Jos Lommerse (1), Diana F Clarke (2), Edward P Acosta (3) Hedy Teppler (4), Anne Chain (4), Betsy Smith (5), Mark Mirochnick (6) and the IMPAACT P1097 Protocol Team
(1) Certara Strategic Consulting, Oss, The Netherlands, (2) Section of Pediatric Infectious Diseases, Boston Medical Center, Boston, MA, USA (3) Division of Pharmacology, University of Alabama at Birmingham, Birmingham, AL, USA, (4) Merck & Co., Inc., Whitehouse Station, NJ, USA, (5) Division of AIDS, National Institute of Health, Bethesda, MD, USA, (6) Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA,
Introduction: Raltegravir, a potent antiretroviral agent, is the only HIV integrase strand transfer inhibitor approved for use in full term infants. Many infants born to mothers living with HIV are low birth weight and/or premature and clinicians are eager to extend raltegravir use to preterm neonates to prevent and/or treat HIV infection. The raltegravir oral granule formulation is scalable and can provide accurate small doses suitable for use in premature infants. However, the pharmacokinetics and safety of raltegravir have not been studied in premature neonates.
Raltegravir is metabolized by uridine 5′-diphospho-glucuronyltransferase 1A1 isoform (UGT-1A1), known to have very low activity at birth which increases dramatically during the first few weeks of life [1,2]. The elimination characteristics of raltegravir are unknown for preterm neonates. Extremely high plasma raltegravir concentrations may displace bilirubin from albumin, potentially leading to brain injury [3].
A PK analysis was carried out using washout data from preterm neonates born to mothers who received raltegravir during pregnancy. An integrated mother-full term neonate population PK model [2] was adjusted to account for reduced raltegravir metabolism in preterm neonates. The new model was verified using observed PK data from two preterm infant therapeutic drug monitoring case reports.
Objectives: To revise the current mother-full term neonate population PK model for preterm neonates and simulate raltegravir exposures in preterm neonates receiving the FDA approved term neonate raltegravir dosing regimen, scaled for body weight.
Methods: The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1097 study [4] provided raltegravir PK washout modeling data for 36 mother-neonate pairs. Full term neonates were defined as having a gestational age (GA) of 38 weeks or more (n=15 neonates), preterm neonates GA less than 35 weeks (n=6) and other neonates as late-preterm (35-≤37 weeks GA, n=15). Neonatal plasma samples were collected at 1–6, 12–24, 36–48, 72–84 and 108–132 hrs and 7-14 days after birth.
Activity of the glucuronyl transferases UGT-2B71 (for zidovudine) and UGT1A1 (for bilirubin) have been shown to increase more slowly in preterm compared to term neonates [5,6]. Therefore, the integrated mother-term neonate population raltegravir PK model was adjusted to account for reduced clearance in preterm and late-preterm neonates using a gestational age dependent covariate on the clearance maturation rate. The new model was fitted against all available neonatal data [2], including the preterm neonatal washout data.
Results: The new model predicted slower raltegravir clearance maturation in preterm neonates compared to full term neonates. E.g. the extent of maturation in a 5-week old full term neonate was predicted to be 66% of being fully matured. In a 5-week old preterm neonate this was predicted to be 20% only.
The washout data did not provide information about clearance beyond 13 days or oral absorption in preterm neonates. Estimates for the PK parameters in preterm neonates were extrapolated using information of full term neonates. To assess the accuracy of the new model in predicting raltegravir PK of preterm neonates with oral dosing spanning several weeks of life, the new model was verified against 2 literature-reported case reports [7,8] by simulation. Oral absorption and extrapolation of predictions to several weeks of life were shown to be sufficiently well characterized.
Use of the FDA approved dosing regimen for full-term neonates was simulated using the preterm neonate model. The simulated raltegravir preterm doses were scaled to provide the mg per kg doses approved for term infants. These simulations predicted excessive and potentially dangerous raltegravir concentrations with use of the term infant raltegravir dosing regimen in preterm neonates.
Conclusion: Modeling and simulation incorporating preterm infant raltegravir washout PK data suggest that infants born prematurely have much slower raltegravir clearance and will require a reduced raltegravir dosing regimen to avoid potentially dangerous plasma raltegravir concentrations. The simulations demonstrate that the current dosing regimen for raltegravir approved in full-term neonates should not be used in preterm neonates, and that safe use of raltegravir in preterm neonates requires study of reduced dosing regimens in this high-risk population.
References:
[1] Kawade, N. and Onishi, S. The prenatal and postnatal development of UDP-glucuronyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver. Biochem. J. 1981; 196, 257–260.
[2] Lommerse J, Clarke D, Kerbusch T, et al. Maternal-Neonatal Raltegravir Population Pharmacokinetics Modeling: Implications for Initial Neonatal Dosing. CPT Pharmacometrics Syst Pharmacol 2019; 8(9): 643-53.
[3]Clarke DF, Wong RJ, Wenning L, Stevenson DK, Mirochnick M. Raltegravir in vitro effect on Bilirubin Binding. Pediatr Infect Dis J. 2013;32(9):978-80.
[4] Clarke DF, Acosta EP, Rizk ML, et al. Raltegravir pharmacokinetics in neonates following maternal dosing. Journal of Acquired Immune Deficiency Syndromes 2014; 67(3): 310-5.
[5] Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003; 142(1): 47-52.
[6] Gartner, L. M. and Lee, K. S. (1992). Unconjugated hyperbilirubinemia. In: A. A. Fanaroff and R. J. Martin (Eds), Neonatal-perinatal medicine. Mosby–Year Book: St Louis. 1078– 1085.
[7] Kreutzwiser D, Sheehan N, Dayneka N, et al. Therapeutic drug monitoring guided raltegravir dosing for prevention of vertical transmission in a premature neonate born to a woman living with perinatally acquired HIV. Antivir Ther 2017; 22(6): 545-9.
[8] Trahan MJ, Lamarre V, Metras ME, Kakkar F. Use of Triple Combination Antiretroviral Therapy With Raltegravir as Empiric HIV Therapy in the High-risk HIV-exposed Newborn. Pediatr Infect Dis J 2019; 38(4): 410-2.
Reference: PAGE () Abstr 9280 [www.page-meeting.org/?abstract=9280]
Poster: Drug/Disease Modelling - Paediatrics