629
High-dose Lopinavir and Standard-dose Emtricitabine Pharmacokinetics during Pregnancy and Postpartum
Brookie Best*1, A Stek2, C Hu3, S Burchett4, S Rossi1, E Smith5, B Sheeran6, J Read7, E Capparelli1, M Mirochnick8, and for the PACTG/IMPAACT P1026s Team
1Univ of California, San Diego, US; 2Univ of Southern California, Los Angeles, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Children`s Hosp Boston, MA, US; 5NIAID, NIH, Bethesda, MD, US; 6Social & Sci Systems, Silver Spring, MD, US; 7Natl Inst of Child Hlth and Human Devt, NIH, Bethesda, MD, US; and 8Boston Univ, MA, US
Background: Emtricitabine (FTC) and the new lopinavir/ritonavir
(LPV/r) tablets are widely used in pregnancy, but no pharmacokinetic data
during pregnancy are available for either. Standard adult LPV/r doses (400 mg/100
mg) with capsules during the third trimester of pregnancy resulted in reduced
LPV exposure. Our objectives were to determine LPV tablet pharmacokinetics with
a higher dose during the third trimester of pregnancy and standard dosing 2
weeks postpartum, and the standard-dose FTC pharmacokinetics in the third
trimester and postpartum.
Methods: Pediatric AIDS Clinical Trials Group (PACTG)
1026s is an ongoing, prospective, non-blinded study of antiretroviral pharmacokinetics
in HIV-infected pregnant women, including an FTC cohort taking 200 mg daily throughout
pregnancy and 6 to 12 weeks postpartum, and a separate LPV/r cohort taking standard
doses in the second trimester and postpartum, and taking 600 mg/150 mg twice
daily in the third trimester. Intensive steady-state 12- and 24-hour pharmacokinetic
profiles were performed for subjects in the LPV/r and FTC cohorts, respectively.
Delivery maternal and umbilical cord blood samples were obtained. Target FTC
and LPV/r AUC's were ³7 and 52 µg·h/mL,
respectively (approximately the 10th percentile AUC in non-pregnant
historical controls).
Results: As of August 2007, LPV and FTC pharmacokinetic
data were available for 21 and 18 women, respectively. Mean cord blood LPV and
FTC concentrations were 1.5±1 µg/mL and 300±268 ng/mL. Mean ratios of cord
blood/maternal delivery LPV and FTC concentrations were 0.28±0.23 (n = 15)
and 1.17±0.6 (n = 9).
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Optional
2nd Trimester
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3rd Trimester
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Postpartum
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Lopinavir/ritonavir
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LPV/r tablet dose
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400/100 twice daily
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600/150 twice daily
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400/100 twice daily
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AUC (µg·h/mL)†
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72 (51 to 88)
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92 (43 to 198)
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131 (66 to 237)
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Met AUC target/Total
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5/6
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19/21
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14/14
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Cmin (µg/mL)†
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3.4 (1.7 to 4.4)
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4.7 (<0.09 to 12.2)
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6.8 (<0.09 to 10.6)
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Emtricitabine
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AUC (µg·h/mL)†
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Not studied
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8.6 (5.2 to 15.9)
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9.8 (7.4 to 30.3)
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Met AUC target/Total
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Not studied
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12/18
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14/14
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Cmin (ng/mL)†
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Not studied
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52 (14 to 180)
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86 (<10 to 306)
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†Median (range)
.
Conclusions: Higher LPV/r dosing provided appropriate
exposure during the third trimester. With standard dosing, the second trimester
AUC was 50% lower than postpartum. The higher LPV/r dose should be used in third
trimester pregnant women and should be considered in second trimester pregnant
women, especially those who are protease inhibitor-experienced. LPV/r dose can be
reduced to standard in the early postpartum period. FTC exposure (AUC) was
lower during pregnancy than postpartum, but the magnitude was small (12%) and
dose adjustments due to pregnancy may not be necessary.
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