UGT1A1 genotyping was an optional evaluation in this study and was obtained for 17 of 22 infants enrolled. Of the 17 infants with UGT1A1 genotyping, pharmacokinetic evaluations were performed on 16 infants. Eight infants (47.1%) were (TA)6/(TA)6 homozygotes, 7 (41.2%) were (TA)6/(TA)7 heterozygotes, 1 (5.9%) was a (TA)5/(TA)6 heterozygote, and 1 (5.9%) was a (TA)7/(TA)7 homozygote. There were no differences in median raltegravir concentrations at any time point or in elimination t1/2 when the (TA)6/(TA)6 infants were compared with the infants with other 3 UGT1A1 genotypes.
Five (22.7%) infants had grade 3 or 4 laboratory events (total bilirubin, creatinine, hemoglobin, neutrophil count, and glucose), 2 (9.1%) had grade 3 or 4 signs and symptoms (fever and neonatal respiratory discomfort), and 1 (4.6%) had a grade 3 or 4 diagnosis (metabolic/endocrine disorder). There was 1 (4.6%) infant with low birth weight (2200 g). No infant death or still birth was reported. None of the adverse events reported in infants were determined to be related to maternal raltegravir use. Only 1 infant received phototherapy for the treatment of hyperbilirubinemia. This infant was heterozygous (TA)6/(TA)7 and had a raltegravir t1/2 of 75.4 hours. None of the infants received an exchange transfusion therapy.
Previously published data on peripartum raltegravir pharmacokinetics are limited to several case reports describing cord blood and maternal delivery raltegravir concentrations in a total of 7 term and preterm infants.9–11 Although these reports suggest that raltegravir readily crosses the placenta, they provide limited data describing the postnatal elimination of transplacentally acquired raltegravir in the infant. One preterm infant has been described as having raltegravir concentrations present 1 month after delivery, suggesting very prolonged elimination.11
This study, to the best of our knowledge, is the first to describe the elimination of transplacentally acquired raltegravir in infants. In this study, we found that raltegravir readily crossed the placenta so that by 3 hours after maternal dosing, the umbilical cord raltegravir concentration equaled or exceeded the maternal plasma concentration at the time of delivery. In the first 12–24 hours after delivery, raltegravir concentrations increased in almost half of the study infants, although they received no postnatal raltegravir doses. Once raltegravir concentrations started to decline, the rate of elimination was highly variable. Although several of our subjects had elimination t1/2 in the range similar to that reported in adults (7–12 hours), most demonstrated very slow elimination, with the longest t1/2 being 184 hours.5 As a result of the excellent placental transport and slow neonatal elimination of raltegravir, infant raltegravir concentrations remained above the IC95 (14 ng/mL) for wild-type HIV through 30–36 hours after delivery, the time of collection of the last sample, in all but one of the study infants.
A limitation of our study is the limited pharmacokinetic sampling time. We did not anticipate that the half-life would be so prolonged and that the plasma concentrations would continue to increase in the absence of raltegravir dosing in some infants. Because these were healthy full-term infants delivered to pregnant women on combination antiretroviral therapy (cART), many were discharged from the hospital within a few days. The study was designed to be completed before discharge from the hospital to not inconvenience the study families. Another limitation of our study is that no raltegravir was directly administered to study neonates, therefore we can provide no data describing neonatal raltegravir absorption. Follow-up IMPAACT studies that are now underway include direct administration of raltegravir to neonates and more extensive pharmacokinetic sampling.
Raltegravir is primarily eliminated through hepatic glucuronidation by UGT1A1 followed by biliary and renal excretion of the glucuronide conjugate.3 Bilirubin is also primarily metabolized by UGT1A1, and its metabolism is known to be slow immediately after birth and to increase dramatically over the first weeks of life. It is therefore not surprising that raltegravir elimination was found to be prolonged in most neonates in the first days of life.6 Genetic variations in the number of TA repeats in the promoter region of the UGT1A1 gene are associated with reduced gene expression and enzyme activity, leading to elevated bilirubin concentrations in the neonate and later in life.12 The wild-type allele (UGT1A1*1) has 6 TA repeats in the promoter of UGT1A1. Alleles with 5 or 7 TA repeats are associated with decreased gene transcription and expression of UGT1A1 and reduced enzyme activity.12 In our small group of infants, no relationship was found between raltegravir concentrations or elimination when infants with the wild-type (TA)6/(TA)6 genotype were compared with those with other UGT1A1 genotypes. It is likely that immaturity of neonatal UGT1A1 enzyme activity accounts for much of the variability in the observed raltegravir pharmacokinetics rather than the infant genotype. The relationship between UGT1A1 genotype and neonatal raltegravir pharmacokinetics and bilirubin metabolism will be explored further in the enrolling IMPAACT follow-up studies.
Nearly half of the study subjects demonstrated an initial increase in the raltegravir concentration over the first 12–24 hours after birth in the absence of any directly administered infant raltegravir dosing. This increase is likely explained by enterohepatic recirculation, where beta-glucuronidase present in the brush border of the fetal and neonatal gut breaks down luminal substrate–glucuronide complexes and allows intestinal reabsorption of the now unconjugated substrates.13 It is likely that immediately after birth when gut motility and raltegravir metabolism are slow, raltegravir glucuronide present in meconium undergoes deconjugation followed by reabsorption of the unconjugated raltegravir resulting in the initial increases in raltegravir plasma concentrations seen in nearly half of the study infants.
In addition to sharing major elimination pathways, raltegravir and bilirubin also compete for plasma albumin-binding sites. Circulating unconjugated bilirubin binds to plasma albumin, so that at low bilirubin concentrations, there is minimal free unbound bilirubin in the circulation. If the unconjugated bilirubin concentration rises above the plasma albumin-binding capacity, then circulating unbound bilirubin is available to cross the blood–brain barrier and cause bilirubin-associated central nervous system toxicity. Administration of a competitor to bilirubin binding to albumin may enhance the potential for bilirubin toxicity by decreasing bilirubin–albumin binding. In the 1950s, administration of sulfisoxazole, which at therapeutic concentrations displaces bilirubin from albumin-binding sites, to low birth weight infants resulted in an increased incidence of kernicterus and mortality.14 Because raltegravir also competes with bilirubin for albumin-binding sites, its use in neonates poses the risk of a similar effect. However, the binding affinity of bilirubin to albumin is much greater that than of raltegravir; and in an in vitro study in neonatal serum, raltegravir was shown to significantly displace bilirubin from albumin only at concentrations 50–100 fold higher than typical therapeutic concentrations.4
Our data suggest that a safe and effective neonatal raltegravir dosing regimen must take into account developmental changes in raltegravir elimination over the first weeks of life. Excessive raltegravir concentrations must be avoided in the neonate, because raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Also, subtherapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must be avoided. Raltegravir administration to preterm infants poses heightened risk of toxicity, because raltegravir and bilirubin elimination are prolonged, plasma albumin binding is reduced, and the blood–brain barrier is more permeable in preterm infants. As a result, administering raltegravir to preterm infants is likely to carry a greater risk of causing central nervous system bilirubin toxicity and should be avoided until raltegravir has been well-studied in term and preterm infants.
Two ongoing IMPAACT studies will investigate the safety of raltegravir administered directly to term infants and washout raltegravir pharmacokinetics in low birth weight infants. IMPAACT P1110 is a dose-finding pharmacokinetic study to evaluate the safety and tolerability of raltegravir oral granules for suspension when administered during the first 6 weeks of life with standard prevention of mother-to-child transmission (PMTCT) antiretroviral (ARV) prophylaxis to HIV-1–exposed infants who are at high risk of HIV infection. P1110 will enroll an initial cohort receiving 2 single doses approximately 1 week apart, followed by a second cohort receiving daily dosing. The study design allows for adjustment of cohort 2 dosing based on analysis of the cohort 1 data. Version 2 of P1097 will investigate raltegravir washout pharmacokinetics in low birth weight infants, and P1110 may be expanded to include low birth weight infants. The goal of these studies is to provide the data necessary to develop regimens that will allow for the safe administration of raltegravir in the first month of life for prevention, treatment, and possibly cure of HIV infection.
The authors acknowledge the expertise of the P1097 protocol team members and thank the women and infants who participated in the protocol and the staff of the participating International Maternal Pediatric Adolescent AIDS Clinical Trials centers. This article is dedicated to Catherine Kneut, PNP, field representative for the protocol, who provided compassionate care for many children with HIV and their families. In addition to the authors, members of the IMPAACT 1097 protocol team include: Elizabeth Hawkins, MA, Social Scientific Systems, Silver Springs, MD; Bobbie Graham, BS, Frontier Science and Technology Research Foundation, Amherst, NY; John Gaeddert, MPH, Frontier Science and Technology Research Foundation, Amherst, NY; Linda Marillo, BA, Frontier Science and Technology Research Foundation, Amherst, NY; Terence Fenton, EdD, Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA; Derek Weibel, BS, Frontier Science and Technology Research Foundation, Amherst, NY; Catherine Kneut, CPNP, MS, Boston Children's Hospital, Boston, MA; Debra McLaud, RN, Boston Medical Center, Boston, MA; Larissa Wenning, PhD, Merck & Co., Inc.,,Whitehouse Station, NJ; Elizabeth Rhee, MD, Merck & Co., Inc., Whitehouse Station, NJ.
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Keywords:© 2014 by Lippincott Williams & Wilkins
raltegravir pharmacokinetics; neonates