Physiologically Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Coadministered With Ritonavir.
J Clin Pharmacol
; 57(10): 1295-1304, 2017 10.
Article
em En
| MEDLINE
| ID: mdl-28569994
ABSTRACT
Management of comorbidities and medications is complex in HIV-1-infected patients. The overall objective of this project was to develop separate physiologically based pharmacokinetic (PBPK) substrate models for the protease inhibitors darunavir and lopinavir. These protease inhibitors are used in the treatment of HIV infection. Both darunavir and lopinavir are coadministered with another medication that inhibits cytochrome (CYP) 3A. The current project focused on PBPK modeling for darunavir and lopinavir coadministered with ritonavir. Darunavir and lopinavir PBPK models that accounted for ritonavir CYP3A inhibition effects (linked PBPK models) were developed. The linked PBPK models were then used to predict the effect on darunavir or lopinavir exposure from CYP modulators. In the next step, the predicted effect of hepatic impairment was evaluated. Additional exploratory analyses predicted CYP3A inhibition effects on darunavir or lopinavir exposure in simulated hepatically impaired subjects. The linked PBPK models reasonably predicted darunavir or lopinavir exposure based on simulations with CYP inhibitors or inducers. Exploratory simulations using the linked darunavir or lopinavir PBPK models indicated CYP3A inhibition may further increase darunavir or lopinavir exposure in patients with hepatic impairment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores da Protease de HIV
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Ritonavir
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Lopinavir
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Inibidores das Enzimas do Citocromo P-450
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Darunavir
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Hepatopatias
/
Modelos Biológicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Clin Pharmacol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos