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Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children,
Hardik Chandasana1, Mita Thapar2, Siobhan Hayes2
1Clinical Pharmacology, Modeling and Simulation, GSK, 1250 South Collegeville Road, Collegeville, PA, 19406, USA. hardik.x.chandasana@gsk.com.
Insights
Dolutegravir dosing for children aged 4 weeks and older achieves adult-like HIV-1 exposure levels. This weight-banded dosing strategy is safe and effective, supporting current World Health Organization recommendations for pediatric HIV treatment.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Infectious Diseases
- Antiretroviral Therapy
Background:
- Pediatric HIV treatment options are limited.
- Dolutegravir is an effective integrase inhibitor for adults and children.
- Dosing optimization is crucial for pediatric populations.
Purpose of the Study:
- To characterize dolutegravir pharmacokinetics in children.
- To evaluate the impact of covariates on dolutegravir exposure.
- To support age/weight-banded dosing recommendations for pediatric HIV patients.
Main Methods:
- Population pharmacokinetic modeling using data from P1093 and ODYSSEY trials.
- Simulation of dolutegravir exposures across weight bands, doses, and formulations.
- Exploratory exposure-safety analyses correlating pharmacokinetic parameters with clinical data.
Main Results:
- A one-compartment model predicted dolutegravir concentrations in pediatric participants.
- Predicted trough concentrations were comparable to adult values across weight bands.
- Body weight, age, and formulation significantly influenced dolutegravir pharmacokinetics.
- No correlation found between dolutegravir exposure and safety endpoints.
Conclusions:
- Age/weight-banded dolutegravir dosing provides comparable exposures to adults in children.
- Higher pharmacokinetic variability was observed in the pediatric population without additional safety concerns.
- Results support current World Health Organization recommendations for weight-banded dolutegravir dosing in children.
Background And Objective:
HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated.
Methods:
A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events.
Results:
A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events.
Conclusions:
The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization.
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