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Nelfinavir Pharmacokinetics with an Increased Dose during the First 2 Weeks of Life
Mark Mirochnick*1, K Nielsen-Saines2, J Pilotto3, J Pinto4, V Veloso5, D Holland6, H Watts7, J Moye7, L Mofenson7, Y Bryson2, and NICHD/HPTN 040/PACTG 1043 Protocol Team
1Boston Univ Sch of Med, MA, US; 2David Geffen Sch of Med, Univ of California, Los Angeles, US; 3Hosp Geral de Nova Iguaçu, Brazil; 4Federal Univ of Minas Gerais, Belo Horizonte, Brazil; 5Fiocruz Inst, Rio de Janeiro, Brazil; 6David Geffen Sch of Med, Univ of California, Los Angeles, US; and 7Natl Inst of Child Hlth and Human Devt, NIH, Bethesda, MD, US
Background: The optimal postnatal ART regimen to
prevent mother-to-child HIV transmission (MTCT) in infants born to mothers with
no ART during pregnancy is unknown. The National Institute of Child Health and
Human Development (NICHD)/HIV Prevention Trials Network (HPTN) 040/Pediatric
AIDS Clinical Trials Group (PACTG) 1043 compares the efficacy of 3 infant ART regimens
to prevent MTCT in infants born to HIV+ mothers receiving no
antepartum ART: zidovudine (ZDV) alone for 6 weeks; ZDV for 6 weeks + 2 weeks
of nelfinavir (NFV) and lamivudine (3TC); ZDV for 6 weeks + 3 doses of
nevirapine (NVP) during the first week post birth. As a previous study of NFV pharmacokinetics
in infants during the first weeks of life demonstrated inadequate exposure in
around a third of infants receiving 40 mg/kg twice daily, an increased NFV dose
is being used in HPTN 040. This report describes NFV pharmacokinetics in
infants with this increased dose.
Methods: A weight band-based NFV dosing regimen was
used: twice-daily dosing with 200 mg if birth weight ≥3000 g, 150 mg if birth
weight was 2001 to 2999 g, and 100 mg if birth weight was 1500 to 2000 g. Serial
plasma samples for NFV concentration were obtained over 12 hours and at age 4
to 7 or 10 to 14 days. NFV concentration was measured by high-performance
liquid chromatography, lower limit of detection was 0.04 ng/mL.
Results: We studied 22 Brazilian infants (mean [± SD], birth weight 2994 (±494) g, mean gestational age = 38.7 (±1.7) weeks) Median (range) per kg NFV dose
was 58.3 (48.4 to 78.9) mg/kg. No pharmacokinetic parameter differed between infants
studied on days 4 to 7 vs days 10 to 14. Median NFV AUC0-12 was 25.9
(1.7 to 125.8) µg·h/mL and median C12h was 1.4 (below quantitation to 14.4) µg/mL.
AUC0-12 was <15 µg·h/mL (the 10th percentile for
adults) in 9 infants (41%). C12h was <0.8 µg/mL (the standard therapeutic
drug monitoring [TDM] trough concentration target for treatment) in 9 infants
(41%) and was <0.05 µg/mL (10 times the upper limit for wild type NFV IC50)
in 2 infants (9%).
Conclusions: Infants receiving this weight-band
dosing regimen had a median dose of 58 mg/kg, and while overall median AUC0-12
and C12h were equivalent to those observed in adults, interindividual variability
in NFV exposure was large and NFV exposure was low in 41%. Given the wide range
of variability in NFV exposure, a further increase in NFV dose would likely result
in some infants with higher and potentially toxic concentration, while others would
remain with low concentration; thus, the dose was not increased in this study
using NFV as part of a combination regimen for MTCT prophylaxis. For use of NFV
for treatment of neonates found to be HIV-infected, TDM should be considered to
ensure adequate exposure.
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