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Raltegravir Pharmacokinetics in Neonates Following Maternal Dosing

Clarke, Diana F. PharmD*; Acosta, Edward P. PharmD; Rizk, Matthew L. PhD; Bryson, Yvonne J. MD§; Spector, Stephen A. MD; Mofenson, Lynne M. MD; Handelsman, Edward MD#; Teppler, Hedy MD; Welebob, Carolee MS; Persaud, Deborah MD**; Cababasay, Mae P. MS††; Wang, JiaJia MS††; Mirochnick, Mark MD‡‡for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1097 Study Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1st, 2014 - Volume 67 - Issue 3 - p 310–315
doi: 10.1097/QAI.0000000000000316
Brief Report: Clinical Science

Abstract: International Maternal Pediatric Adolescent AIDS Clinical Trials P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother–infant pairs were enrolled; evaluable pharmacokinetic data were available from 19 mother–infant pairs. Raltegravir readily crossed the placenta, with a median cord blood/maternal delivery plasma raltegravir concentration ratio of 1.48 (range, 0.32–4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t1/2 26.6 (range, 9.3–184) hours]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate because raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Subtherapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must also be avoided. Two ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials studies are further investigating the pharmacology of raltegravir in neonates.

*Section of Pediatric Infectious Diseases, Boston Medical Center, Boston, MA;

Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL;

Merck & Co., Inc., Whitehouse Station, NJ;

§Department of Pediatric Infectious Diseases, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA;

Department of Pediatrics, University of California, San Diego and Rady Children's Hospital San Diego, La Jolla, CA;

Eunice Kennedy Shriver National Institute of Child Health and Human Development,

#Division of AIDS, National Institute of Health, Bethesda, MD;

**Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD;

††Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA; and

‡‡Department of Pediatrics, Boston University School of Medicine, Boston, MA.

Correspondence to: Diana F. Clarke, PharmD, Section of Pediatric Infectious Diseases, Department of Pediatrics, Boston University School of Medicine/Boston Medical Center, 670 Albany Street, 6th Floor, Boston, MA 02118 (e-mail:

Supported by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT). Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632); and the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number: N01-DK-9-001/HHSN267200800001C).

H.T., M.L.R., and C.W. are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, and may own stock and/or stock options in the company. The remaining authors have no conflicts of interest to disclose.

Presented in part at the 13th International Workshop on Clinical Pharmacology of HIV Therapy, April, 16–18, 2012, Barcelona, Spain [Abstract O_22; Raltegravir pharmacokinetics and safety in neonates: Washout PK of transplacental RAL (IMPAACT P1097)], and abstract presented at Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta, GA (Raltegravir Pharmacokinetics and Safety in Neonates: IMPAACT P1097, 2013).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Received April 06, 2014

Accepted July 17, 2014

© 2014 by Lippincott Williams & Wilkins