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Aims: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV‐1 RNA viral load (VL) during maintenance dual therapy. Methods: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. Results: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow‐up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P =.015). Conclusion: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin. [ABSTRACT FROM AUTHOR]

Aims Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (Ctrough) of MHD (3-35 mg l-1). Methods A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain Ctrough between 3-35 mg l-1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg-1 day-1. Results A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h-1 70 kg-1, 337 l 70 kg-1, 60.7 l and 62.5 l h-1, respectively. Typical values for MHD clearance and distribution volume were 4.11 l h-1 70 kg-1 and 54.8 l 70 kg-1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg-1 day-1 instead of the recommended target maintenance dose (30-45 mg kg-1 day-1) to obtain Ctrough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg-1 day-1 instead of the maximum recommended dose of 60 mg kg-1 day-1. Conclusion This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Anti-angiogenic drugs have been developed as an effective therapeutic strategy for inhibiting tumour growth. However, their pharmacokinetics (PK) and their ligand inhibition properties have not been well characterized. The binding to a circulating target, such as vascular endothelial growth factor (VEGF), makes the PK of these drugs more complex. WHAT THIS STUDY ADDS • The underlying mechanism of disposition of aflibercept, where a saturable and high affinity binding of aflibercept to VEGF was adequately characterized by the Michaelis-Menten approximation of a target-mediated drug distribution model. To our knowledge, this is the first published mechanism-based population PK model for an anti-VEGF drug. AIM Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects. METHODS Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration−time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1. RESULTS The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis-Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day−1 and 0.14 l day−1, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day−1 and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml−1. Interindividual variability of model parameters was moderate, ranging from 13.6% ( Vmax) to 49.8% ( Q). CONCLUSION The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF. [ABSTRACT FROM AUTHOR]