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Aims: This prospective study aimed to develop a population pharmacokinetics (PK) model of hydroxyurea (HU) in patients with sickle cell disease. This model can be used to determine the impact of glomerular filtration rate (GFR) on HU kinetics., Methods: We included 30 patients. They underwent HU pharmacokinetics analyses of plasma and urine. Six underwent PK analyses in 2 periods with and without angiotensin-converting enzyme inhibitor. HU was assayed with a validated high-performance liquid chromatography-UV method. Noncompartmental PK analysis was conducted and a population PK model built with Monolix. This model was validated externally on another 56 patients. HU PK was simulated as a function of GFR., Results: The HU PK model was constructed as a 2-compartment model with first-order absorption and elimination. The quality criteria were good, including for external validation. We found that estimated GFR (eGFR) and body weight affected HU PK, with lower eGFR or body weight associated with a higher HU area under the curve. We recommend the monitoring of HU through eGFR and body weight, which together account for 47% of its variability. Urinary HU fractions and renal clearance were higher in the glomerular hyperfiltration group and lower in the moderate chronic kidney disease group, respectively. No differences in nonrenal HU clearance were observed., Conclusion: Estimated GFR has an impact on the kinetics of hydroxyurea, and HU dose should be adapted accordingly. Angiotensin-converting enzyme inhibitor seems to have minor effect on HU PK in adults with sickle cell disease., (© 2020 British Pharmacological Society.)

Aims: A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole [sulfamethoxazole (SMX) and trimethoprim (TMP)] advised by the WHO., Methods: Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/40 mg of TMP once daily). A nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Factors that could impact the pharmacokinetic profile were investigated. The model was subsequently used to simulate individual exposure and evaluate different administration schemes., Results: The cohort comprised 136 children [average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3])]. A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetics. SMX and TPM clearance were estimated at 0.49 l h -1 /9.5 kg and 3.06 l h -1 /9.5 kg, respectively. The simulated exposures obtained after administration of oral dosing recommended by the WHO for children from 10 to 15 kg were significantly lower than in adults for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg kg -1 of SMX and 6 mg kg -1 of TMP in the 5-10 kg group and 25 mg kg -1 of SMX and 5 mg kg -1 of TMP in the 10-15 kg group are more suitable doses., Conclusions: In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed., (© 2017 The British Pharmacological Society.)

Aims: Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively., Methods: Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models., Results: Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo., Conclusion: The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics., (© 2015 The British Pharmacological Society.)