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J Antimicrob Chemother. 2019 Jan 30. doi: 10.1093/jac/dky567. [Epub ahead of print]

Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling.

Author information

1
Department of Pharmacy, Radboud Institute for Health Sciences (RIHS), Radboud university medical center, Nijmegen, The Netherlands.
2
Department of Pharmacology & Toxicology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud university medical center, Nijmegen, The Netherlands.
3
Skaggs School of Pharmacy and Pharmaceutical Sciences & School of Medicine, University of California San Diego, San Diego, CA, USA.
4
Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
5
Harvard T.H. Chan School of Public Health, Boston, MA, USA.
6
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
7
Fundació Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
8
Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
9
Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
10
Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.
11
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Abstract

Background:

Darunavir 800 mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available.

Objectives:

To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women.

Patients and methods:

A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC0-τ and Ctrough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure.

Results:

Simulations predicted that total darunavir exposure (AUC0-τ) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC0-τ was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%).

Conclusions:

The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.

PMID:
30715324
PMCID:
PMC6477987
[Available on 2020-01-30]
DOI:
10.1093/jac/dky567

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