WB-PBPK Approach in Predicting Zidovudine Pharmacokinetics in Preterm Neonates

Liuya Wei, Najia Mansoor, Rafeeq Alam Khan, Martin Czejka, Tasneem Ahmad, Mansoor Ahmed, Mohsin Ali, Dong-Hua Yang
Biopharmaceutics & Drug Disposition 2019 November 6
Antiretroviral therapy has been the main stay of treatment of neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for treatment of HIV has been approved for the use in preterm neonates both prophylactically and therapeutically. The present work shows whole body physiologically based pharmacokinetic (WB-PBPK) WB-PBPK model development for Zidovudine in preterm neonates of varying gestational ages to observe the pharmacokinetic behavior of the drug in this vulnerable group of population. Along with the height, weight, post-natal and gestational ages of the preterm neonates; metabolic enzymes CYP2A6, CYP2C8 etc. were incorporated in each neonate. Different organs' composition in terms of water and lipid components, blood flow rates etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 μmol·min/l, Cmax 6.46 ± 0.74 μmol/l, half-life 8.98 ± 2.36 h, Mean residence time 12.23 ± 3.43 h and total plasma clearance 1.48 ± 0.19 ml /min/kg in comparison to the observed PK parameters of Mirochknic clinical study in preterm neonates with AUC 2020.04 μmol· min/l, Cmax 6.10 μmol/l and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational age on the pharmacokinetic behavior of zidovudine in preterm neonates.

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