Paper # 875
A Pharmacokinetic Study of Ritonavir-boosted Saquinavir in HIV-infected Children 4 Months to <6 Years Old
Joshua Haznedar*1, A Zhang2, E Labriola-Tompkins2, G Ezcurra3, T Bunupuradah4, P Kosalaraksa5, T Chotpitayasunondh6, M Salgo2, L Donatacci2, and I Patel2
1Roche, Palo Alto, CA, US; 2Roche, Nutley, NJ, US; 3Hosp de Nińos Dr Orlando Alassia, Santa Fe, Argentina; 4HIVNAT Res Collaboration, Thai Red Cross AIDS Res Ctr, Bangkok; 5Srinagarind Hosp, Khon Kaen, Thailand; and 6Queen Sirikit Natl Inst of Child Hlth, Bangkok, Thailand
Background: An estimated 2.3 million children under
the age of 15 years are living with HIV, and 12% of all new HIV infections
worldwide are among children under the age of 15 years. The availability of ART,
especially protease inhibitor in young HIV-infected children is limited.
Methods: A multi-center, open-label, non-randomized
study was conducted in children in 2 age range groups (group A: 4 months to
<2 years; group B: 2 to <6 years) to evaluate the pharmacokinetics of
saquinavir (SQV) when boosted with low-dose ritonavir (RTV), and derive appropriate
dose recommendation. Patients received SQV at a dose of 50 mg/kg twice daily
and RTV at a dose of 3 mg/kg twice daily (5 to <15 kg), 2.5 mg/kg twice
daily (15 to 40 kg), and 100 mg twice daily (>40 kg). Blood samples were
collected on day 14 at pre-dose, and 3, 4, 8, and 12 hours post-morning
dose, weeks 8, 12, and 24, and analyzed using a validated HPLC-MS/MS method. Steady-state
AUC0-12h, Cmax, and Ctrough were
determined and compared to SQV ranges seen in older children (age >6 years)
and adults. If exposures (primarily Ctrough) were found outside of
that range and/or associated with toxicities, dose adjustments were made for
individual patients (5 of 18).
Results: Pharmacokinetic data were available
from 18 subjects (5 were in the <2-years and 13 were in the 2- to
<6-years group). In addition, SQV and RTV pharmacokinetic parameters were
dose normalized to 50 mg/kg and 100 mg, respectively, due to dose differences
in each group of patients. Compared to <2-years group, SQV pharmacokinetic
exposure was higher (18.9 vs 38.1 µg.h/mL for AUC0-12 h,
2910 vs. 5570 ng/mL for Cmax and 645 vs 1860 ng/mL for Ctrough)
and the inter-patient variability was lower (%CV ranged from 83% to 107% vs 48%
to 57%) in the 2- to <6-years group. Similar findings were seen for RTV
(13.6 vs 21.8 µg.h/mL for AUC0-12 h, 2050 vs 3370 ng/mL
for Cmax, and 577 vs 995 ng/mL for Ctrough). The study did
not reveal any new or unexpected safety concerns and resulted in acceptable
therapeutic effect comparable for both patient groups and appears to be a
reasonable approach in achieving adequate pharmacokinetics.
Conclusions: SQV at a dose of 50 mg/kg boosted with
RTV provided the desired pharmacokinetic exposure in group B (2 to <6 years)
patients similar to that found in older children (6 to 15 years). Data were
insufficient to recommend a SQV dose in group A (4 months to <2 years)
patients. SQV at a dose of 50 mg/kg with RTV provides a new protease inhibitor–based
treatment option for HIV-infected children aged 2 to 6 years old.
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