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

• Main Authors: Stein Schalkwijk, Rob Ter Heine, Angela Colbers, Edmund Capparelli, Brookie M. Best, Tim R. Cressey, Rick Greupink, Frans G.M. Russel, José Moltó, Mark Mirochnick, Mats O. Karlsson, David M. Burger
• Format: Journal
• Published: 2019
• Subjects: Medicine; Pharmacology, Toxicology and Pharmaceutics
• Online Access: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072058593&origin=inward; http://cmuir.cmu.ac.th/jspui/handle/6653943832/66721
• Institution: Chiang Mai University

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [e-mail]. 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.