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Darunavir Dosing Determined for Naive and Experienced Children and Teens
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14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Two 48-week trials established darunavir/ritonavir doses for antiretroviral-naive and experienced children and adolescents by yielding exposures equivalent to those recorded in adults [1].
The DELPHI trial explored twice-daily darunavir/ritonavir dosing in antiretroviral-experienced youngsters from 6 to under 18 years old [2]. To further inform darunavir/ritonavir dosing in experienced and naive children and adolescents, Janssen researchers conducted the phase 2, open-label, single-arm, 48-week ARIEL and DIONE trials [3], the first in experienced children 3 to under 6 and the second in 12- to 18-year-olds with no antiretroviral experience.
One aim of both studies was to achieve a darunavir area under the concentration-time curve (AUC) range within 80% to 130% of that recorded in adults, that is, 62.3 ug x h/mL for twice-daily dosing and 89.7μg x h/mL for once-daily dosing. The Janssen team used modeling and simulation to figure once-daily dosing recommendations for children 6 to under 12 years old.
ARIEL involved antiretroviral-experienced children 3 to under 6 years old who weighed 10 to under 20 kg. First they received twice-daily darunavir/ritonavir at a dose of 20/3 mg/kg plus at least two other active antiretrovirals. After 24 weeks children could join a substudy assessing once-daily darunavir/ritonavir at 40/7 mg/kg in children under 15 kg and at 600/100 mg in children weighing 15 kg or more. After 2 weeks of pharmacokinetic assessment, children returned to twice-daily dosing.
Twice-daily darunavir/ritonavir at 20/3 mg/kg yielded the following darunavir geometric means (and standard deviations), which were equivalent to twice-daily exposure in adults with antiretroviral experience:
Overall AUC12h: 63.8 (26.7) ug x h/mL (n = 19); 106% of adult AUC12h
Children 10 to <15 kg AUC12h: 65.5 (25.7) ug x h/mL (n = 10); 109% of adult AUC12h
Children 15 to <20 kg AUC12h: 62.1 (29.4) ug x h/mL (n = 9); 103% of adult AUC12h
After week 2, when the researchers adjusted the dose to 25/3 mg/kg twice daily for children under 15 kg and to 375/50 mg twice daily for children 15 to under 20 kg, darunavir exposure increased to levels higher than those seen in adults:
Overall AUC12h: 78.5 (25.1) ug x h/mL (n = 19); 136% of adult AUC12h
Children 10 to <15 kg AUC12h: 89.1 (20.7) ug x h/mL (n = 5); 148% of adult AUC12h
Children 15 to <20 kg AUC12h: 75.1 (26.4) ug x h/mL (n = 14); 125% of adult AUC12h
In the once-daily dosing substudy of 10 children, darunavir mean AUC24h was 115 (40.6) ug x h/mL, which was 128% of the adult AUC24h with once-daily dosing.
In DIONE, the study of once-daily darunavir/ritonavir at 800/100 mg once daily in 12 antiretroviral-naive adolescents 12 to under 18, 24-week darunavir geometric mean AUC24h stood at 80.7 (23.6) ug x h/mL, equivalent to 90% of the adult AUC24h in previously untreated adults.
The investigators found no apparent relationships between darunavir AUC and log-change in viral load in either ARIEL or DIONE. Nor did they find relationships between darunavir AUC and adverse events of interest in either study.
Recommended darunavir/ritonavir doses in the United States are as follows:
Antiretroviral-experienced children 3 to under 6:
10 to under 15 kg: 20/3 mg/kg twice daily
15 to under 20 kg: 375/50 mg twice daily
Antiretroviral-experienced children 6 to under 18:
20 to under 30 kg: 375/50 mg twice daily
30 to under 40 kg: 450/60 mg twice daily
40 kg or more: 600/100 mg twice daily
Antiretroviral-naive children 3 to under 12:
10 to under 15 kg: 35/7 mg/kg once daily
15 to under 30 kg: 600/100 mg once daily
30 to under 40 kg: 675 to 100 mg once daily
Antiretroviral-naive adolescents 12 to under 18:
40 kg or more: 800/100 mg once daily
References
1. Kakuda TN, Brochot A, van de Casteele T, Opsomer M, Tomaka F. Establishing darunavir dosing recommendations in treatment-naive and treatment-experienced pediatric patients. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_13.
2. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS. 2009;23:2005-2013. http://www.ncbi.nlm.nih.gov/pubmed/19724191
3. Flynn P, Blanche S, Giaquinto C, et al. DIONE--24 week efficacy, safety, tolerability and pharmacokinetics of DRV/r QD in treatment-naive adolescents, 12 to <18 years. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Rome, July 17-20, 2011. Abstract WEPDB0101. http://www.natap.org/2011/IAS/IAS_40.htm
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