Leveraging physiologically based pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients.
Pharmacotherapy
; 43(7): 638-649, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-35607886
ABSTRACT
STUDY OBJECTIVE:
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).DESIGN:
Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P-glycoprotein inhibition and induction. SETTING (OR DATA SOURCE) Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group. PATIENTS Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age). INTERVENTION Exposure following super-boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated. MEASUREMENTS AND MAINRESULTS:
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/m2 ) PO BID without rifampin and 230/230 mg/m2 LPV/RTV PO BID with 10 mg/kg PO daily rifampin in pediatric patients. Sixteen mg/kg of super-boosted LPV (LPV/RTV 11) PO BID with 15 mg/kg PO daily rifampin achieved simulated LPV troughs >1 mg/L in ≥93% of virtual children weighing 3.0-24.9 kg, which was comparable with 10 mg/kg PO daily rifampin.CONCLUSIONS:
Super-boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB-infected simulated children.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
/
Inibidores da Protease de HIV
/
Fármacos Anti-HIV
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Child
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article