted in accurate predictions of both (S)-ketamine and (S)-norketamine and thereby provides a solid foundation for future simulation studies of (S)-(nor)ketamine PK in healthy volunteers after (S)-ketamine infusion.

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Pharmacokinetic Modeling of Ketamine Enantiomers and Their Metabolites After Administration of Prolonged‐Release Ketamine With Emphasis on 2,6‐Hydroxynorketamines

Weiß

Siegmund

2021

Clinical Pharm in Drug Dev

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Modeling of metabolite kinetics after oral administration of ketamine is of special interest because of the higher concentrations of active metabolites because of the hepatic first-pass effect. This holds especially in view of the potential analgesic and antidepressant effects of 2R,6R-and 2S,6S-hydroxynorketamine at low doses of ketamine. Therefore, a 9compartment model was developed to analyze the pharmacokinetics of ketamine enantiomers and their metabolites after racemic ketamine administered intravenously (5 mg) and as 4 doses (10, 20, 40, and 80 mg) of a prolonged-release formulation (PR-ketamine). Using a population approach, the serum concentration-time data of the enantiomers of ketamine, norketamine, dehydronorketamine, and 2,6-hydroxynorketamine obtained in 15 healthy volunteers could be adequately fitted. The estimated model parameters were used to simulate serum concentration-time profiles; after multiple dosing of PR-ketamine (2 daily doses of 20 mg), the steady-state concentrations of R-and S-ketamine were 1.4 and 1.3 ng/mL, respectively. The steady-state concentration of 2R,6R-hydroxynorketamine exceeded those of R-norketamine (4-fold), R-dehydonorketamine (8-fold), and R-ketamine (46-fold), whereas that of 2S,6S-hydroxynorketamine exceeded that of S-ketamine by 14-fold. The model may be useful for identifying dosing regimens aiming at optimal plasma concentrations of 2,6-hydroxynorketamines.

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Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis

Cited by 39 publications

References 20 publications

Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers

Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers

Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers

Pharmacokinetic Modeling of Ketamine Enantiomers and Their Metabolites After Administration of Prolonged‐Release Ketamine With Emphasis on 2,6‐Hydroxynorketamines

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