Paper # 714 
Pharmacokinetics of DRV/r in Asian HIV-1+ 6-Year-old Children
K Chokephaibulkit1, W Prasitsuebsai2, O Wittawatmongkol1, M Gorowara2, W Phongsamart1, J Wongsabut2, N Vanprapar1, T Puthanakit2,3, D Burger4, Jintanat Ananworanich*2,3,5, on behalf of the HIV-NAT 113 Study Group
1Faculty of Med, Siriraj Hosp, Mahidol Univ, Bangkok, Thailand; 2HIVNAT Res Collaboration, Thai Red Cross AIDS Res Ctr, Bangkok; 3Faculty of Med, Chulalongkorn Univ, Bangkok, Thailand; 4Radboud Univ Nijmegen Med Ctr, The Netherlands; and 5South East Asia Res Collaboration with Hawaii, Bangkok, Thailand
Background: Extensive evidence indicates that Asians
have higher protease inhibitor plasma concentrations than Caucasians and blacks
who take the same dose. Whether this is also true for darunavir/ritonavir
(DRV/r) in Asian children is currently unknown.
Methods: Thai children aged ≥6 years and
weighing ≥20 kg who were on DRV/r as part of their second-line or salvage
regimens for ≥2 weeks underwent 12-hour pharmacokinetic with blood
sampling before, and at 1, 2, 4, 6, 8, 10, and 12 hours post dosing. DRV/r
doses were 375/100 mg twice daily (body weight 20 to <30 kg, n = 12),
450/100 mg twice daily (body weight 30 to <40 kg, n = 2) or 600/100 mg twice
daily (body weight ≥40 kg, n = 5). Plasma concentrations were measured by
validated HPLC method, and pharmacokinetic parameters were calculated using
WinNonlin software.
Results: We enrolled 19 children: 8 (42%) were
female, median age (IQR) was 13 (10 to 15) years and median body weight was
(IQR) 29.4 (24. to 43.4) kg. The median (IQR) duration of DRV/r treatment was
11 (6 to 13) months. The median (IQR) values were 54.7 (46.4 to 92.5) h*mg/L
for AUC0-12, 8.2 (6.3 to 10.8) mg/L for Cmax and 2.8 (1.9
to 4.8) mg/L for Ctrough. All had Ctrough above the
protein-binding adjusted IC50 of PI-resistant virus (0.55 mg/L).
There were no significant differences in the DRV AUC0–12, Cmax
or Ctrough across the 3 weight bands. The median (IQR) of ritonavir
(RTV) AUC0-12 was 9.3 (13.0 to 70.6) h*mg/L. In regression models,
there was a significant relationship between the RTV AUC0–12 and DRV
AUC0–12, Cmax and Ctrough. There were 8
adverse events ≥grade 2: 2 acute bronchitis, 5 hypercholesterolemia, and
1 hypertriglyceridemia. Compared to pediatric DELPHI study data (n = 76,
predominantly white and black, approximately half used RTV boosting of 50 or 60
mg), the median values in our children were 13% higher for AUC0–12 and
27% higher for Ctrough.
Conclusions: Thai children aged ≥6 years, who
were on standard DRV dosing with 100 mg RTV boosting had adequate DRV AUC0–12,
Cmax and Ctrough. The regimen was well tolerated. Our
data suggest that Asian children may have slightly higher DRV concentrations
than non-Asian children of similar age and body weight possibly due to genetic
factors or the higher RTV boosting dose.
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