| Popis: |
Treatment of HIV and tuberculosis co-infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug-drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO-revised doses of rifampin (15 mg/kg daily).Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P-glycoprotein inhibition and induction.Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group.Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age).Exposure following super-boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated.Simulated parameters were within twofold observations for LPV, RTV, and rifampin in adults and children ≥2 weeks old. The model predicted that, in healthy adults receiving 400/100 mg oral LPV/RTV twice daily (BID), co-treatment with 600 mg oral rifampin daily decreased the steady-state area under the concentration vs. time curve of LPV by 79%, in line with the observed change of 75%. Simulated and observed concentration profiles were comparable for LPV/RTV (230/57.5 mg/mSuper-boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB-infected simulated children. |
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