Tim R Cressey1, Baralee Punyawudho, Sophie Le Coeur, Gonzague Jourdain, Chalermpong Saenjum, Edmund V Capparelli, Kanokwan Jittayanun, Siriluk Phanomcheong, Anita Luvira, Thitiporn Borkird, Achara Puangsombat, Leon Aarons, Pra-Ornsuda Sukrakanchana, Saik Urien, Marc Lallemant. 1. *PHPT/IRD 174, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; †Department of Immunology and Infectious Diseases, Harvard T.H Chan School of Public Health, Boston, MA; ‡Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom; §Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand; ‖Institut d'Etudes Démographiques, Paris, France; ¶Institut de Recherche pour le Développement (IRD) UMI 174-PHPT, Marseille, France; #Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand; **Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA; ††Department of Pediatric, Health Promotion Center Region 10, Chiang Mai, Thailand; ‡‡Department of Pediatric, Banglamung Hospital, Chonburi, Thailand; §§Department of Pediatric, Nopparat Rajathanee Hospital, Bangkok, Thailand; ‖‖Department of Pediatric, Hat Yai Hospital, Hat Yai, Thailand; ¶¶Department of Pediatric, Samutprakarn Hospital, Samut Prakan, Thailand; ##Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom; and ***EAU7323 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Abstract
BACKGROUND: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates. METHODS: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies. RESULTS: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks. CONCLUSION: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.
BACKGROUND:Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates. METHODS: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies. RESULTS: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks. CONCLUSION: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.
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