Jos Lommerse (1), Diana F Clarke (3), Anne Chain (2), Han Witjes (1), Hedy Teppler (2), Edmund Capparelli (4), Edward P Acosta (5), Matthew Rizk (2), Larissa Wenning (2), Thomas Kerbusch (1), Stephen A Spector (7), Betsy Smith (8), Mark Mirochnick (6)
(1) Quantitative Solutions, Oss, The Netherlands (2) Merck Research Laboratories, Rahway, USA (3) Boston Medical Center, Boston, MA, USA (4) University of California at San Diego, San Diego, CA, USA (5) University of Alabama at Birmingham, Birmingham, AL, USA (6) Boston University School of Medicine, Boston, MA, USA (7) San Diego and Rady Children’s Hospital, San Diego, CA, US (8) National Institute of Health, NIAID, Division of AIDS, Bethesda. MD, USA.
Objectives: To determine a raltegravir (RAL) daily dosing regimen for prevention or treatment of HIV infection in 0-6 week old infants for use in IMPAACT P1110 using a two cohort adaptive design where PK data from Cohort 1 are included in PK modeling to guide daily dosing in Cohort 2.
Methods: IMPAACT P1110 is an open label, non-comparative dose-finding study of raltegravir in HIV exposed neonates at high risk of acquiring HIV-1 infection. An initial cohort of 6 full-term infants (2.9-3.8 kg, 3/3 M/F) received two 3 mg/kg doses of raltegravir – one within 48 hours after birth and a second at 7-10 days of life. Plasma samples for RAL assay were collected around each dose. RAL concentrations were measured by a validated LCMS assay.
A population PK model was developed based on the P1110-cohort 1 data and RAL concentrations from a phase 1 study in 24 HIV infected infants and children (IMPAACT P1066, cohorts 4-5, 4 wks to
Results: A 2-compartment model with first order absorption provided best fit. Apparent clearance changed dramatically from very low at birth to fully matured at 6 months. The absorption rate also changed rapidly, from 16% at birth to 90% of the maximum rate within 2 weeks. Despite the considerable maturation and body-size changes, the model described the observed RAL concentration data well. Subsequently, the model was used to simulate typical individual RAL exposures receiving various dosing regimens and evaluate their ability to meet the defined exposure criteria.
Conclusions: There are few antiretrovirals with an appropriate formulation and adequate PK data for use in neonates. RAL is metabolized via UGT-1A1, whose activity is known to be extremely low immediately after a birth followed by a dramatic increase over the first weeks and months of life [3,4]. Using simulations from our model, we have selected a daily dosing regimen for evaluation in Cohort 2 of P1110.
References:
[1] Nachman S, Alvero C, Acosta EP, et.al. Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-infected Children 4 Weeks to 2 Years of Age. J Ped Infect Dis 2015; doi: 10.1093.jpids/piu146
[2] Rizk ML, Du L, Bennetto-Hood C, et.al. Population pharmacokinetic analysis of raltegravir pediatric formulations in HIV-infected children 4 weeks to 18 years of age. J Clin Pharmacol 2015; doi: 10.1002/jcph.493
[3] Kawade N, 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 Apr 15;196(1):257-60.
[4] Krekels EH, Danhof M, Tibboel D, et.al. Ontogeny of hepatic glucuronidation; methods and results. Curr Drug Metab. 2012 Jul;13(6):728-43.
Reference: PAGE 24 (2015) Abstr 3627 [www.page-meeting.org/?abstract=3627]
Poster: Drug/Disease modeling - Paediatrics