Julia C Rosebush1, Brookie M Best2, Ellen G Chadwick3, Kevin Butler4, John Moye5, Elizabeth Smith6, Sarah Bradford7, Christina A Reding8, Sisinyana R Mathiba9, Sherika Hanley10, Mariam Aziz11, James Homans12, Edward P Acosta13, William Murtaugh14, Manoli Vourvahis15, Lynn Mcfadyen16, Katy Hayward17, Mark Mirochnick18, Pearl Samson4,8. 1. University of Chicago, Chicago, Illinois. 2. University of California San Diego, La Jolla, California. 3. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 4. Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 5. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda. 6. Division of AIDS, National Institute of Allergy and Infectious Diseases, Rockville, Maryland. 7. FHI 360, Durham, North Carolina. 8. Frontier Science & Technology Research Foundation, Inc., Amherst, New York, USA. 9. Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg. 10. Centre for the AIDS Programme in South Africa, University of KwaZulu-Natal, Durban, South Africa. 11. Rush University Medical Center, Chicago, Illinois. 12. University of Southern California, Los Angeles, California. 13. Deparment of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama. 14. IMPAACT Laboratory Center, Children's Hospital of Los Angeles, Los Angeles, California. 15. Clinical Pharmacology, Pfizer Global Research and Development, New York, New York, USA. 16. Pharmacometrics, Pfizer Global Research and Development, Sandwich, UK. 17. ViiV HealthCare, Research Triangle Park, North Carolina. 18. Boston University, Boston, Massachusetts, USA.
Abstract
OBJECTIVE: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life. DESIGN: A phase I, multicentre, open-label study enrolling two sequential cohorts. METHODS: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety. RESULTS: Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17-33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred. CONCLUSION: Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.
OBJECTIVE: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life. DESIGN: A phase I, multicentre, open-label study enrolling two sequential cohorts. METHODS: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety. RESULTS: Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17-33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred. CONCLUSION: Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.
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