Population pharmacokinetics of ritonavir as a booster of lopinavir, atazanavir, or darunavir in African children with HIV
Ritonavir is important in antiretroviral therapy (ART) because it is used to boost the drug exposure of its fellow protease inhibitors (PIs). While PIs are commonly used in children, ritonavir data in this population are quite scarce. We investigated the population pharmacokinetics of ritonavir given to boost exposures of lopinavir, atazanavir, or darunavir, and co-administered with nucleoside reverse transcriptase inhibitors (NRTIs) in African children, and investigated factors affecting its exposure. We conducted a pharmacokinetic sub-study within the CHAPAS-4 (ISRCTN22964075) trial, which randomized children to two NRTIs with twice-daily lopinavir/ritonavir, once-daily atazanavir/ritonavir, or once-daily darunavir/ritonavir, as second-line ART. Intensive pharmacokinetic blood samples were collected at week 6, and nonlinear mixed-effects modeling was used to identify factors affecting ritonavir pharmacokinetics. In all, 170 children were enrolled in the ritonavir-boosted PI arms of the CHAPAS-4 pharmacokinetic sub-study, with median age 10.6 (range 3.2-15.6) years and weight 26.0 (14.2-64.2) kg. Despite similar dose levels, ritonavir exposure varied widely depending on the companion PI. Compared to children on darunavir/ritonavir, those on atazanavir/ritonavir had 137% (95% CI 107%-190%) higher bioavailability and 20% (95% CI 11.3%-31.3%) faster clearance, while those on lopinavir/ritonavir had 23.4% (95% CI 8.20%-34.4%) lower bioavailability. No effect of NRTIs on ritonavir pharmacokinetics was observed. Ritonavir exposure is higher with atazanavir than with lopinavir or darunavir. These data provide greater insight into the use of ritonavir for boosting PIs in children and help reduce the knowledge gap regarding its exposure in children.
Authors
- Ellen shingalili
- Disan Mulima
- Caroline Otike
- Mercy Tukamushaba
- J. Chipili
- Denis Odoch
- Veronica Mulenga (ORCID: https://orcid.org/0000-0003-1843-8169)
- Alexander J. Szubert (ORCID: https://orcid.org/0000-0002-2082-0861)
- Kevin Zimba
- Faith Mbasani
- U Abbas
- Mariam Naabalamba
- Anna Turkova (ORCID: https://orcid.org/0000-0002-7008-4145)
- Jimmy Okello (ORCID: https://orcid.org/0000-0002-4276-6034)
- Munifatul Zahara
- Ian Natuhurira
- David Baliruno
- Carly Au (ORCID: https://orcid.org/0000-0003-1385-9239)
- J Acen
- Edridah Keminyeto
- Chishala Chabala (ORCID: https://orcid.org/0000-0002-5551-5752)
- David Marinus Burger (ORCID: https://orcid.org/0000-0001-7279-2818)
- Hylke Waalewijn (ORCID: https://orcid.org/0000-0002-5135-8729)
- Clare Shakeshaft
- Margaret J. Thomason
- Helen McIlleron (ORCID: https://orcid.org/0000-0002-0982-6226)
- Barbara Mukanza
- Alasdair Bamford (ORCID: https://orcid.org/0000-0003-4764-229X)
- Rogers Ankunda
- Edward Bagirigomwa
- Victor Musiime (ORCID: https://orcid.org/0000-0001-7472-9054)
- John Ahuura
- Diana M. Gibb (ORCID: https://orcid.org/0000-0002-9738-5490)
- Samson kariisa
- Lorna Atwine
- Claire Nasaazi
- Shafic Makumbi (ORCID: https://orcid.org/0009-0009-2284-9017)
- Moira J. Spyer (ORCID: https://orcid.org/0000-0001-9149-6029)
- Emily Ninsiima
- Eva Natukunda (ORCID: https://orcid.org/0000-0002-2944-5412)
- Rashida Nazzinda
- Christine Inyakuwa
- Nimisha Dudakia
- Alex Musiime (ORCID: https://orcid.org/0000-0001-5978-109X)
- Angela Colbers
- Paolo Denti (ORCID: https://orcid.org/0000-0001-7494-079X)
- Priscilla Kyobutungi
- Sula Myalo
- Milly Ndigendawani
- Mariam Kasozi
- Ritah Mbabazi
- Monica Kapasa
- Dorothy Zangata
- Barbara Ainebyoona
- Hannah Sweeney
- Annabelle South (ORCID: https://orcid.org/0000-0001-8912-2001)
- Mutsa Bwakura‐Dangarembizi (ORCID: https://orcid.org/0000-0001-7751-6177)
- J Kukundakwe
- Barry R. Nobert
- Diana Rutebarika
- Katja Doerholt (ORCID: https://orcid.org/0000-0001-5105-0970)
- Josephine Namusanje
- Roeland E. Wasmann (ORCID: https://orcid.org/0000-0002-5769-8150)
- Abbas Lugemwa
- Sharif Musumba
- B A Enoch
- Eddie Rubanga
- Aidah Nakalyango
- Agnes Uyungrwoth
- Joan Nangiya
- Lara Monkiewicz
- Ibrahim Yawe
- Linda Jovia
- Paul Oronon
- Phyllis Mwesigwa
- Sarah Walker (ORCID: https://orcid.org/0000-0001-8126-9156)
- Sue Massingham
- Amanda Bigault
- Imelda Namyalo
- Lilian Nabeeta
- Lilian Kobusingye
- Phionah Ampaire
- Paul Ociti
- Juliet Ankunda
- Josephine Kobusingye
- Lutaro Ezra
- Christine Nambi
- Nansaigi Mangadalen
- Edward Mawejje
- Beatrice Tumusiime
- Violet Nagasha
- Musumba Sharif
- Anna Griffiths
- Winnie Namala
- N. Mumba
- Nguyen Van Van
- Otim Thomas
- Moses Chitsamatanga
- Esether Nambi
- Khonzya Zyambo
- Ayesiga Edgar
- Mary Nannungi
- Deogracious Tukwasibwe
- Rubinga Baker
- Lufina Tsirizani
- Eva David
- Nicholas Jinta
- Gershom Kananura
- Zambia Veronica
- Uganda Cissy
- Ritah Winnie
Institutions
- Women's University in Africa (ZW)
- Radboud University Nijmegen (NL)
- University of Zimbabwe (ZW)
- University of Cape Town (ZA)
- Kamuzu Central Hospital (MW)
- University Teaching Hospital (ZM)
- University Medical Center (US)
- Radboud University Medical Center (NL)
- University of Zambia (ZM)
- Joint Research Centre (DE)
- Wellcome Centre for Infectious Diseases Research in Africa (ZA)
- Joint Clinical Research Centre (UG)
- University College London (GB)
- Makerere University (UG)
- Medical Research Council (GB)
Publication Details
- Journal
- Antimicrobial Agents and Chemotherapy
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1128/aac.00771-25
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00