Paper # 906 
Pharmacokinetics of Lopinavir Boosted with Ritonavir Initiated during the Third Trimester of Pregnancy in HIV-1-infected Thai Women
Tim Cressey*1,2, G Jourdain1,2, B Rawangban3, P Yuthavisuthi4, S Varadisai5, R Kongpanichkul6, P Sabsanong7, N Ngo-Giang-Huong1,2, S Pattarakulwanich8, M Lallemant1,2, and the PHPT-5 Study Team
1Faculty of Associated Med Sci, Chiang Mai Univ, Thailand; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Nopparat Rajathanee Hosp, Bangkok, Thailand; 4Prapokklao Hosp, Chantaburi, Thailand; 5Samutsakhon Hosp, Thailand; 6Nakhonpathom Hosp, Thailand; 7Samutprakarn Hosp, Thailand; and 8Ministry of Publ Hlth, Nonthaburi, Thailand
Background: Studies of lopinavir boosted with
ritonavir (LPV/r) in US pregnant women have shown a 50% reduction in LPV drug
exposure with standard dosing in the third trimester of pregnancy compared with
that seen in non-pregnant adults, prompting the use of higher LPV doses. It is
unknown if LPV/r dose increases are appropriate for pregnant women in other populations.
We investigated the pharmacokinetics of standard LPV/r dosing during the third
trimester in pregnant, HIV-infected Thai women.
Methods: The first 25 women enrolled in PHPT-5, a
phase III trial for the prevention of mother-to-child-transmission of HIV
(ClinicalTrials.gov Identifier: NCT00409591), and randomized to receive zidovudine
(ZDV 300 mg, twice daily) plus LPV/r standard dosing (400/100 mg, Aluvia®
tablets), twice daily from 28 weeks gestation were scheduled to have intensive
12-hour blood sampling after at least 2 weeks of treatment. Pharmacokinetic
parameters were calculated by non-compartmental analysis. Target LPV area under
the concentration-time curve (AUC) was ≥52 µg*h/mL (10th percentile for
LPV AUC in non-pregnant adults). As per protocol, if 3 or more of the first 6
women, or 4 or more of the first 12 women, or 6 or more of the first 25 women failed
to meet the target (i.e. we would have 95% confidence that the true rate of
pharmacokinetic failure exceeds 10%) the dose of LPV/r would be escalated and
the pharmacokinetics reassessed.
Results: We enrolled in this substudy 27 women, median
(range) age 29 years (19 to 43), CD4 cell count 431 cells/mm3
(250 to 875), and HIV-1 RNA viral load 9,102 copies/mL (<50 to 402,015).
At the time of LPV pharmacokinetic sampling the median gestational age was 33
weeks (30 to 38), weight 61 kg (45 to 88), body mass index 26 kg/m2
(21 to 36), and LPV/r duration of 2 weeks (2 to 4). Geometric mean (90%
confidence interval) LPV AUC, Cmax and Cmin were 61.5 µg*h/mL
(56.0 to 67.5), 7.8 µg/mL (7.1 to 8.5), and 2.6 µg/mL (2.3 to 3.0),
respectively. Of 26 evaluable women, 21 (81%) had an LPV AUC ≥52 µg*h/mL
and 25 (96%) a Cmin above 1.0 mg/L. At delivery, 60% of the women
had a HIV-1 RNA viral load <50 copies/mL and all were <400 copies/mL,
after a median of 9 weeks (3 to 12) of LPV/r.
Conclusions: The reduction of LPV/r exposure with
standard dosing in pregnant Thai women was approximately 25%, less pronounced
than the 50% reduction reported in US women. The threshold for assessing a
higher LPV/r dose was not met.
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