Helena Rabie1, Holly Rawizza2, Peter Zuidewind1, Jana Winckler3, Heather Zar3, Annelies Van Rie4,5, Lubbe Wiesner6, Helen McIlleron6. 1. Department of Paediatrics and Child Health and Children's Infectious Diseases Clinical Research Unit, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa. 2. Brigham and Women's Hospital, Harvard Medical School, Boston, USA. 3. Department of Paediatrics and Child Health, and Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa. 4. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 5. International Health Unit, Epidemiology and Social Medicine, Faculty of Medicine, University of Antwerp, Antwerp, Belgium. 6. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Abstract
OBJECTIVES: To evaluate the proportion of children with lopinavir Cmin ≥1 mg/L when receiving a novel 8-hourly lopinavir/ritonavir dosing strategy during rifampicin co-treatment. METHODS: HIV-infected children on lopinavir/ritonavir and rifampicin were enrolled in a prospective pharmacokinetic study. Children were switched from standard-of-care lopinavir/ritonavir-4:1 with additional ritonavir (1:1 ratio) twice daily to 8-hourly lopinavir/ritonavir-4:1 using weight-banded dosing. Rifampicin was dosed at 10-20 mg/kg/day. After 2 weeks, plasma samples were collected ∼2, 4, 6, 8 and 10 h after the morning lopinavir/ritonavir-4:1 dose, ALT was obtained to assess safety and treatment was switched back to standard of care. ClinicalTrials.gov registration number: NCT01637558. RESULTS: We recruited 11 children in two weight bands: 5 (45%) were 10-13.9 kg and received 20-24 mg/kg/dose of lopinavir and 6 (55%) children weighed 6-9.9 kg and received 20-23 mg/kg/dose of lopinavir. The median age was 15 months (IQR = 12.6-28.8 months). The median (IQR) lopinavir Cmin was 3.0 (0.1-5.5) mg/L. Seven (63.6%) of the 11 children had Cmin values ≥1 mg/L. Children with a lopinavir mg/kg dose below the median 21.5 were more likely to have Cmin <1 mg/L (P = 0.02). There was a strong positive correlation between lopinavir and ritonavir concentrations. No associations were found between lopinavir AUC2-10 and age, sex, weight, nutritional status or mg/kg/dose of lopinavir. CONCLUSIONS: These data do not support the use of 8-hourly lopinavir/ritonavir at studied doses. Evaluation of higher doses is needed to optimize treatment outcomes of TB and HIV in young children.
OBJECTIVES: To evaluate the proportion of children with lopinavir Cmin ≥1 mg/L when receiving a novel 8-hourly lopinavir/ritonavir dosing strategy during rifampicin co-treatment. METHODS:HIV-infectedchildren on lopinavir/ritonavir and rifampicin were enrolled in a prospective pharmacokinetic study. Children were switched from standard-of-care lopinavir/ritonavir-4:1 with additional ritonavir (1:1 ratio) twice daily to 8-hourly lopinavir/ritonavir-4:1 using weight-banded dosing. Rifampicin was dosed at 10-20 mg/kg/day. After 2 weeks, plasma samples were collected ∼2, 4, 6, 8 and 10 h after the morning lopinavir/ritonavir-4:1 dose, ALT was obtained to assess safety and treatment was switched back to standard of care. ClinicalTrials.gov registration number: NCT01637558. RESULTS: We recruited 11 children in two weight bands: 5 (45%) were 10-13.9 kg and received 20-24 mg/kg/dose of lopinavir and 6 (55%) children weighed 6-9.9 kg and received 20-23 mg/kg/dose of lopinavir. The median age was 15 months (IQR = 12.6-28.8 months). The median (IQR) lopinavir Cmin was 3.0 (0.1-5.5) mg/L. Seven (63.6%) of the 11 children had Cmin values ≥1 mg/L. Children with a lopinavir mg/kg dose below the median 21.5 were more likely to have Cmin <1 mg/L (P = 0.02). There was a strong positive correlation between lopinavir and ritonavir concentrations. No associations were found between lopinavir AUC2-10 and age, sex, weight, nutritional status or mg/kg/dose of lopinavir. CONCLUSIONS: These data do not support the use of 8-hourly lopinavir/ritonavir at studied doses. Evaluation of higher doses is needed to optimize treatment outcomes of TB and HIV in young children.
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