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Prediction of dolutegravir pharmacokinetics and dose optimization in neonates via physiologically based
Fazila Bunglawala1, Rajith K R Rajoli1, Mark Mirochnick2
1Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK.
Insights
Dolutegravir dosing for newborns was simulated using a pharmacokinetic model. A 5mg dose every 48 hours for the first three weeks may provide effective HIV treatment and prophylaxis in neonates.
Area of Science:
- Pharmacology
- Neonatal Medicine
- HIV Research
Background:
- Limited antiretroviral drugs (ARVs) are approved for neonatal use, necessitating expanded treatment and prophylaxis options.
- Dolutegravir, an integrase inhibitor, shows promise for neonatal HIV treatment and transmission prophylaxis.
Purpose of the Study:
- To develop a pharmacokinetic model for dolutegravir in neonates.
- To simulate an optimal dolutegravir dosing regimen for this population.
Main Methods:
- A physiologically based pharmacokinetic (PBPK) model was constructed, accounting for neonatal age-related physiological changes.
- Virtual neonates (0-28 days) were simulated.
- The PBPK model was validated using existing raltegravir and midazolam neonatal data.
Main Results:
- The validated PBPK model accurately predicted neonatal pharmacokinetics.
- Simulated dolutegravir regimens showed exposures comparable to those in pediatric patients.
- A regimen of 5mg every 48 hours for the first 20 days, followed by 5mg daily, yielded target plasma concentrations.
Conclusions:
- The neonatal PBPK model successfully simulated dolutegravir pharmacokinetics.
- A 5mg every 48-hour dosing regimen during the first three weeks of life appears to achieve adequate plasma exposures for neonatal HIV therapy and prophylaxis.
Background:
Only a few antiretroviral drugs (ARVs) are recommended for use during the neonatal period and there is a need for more to be approved to increase treatment and prophylaxis strategies. Dolutegravir, a selective integrase inhibitor, has potential for treatment of HIV infection and prophylaxis of transmission in neonates.
Objectives:
To model the pharmacokinetics of dolutegravir in neonates and to simulate a theoretical optimal dosing regimen.
Methods:
The physiologically based pharmacokinetic (PBPK) model was built incorporating the age-related changes observed in neonates. Virtual neonates between 0 and 28 days were simulated. The model was validated against observed clinical data for raltegravir and midazolam in neonates, prior to the prediction of dolutegravir pharmacokinetics.
Results:
Both raltegravir and midazolam passed the criteria for model qualification, with simulated data within 1.8-fold of clinical data. The qualified model predicted the pharmacokinetics for several multidose regimens of dolutegravir. Regimen 6 involved 5 mg doses with a 48 h interval from Day 1-20, increasing to 5 mg once daily on Week 3, yielding AUC and Ctrough values of 37.2 mg·h/L and 1.3 mg/L, respectively. These exposures are consistent with those observed in paediatric patients receiving dolutegravir.
Conclusions:
Dolutegravir pharmacokinetics were successfully simulated in the neonatal PBPK model. The predictions suggest that during the first 3 weeks of life a 5 mg dose administered every 48 h may achieve plasma exposures needed for therapy and prophylaxis.
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