Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers.
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...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 77; no. 8; pp. 1181 - 1193 |
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| Autores principales: | , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Springer Nature
Aug2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=151387362&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 151387362 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Aug2021 vid: 77 iid: 8 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 151387362 148645559 151387362 151387362 10.1007/s00228-021-03104-1 151387362 ppf: 1181 ppct: 12 formats: fmt: @attributes: type: P tig: atl: Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers. aug: au: Otto, M. E. Bergmann, K. R. Jacobs, G. van Esdonk, Michiel J. affil: Centre for Human Drug Research, Leiden, The Netherlands sug: subj: Models, Statistical Ketamine Therapeutic Use Ketamine Pharmacokinetics Validation Studies Human Descriptive Statistics Comparative Studies Prediction Models ab: 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. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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