Affordable Access

deepdyve-link deepdyve-link
Publisher Website

Physiologically Based Pharmacokinetic Modeling for Predicting the Effect of Intrinsic and Extrinsic Factors on Darunavir or Lopinavir Exposure Coadministered With Ritonavir.

Authors
  • Wagner, Christian1
  • Zhao, Ping2
  • Arya, Vikram1
  • Mullick, Charu3
  • Struble, Kimberly3
  • Au, Stanley1
  • 1 Division of Clinical Pharmacology IV, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA, Silver Spring, MD, USA.
  • 2 Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA, Silver Spring, MD, USA.
  • 3 Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, CDER, FDA, Silver Spring, MD, USA.
Type
Published Article
Journal
Journal of clinical pharmacology
Publication Date
Oct 01, 2017
Volume
57
Issue
10
Pages
1295–1304
Identifiers
DOI: 10.1002/jcph.936
PMID: 28569994
Source
Medline
Keywords
License
Unknown

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.

Report this publication

Statistics

Seen <100 times