Diana F Clarke1, Jos Lommerse2, Edward P Acosta3, Mae P Cababasay4, Jiajia Wang4, Stephen A Spector5,6, Anne Chain7, Elizabeth Smith8, Hedy Teppler7, Rohan Hazra9, Kat Calabrese10, Bobbie Graham11, Stephanie Popson11, Yvonne Bryson12, Mark Mirochnick13. 1. Section of Pediatric Infectious Diseases, Boston Medical Center, Boston, MA. 2. Modeling and Simulations, Certara Strategic Consulting, Oss, The Netherlands. 3. Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL. 4. Department of Biostatistics, Statistical and Data Analysis Center, Harvard T.H. Chan School of Public Health, Boston, MA. 5. Department of Pediatrics, University of California, San Diego, La Jolla, CA. 6. Division of Pediatric Infectious Diseases, Rady Children's Hospital San Diego, CA. 7. Quantitative Pharmacology, Merck & Co., Inc., Kenilworth, NJ. 8. Maternal, Adolescent, and Pediatric Research Branch, Division of AIDS, National Institute of Health, Bethesda, MD. 9. Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD. 10. Clinical Research, FHI 360, Durham, NC. 11. Frontier Science Foundation, Amherst, NY. 12. Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA; and. 13. Department of Pediatrics, Boston University School of Medicine, Boston, MA.
Abstract
BACKGROUND: HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict raltegravir plasma concentrations for term and preterm neonates. METHODS: Mothers living with HIV who received raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal raltegravir plasma concentrations. RESULTS: Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants. CONCLUSIONS: Modeling suggests that prematurity reduces raltegravir clearance and a modified raltegravir dosing regimen will be necessary to avoid elevated plasma raltegravir concentrations.
BACKGROUND: HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict raltegravir plasma concentrations for term and preterm neonates. METHODS: Mothers living with HIV who received raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal raltegravir plasma concentrations. RESULTS: Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants. CONCLUSIONS: Modeling suggests that prematurity reduces raltegravir clearance and a modified raltegravir dosing regimen will be necessary to avoid elevated plasma raltegravir concentrations.
Authors: Diana F Clarke; Ronald J Wong; Larissa Wenning; David K Stevenson; Mark Mirochnick Journal: Pediatr Infect Dis J Date: 2013-09 Impact factor: 2.129
Authors: Diana F Clarke; Edward P Acosta; Matthew L Rizk; Yvonne J Bryson; Stephen A Spector; Lynne M Mofenson; Edward Handelsman; Hedy Teppler; Carolee Welebob; Deborah Persaud; Mae P Cababasay; JiaJia Wang; Mark Mirochnick Journal: J Acquir Immune Defic Syndr Date: 2014-11-01 Impact factor: 3.731
Authors: Diana F Clarke; Mark Mirochnick; Edward P Acosta; Edmund Capparelli; Anne Chain; Hedy Teppler; Betsy Smith; Jos Lommerse Journal: J Acquir Immune Defic Syndr Date: 2019-12-01 Impact factor: 3.731