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. 2017 Oct;57(10):1295-1304.
doi: 10.1002/jcph.936. Epub 2017 Jun 1.

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

Christian Wagner  1 , Ping Zhao  2 , Vikram Arya  1 , Charu Mullick  3 , Kimberly Struble  3 , Stanley Au  1
Affiliations

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

Christian Wagner et al. J Clin Pharmacol. 2017 Oct.

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.

Keywords: darunavir; drug interactions; hepatic impairment; lopinavir; physiologically based pharmacokinetic modeling; protease inhibitors.

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Figures

Figure 1
Figure 1
Overview of the strategy used to predict the impact of CYP modulators on the exposure of boosted LPV and DRV, respectively Abbreviations: CYP=cytochrome P450, DRV=darunavir, LPV=lopinavir, PBPK= physiologically based pharmacokinetic modeling, PK=pharmacokinetic, RTV=ritonavir
Figure 2
Figure 2
Predicted and observed mean arithmetic DRV and LPV concentration profiles. A.1: LPV/RTV, 800 mg/200 mg QD. A.2. LPV/RTV, 400 mg/100 mg BID. B.1: DRV/RTV 800 mg/100 mg QD. B.2: DRV/RTV, 600 mg/100 mg BID. The observed concentration profiles were obtained using the Plot Digitizer program to estimate the concentration values (digitized). Green, solid lines: Predicted LPV or DRV (without RTV coadministration) plasma concentration-time profiles. Black, solid lines: Predicted LPV and DRV (with RTV coadministration) plasma concentration-time profiles. Red symbols: observed LPV (A.1, A.2,,) and observed DRV B.1, and B2) with concomitant use of RTV. Red and brown symbols: observed DRV (B.2) Abbreviations: DRV=darunavir, hr=hour, LPV=lopinavir, μg=microgram
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