CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: No differences in neurodevelopment from 36-48 months were observed between children with and without prenatal PrEP exposure. Our results support a growing body of evidence demonstrating the safety of prenatal PrEP use and add to the limited data on neurodevelopmental outcomes in PrEP exposed children.

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Simplifying Dosing by Harmonizing Weight-Band-Based Dosing Across Therapeutic Areas in Children Hylke Waalewijn 1 , Mounier Almett 1 , Roeland E. Wasmann 1 , Tim R. Cressey 2 , Phillipa Easterbrook 3 , Peter Ehizibue Olumese 3 , Anneke C. Hesseling 4 , Joel Tarning 5 , Anna Turkova 6 , Elin Svensson 7 , Angela Colbers 8 , Wilson M. Were 3 , Paolo Denti 1 , Martina Penazzato 3 1 University of Cape Town, Cape Town, South Africa, 2 Chiang Mai University, Chiang Mai, Thailand, 3 World Health Organization, Geneva, Switzerland, 4 Desmond Tutu TB Centre, Western Cape, South Africa, 5 Mahidol University, Bangkok, Thailand, 6 University College London, London, United Kingdom, 7 Uppsala University, Uppsala, Sweden, 8 Radboud University Medical Center, Nijmegen, Netherlands Background: Pediatric WHO dosing guidance recommends using dosing weight bands, but these are not standardized across therapeutic areas. This adds to the complexity of drug prescribing and administration when treating individual children for multiple diseases and comorbidities, increasing the risk of dosing errors. Harmonized weight bands across therapeutic areas are expected to simplify dosing, relieve the burden on practitioners and caregivers, reduce dosing errors, and provide clear dosing guidance for future pediatric drug development programs. However, this cannot come at the expense of drug efficacy or safety. We investigated the impact of harmonizing weight bands for HIV, tuberculosis (TB), malaria, and Hepatitis C (HCV) treatment, based on simulated drug exposures, with the goal of providing evidence for future harmonization of pediatric weight bands. Methods: Weight bands recommended in the Pocket Book for Hospital Care in Children, WHO Antibiotic Book, and guidance documents for HIV, TB, malaria, and HCV were selected to assess the potential for harmonization. Using available population pharmacokinetic models for individual drugs, the impact of harmonizing weight bands on drug exposures were simulated and the corresponding changes discussed with panels of clinical and pharmacological experts. Results: The proposed weight bands align with those recommended in the WHO antibiotic book and the pocket book, Table 1. For drugs used in HIV, HCV, and for treatment and prevention of drug-susceptible TB, harmonization had minimal impact on drug exposures and are not expected to affect drug efficacy or safety. For children weighing <10 kg treated for drug-resistant TB, harmonization had a pronounced impact; nevertheless, safe, and effective exposures are expected after optimizing drug doses based on age to account for maturation of elimination pathways. Safe and effective exposures are expected with harmonized dosing for 7/9 priority malaria drugs and for all 3 drugs currently used for seasonal malaria chemoprevention. Conclusion: This work demonstrates that harmonized pediatric weight bands, with additional age-based dosing for infants, provides sufficient flexibility for safe and effective pediatric dosing for treatment of HIV, HCV, TB, and seasonal malaria chemoprevention. For malaria treatment, additional safety, and efficacy studies are recommended due to expected exposures in 2/9 priority drugs. This analysis is expected to inform future revision of WHO guidelines.

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Single-Dose PK/Safety of DTG-Dispersible Tablets in Neonates Supports Multi-Dosing: Petite-DTG Study Adrie Bekker 1 , Nicolas Salvadori 2 , Helena Rabie 1 , Samantha du Toit 1 , Kanchana Than-in-at 2 , Maria Groenewald 1 , Edmund Capparelli 3 , Andrew Owen 4 , Ratchada Cressey 2 , Marc Lallemant 2 , Mark F. Cotton 1 , Tim R Cressey 5 , for the PETITE-DTG Study Team 1 Stellenbosch University, Cape Town, South Africa, 2 Chiang Mai University, Chiang Mai, Thailand, 3 University of California San Diego, San Diego, CA, USA, 4 University of Liverpool, Liverpool, United Kingdom, 5 AMS-PHPT Research Collaboration, Chiang Mai University, Chiang Mai, Thailand Background: Dolutegravir dispersible tablets (DTG-DT) are approved for infants ≥3 kg and aged >4 weeks but their suitability for neonates remains unknown. We evaluated the pharmacokinetics (PK) and safety of pediatric DTG-DT in neonates born to women on DTG-based therapy. Methods: PETITE-DTG is an ongoing phase I/II, open-label, single center, two-stage trial in South Africa evaluating the PK and safety of DTG-DT (10 mg, scored) in term neonates (birth weights ≥2kg). Stage 1 was designed to assess single doses of DTG on top of standard ARV prophylaxis to inform a multi-dose strategy in Stage 2. In Stage 1, a single 5 mg DTG-DT dose was administered to 8 neonates between ≥14 & <28 days of life (Cohort 1A) followed by intensive PK and safety assessments. After no safety signal was observed, 8 additional neonates received a single 5 mg DTG-DT dose at <14 days of life (Cohort 1B) followed by identical PK and safety assessments. A population PK model was developed using Stage 1 data, and different dosing scenarios were simulated to select the optimal 5 mg DTG multi-dose strategy through 28 days of life [target DTG criteria: geometric mean (GM) C tau >0.67 µg/mL and individual C max <17.0 µg/mL] Results: 16 neonates, 8 per Cohort, completed Stage 1. Median (range) birth weight was 3.1 (2.6-4.2) kg and PK sampling performed between 3 to 22 days of life (Figure a). Single dose DTG C max ranged from 2.0-6.6 µg/mL. No grade ≥3 adverse events (AEs) were reported, and no AEs were related to DTG. One neonate required hospitalization for a skin rash (grade 2). A one-compartment PK model described DTG plasma concentrations, with clearance (CL/F) influenced by weight and postnatal age. DTG CL/F rapidly increased after birth with ~6-fold change between day 1 and 14 of life. Simulations predicted >10% of neonates had a C max >17.0 µg/mL with 5 mg DTG-DT once daily (q24) during the first 2 weeks of life. Administration of 5 mg DTG-DT every 48 hrs (q48) from Day 1 to 14 of life, followed by 5 mg DTG q24 though day 28 day would be an optimal dosing strategy (Figure b) with the predicted C tau between 0.86-4.35 µg/mL and 98% of neonates with a C max <17.0 µg/mL. Conclusion: Single doses of 5 mg DTG-DT were safe in neonates. Due to slow DTG CL/F in early life, 5 mg DTG q24 was not optimal from birth. In Stage 2, the safety and PK of 5 mg DTG q48 for the first 2 weeks of life, followed by q24 through 28 days of life, will be assessed. Both the DTG-DT and the recently approved 5 mg DTG oral dispersible film will be investigated.

Poster Abstracts

CROI 2024 297