Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model.
Darunavir
External validation
HIV
Limited sampling strategy
Optimal sampling strategy
Population pharmacokinetics
Journal
European journal of clinical pharmacology
ISSN: 1432-1041
Titre abrégé: Eur J Clin Pharmacol
Pays: Germany
ID NLM: 1256165
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
12
08
2020
accepted:
31
10
2020
pubmed:
12
11
2020
medline:
25
2
2023
entrez:
11
11
2020
Statut:
ppublish
Résumé
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. 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. 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. Optimal sampling strategies derived from this model could be used in clinical practice to enhance therapeutic drug monitoring or to conduct additional pharmacokinetic studies.
Identifiants
pubmed: 33175180
doi: 10.1007/s00228-020-03036-2
pii: 10.1007/s00228-020-03036-2
pmc: PMC7935830
doi:
Substances chimiques
HIV Protease Inhibitors
0
Darunavir
YO603Y8113
Types de publication
Journal Article
Validation Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
607-616Subventions
Organisme : Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA)
ID : FC16749
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