Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model.
Purpose: A variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the model building dataset and to additional data generated through Monte Carlo simulations, is often sufficient, but external...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 77; no. 4; pp. 607 - 617 |
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| Autores principales: | , , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Apr2021
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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=149092718&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 149092718 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Apr2021 vid: 77 iid: 4 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 149092718 146944911 149092718 149092718 10.1007/s00228-020-03036-2 149092718 ppf: 607 ppct: 10 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model. aug: au: Stillemans, Gabriel Belkhir, Leila Vandercam, Bernard Vincent, Anne Haufroid, Vincent Elens, Laure affil: Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier 72, B01.72.0, Brussels, Belgium sug: subj: HIV Infections Drug Therapy HIV Protease Inhibitors Pharmacokinetics Ritonavir Pharmacokinetics Acids, Acyclic Pharmacokinetics Drug Combinations Pharmacokinetics Prediction Models Population Surveillance Human Validation Studies Drug Monitoring Methods Drug Hypersensitivity HIV Protease Inhibitors Administration and Dosage ab: Purpose: A variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the model building dataset and to additional data generated through Monte Carlo simulations, is often sufficient, but external validation, which requires a new dataset, is considered a more rigorous approach, especially if the model is to be used for predictive purposes. Our first objective was to validate a previously published population pharmacokinetic model of darunavir, an HIV protease inhibitor boosted with ritonavir or cobicistat. Our second objective was to use this model to derive optimal sampling strategies that maximize the amount of information collected with as few pharmacokinetic samples as possible. Methods: A validation dataset comprising 164 sparsely sampled individuals using ritonavir-boosted darunavir was used for validation. Standard plots of predictions and residuals, NPDE, visual predictive check, and bootstrapping were applied to both the validation set and the combined learning/validation set in NONMEM to assess model performance. D-optimal designs for darunavir were then calculated in PopED and further evaluated in NONMEM through simulations. Results: External validation confirmed model robustness and accuracy in most scenarios but also highlighted several limitations. The best one-, two-, and three-point sampling strategies were determined to be pre-dose (0 h); 0 and 4 h; and 1, 4, and 19 h, respectively. A combination of samples at 0, 1, and 4 h was comparable to the optimal three-point strategy. These could be used to reliably estimate individual pharmacokinetic parameters, although with fewer samples, precision decreased and the number of outliers increased significantly. Conclusions: Optimal sampling strategies derived from this model could be used in clinical practice to enhance therapeutic drug monitoring or to conduct additional pharmacokinetic studies. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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