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J Antimicrob Chemother. 2017 Feb;72(2):490-495. doi: 10.1093/jac/dkw444. Epub 2016 Oct 24.

Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.

Author information

1
EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France naim.bouazza@aphp.fr.
2
Unité de Recherche Clinique Necker Cochin, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
3
CIC-1419 Inserm, Paris, France.
4
Program for HIV Prevention and Treatment (PHPT/IRD UMI 174), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
5
Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
6
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
7
EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
8
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
9
Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
10
HIV Department, World Health Organization, Geneva, Switzerland.
11
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
12
University of California San Diego, La Jolla, CA, USA.

Abstract

BACKGROUND:

Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children.

METHODS:

Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets.

RESULTS:

The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target.

CONCLUSIONS:

According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population.

PMID:
27798221
DOI:
10.1093/jac/dkw444
[Indexed for MEDLINE]

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