Urinary recovery and kinetics of sulphamethoxazole and its metabolites in HIV-seropositive patients and healthy volunteers after a single oral dose of sulphamethoxazole.

1. The urinary excretion of sulphamethoxazole and its metabolites was compared between healthy volunteers and HIV-seropositive patients in order to get a better understanding of why HIV seropositives are more predisposed to idiosyncratic toxicity of sulphonamides. 2. A single 800 mg oral dose of sulphamethoxazole was administered to seven healthy volunteers and seven asymptomatic HIV seropositives without previous use of sulphonamides. 3. Urine was collected for 4 days and drug analysis was by h.p.l.c. 4. No difference was observed between seropositive and seronegative individuals in the urinary recovery of sulphamethoxazole, N4-acetyl-, 5-hydroxy-, N4-acetyl-5-hydroxy-sulphamethoxazole and the N1-glucuronide conjugate. However the recovery of the hydroxylamine metabolite of sulphamethoxazole was significantly lower in the HIV seropositives (0.50 +/- 0.51 vs 2.23 +/- 0.85%; 95% CI on the difference, -0.90 to -2.55; P = 0.0006). 5. Sulphamethoxazole hydroxylamine may be a factor in the susceptibility of HIV infected individuals to sulphonamides

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling. Methods Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C-trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis. Results A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)(0-24h) was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C-trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure. Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data

International Interlaboratory Quality Control Program for Measurement of Antiretroviral Drugs in Plasma

An international interlaboratory quality control program for measurement of antiretroviral drugs was initiated. The first round was confined to protease inhibitors and showed large variability in the performance of participating laboratories. The results demonstrate the need for and utility of an ongoing quality control program in this area of bioanalysis