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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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Ritonavir, used at low doses as a boosting agent of other protease inhibitors (PIs), is known to be associated with metabolic complications and gastrointestinal disturbances. The rate of accumulation of ritonavir within cells is still debated due to scarce data and methodological limitations. Therefore, our aim was to evaluate intracellular ritonavir penetration when used with different boosted PIs in the clinical setting., Methods: Patients administered with atazanavir/ritonavir (300/100 mg, once daily), darunavir/ritonavir [600/100 mg, twice daily (darunavir-600) and 800/100 mg, once daily (darunavir-800)], lopinavir/ritonavir (400/100 mg, twice daily) and tipranavir/ritonavir (500/200 mg, twice daily) were considered. Blood sampling at the end of the dosing interval (Ctrough) was performed. Peripheral blood mononuclear cell (PBMC)-associated and plasma ritonavir and PI concentrations were measured by validated HPLC methods. PBMC count and individual mean cell volume (MCV) were measured using a Coulter Counter instrument., Results: One hundred patients were enrolled. Frequencies of ritonavir-boosted PIs were atazanavir, 37%; darunavir-600, 23%; lopinavir, 19%; tipranavir, 13%; and darunavir-800, 8%. The median intracellular and plasma concentrations of ritonavir were 1279 ng/mL (IQR 727-2087) and 170 ng/mL (IQR 82-384), respectively, accounting for a cellular accumulation ratio of 7.69 (5.7-10.9). Significant differences in ritonavir intracellular concentrations emerged among different PIs (P<0.001): specifically between darunavir-600 and atazanavir (P<0.001), between darunavir-600 and tipranavir (P=0.009), between atazanavir and lopinavir (P<0.001) and between lopinavir and tipranavir (P=0.027)., Conclusions: Our study showed a higher rate of ritonavir intracellular accumulation than previously reported, possibly due to the more accurate calculation of intracellular concentrations by MCV. The ratio varied according to concomitantly administered PIs, suggesting their influence on the rate of ritonavir intracellular penetration.