Model-based prediction of Dolutegravir dose requirement for HIV exposed neonates in Uganda

Abstract

Introduction: Mother-to-child transmission of HIV is the primary source of HIV infections in children, especially in low-income countries accounting for 14% of all new infections in Uganda. It is recommended that HIV-exposed newborns be given prophylactic antiretroviral therapy for their first 6 weeks of life to mitigate mother-to-child HIV transmission. However, due to limited safety and pharmacokinetics data, only a few antiretroviral drugs are approved for use in neonates leaving them with very few options. Dolutegravir-based regimens have been adopted as preferred first-line regimens in many countries including Uganda. However, pediatric dolutegravir dosing recommendations are optimized for only those above 4 weeks of age weighing at least 3kg. This leaves out neonates below this age/weight. Aim: To predict weight band-based dosing of dolutegravir for neonates at risk of HIV infection in Uganda. Methods: This was a prospective pharmacokinetics study that involved infants and children aged 0 to <3 years taking dolutegravir-based regimens at Baylor College of Medicine Children’s Foundation Uganda. Twenty study participants were included in this study. Blood samples were taken at pre-dose and 3,6,8 and 24 hours post-drug administration at different dosing occasions. Dolutegravir plasma concentrations were measured using the liquid chromatography-mass spectrometry bioanalytical quantification method. The data was formatted into a NONMEM data file using R. A population pharmacokinetics model for dolutegravir was built using the nonlinear mixed-effects modeling approach and used to predict the Ctrough and AUC. The final population pharmacokinetics model was used to simulate the Ctrough concentrations of a virtual neonatal population at different dosing schedules. The dose that achieved a geometric mean Ctrough with in the target ranges was selected as the optimal. Results: The data from the study participants was adequately described by a one-compartment model with first-order absorption. The model estimated an absorption rate constant of 0.117 (95% CI 0.073-0.161) hr-1, clearance of 1.2 (95% CI 0.879-1.521) L/h, volume of distribution of 6.25 (95% CI 2.232-10.268) L. The predicted Ctrough and AUC were within the target ranges for dolutegravir efficacy. The 2.5 mg dose twice daily tested in the virtual neonates gave a geometric mean Ctrough within the target limits. Conclusions: The 2.5 mg dose of dolutegravir given twice daily is required by Ugandan HIV-Exposed neonates for prevention of HIV infection.