Stein Schalkwijk1,2, Rob Ter Heine1, Angela Colbers1, Edmund Capparelli3, Brookie M Best3, Tim R Cressey4,5,6, Rick Greupink2, Frans G M Russel2, José Moltó7,8,9, Mark Mirochnick10, Mats O Karlsson11, David M Burger1. 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.
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.
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