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Nelfinavir Pharmacokinetics (625-mg Tablets) during the Third Trimester of Pregnancy and Post-partum
Jennifer Read*1, B Best2, A Stek3, C Hu4, E Capparelli2, D Holland2, S Burchett5, E Smith6, B Sheeran7, and M Mirochnick8
1Natl Inst of Child Hlth and Human Devt, NIH, Bethesda, MD, US; 2Univ of California, San Diego, US; 3Univ of Southern California, Los Angeles, US; 4Harvard Sch of Publ Hlth, Boston, MA, US; 5Children's Hosp Boston, MA, US; 6NIAID, NIH, Bethesda, MD, US; 7Social & Sci Systems, Silver Spring, MD, US; and 8Boston Univ, MA, US
Background: Previous data indicated that nelfinavir (NFV)
exposure was inadequate in most pregnant women receiving NFV (250-mg tablets) 750
mg 3 times daily, but was much improved with 1250 mg twice daily. As part of the Pediatric AIDS Clinical Trials Group (PACTG)
1026s protocol, NFV pharmacokinetics
during pregnancy were determined following administration of the newer 625-mg tablet
formulation.
Methods:
P1026s is an
ongoing, prospective, non-blinded study of ART pharmacokinetics in
HIV-1-infected pregnant women receiving ≥1 ART for routine clinical care, including a cohort receiving NFV (625-mg tablets)
1250 mg twice daily. Intensive steady-state 12-hour NFV pharmacokinetic
profiles were performed at 30 to 36 weeks gestation (third trimester) and at 6
to 12 weeks post-partum. Concentrations of NFV and its active M8 metabolite were
determined by high performance liquid chromatography. The target NFV AUC12
was ≥10th percentile NFV AUC12 in non-pregnant
historical controls (18.5 µg*h/mL). The Wilcoxon signed rank test was used to
calculate p values for comparisons.
Results: As of mid-August 2006, third trimester NFV pharmacokinetic
data were available for 25 women (14 black, 9 Hispanic, 2 white; median age 30
years, median weight 78 kg). Post-partum
pharmacokinetic data were available for 12 of these women. At the time of the third
trimester pharmacokinetics, the median duration of NFV treatment was 17 weeks
(range 3 to 138). NFV AUC exceeded the AUC target
for 13 of 25 (52%, 95%CI 31 to 72%) third trimester subjects compared to 100% (12 of 12) post-partum subjects. Few
subjects (4 of 25 [16%] at third trimester and 1 of 12 [8%] post-partum) had Cmin
values above the suggested minimum trough concentration of 800 ng/mL. Nearly all (21 of 22 [96%] third trimester and 6 of 7 [86%]
post-partum) had a viral load ≤400 copies/mL.
Conclusions: With the new 625-mg tablet formulation, NFV AUC,
NFV Cmax, M8 AUC, and M8/NFV ratio were lower during the third
trimester compared with post-partum.
Few women had a Cmin that exceeded the usual therapeutic drug
monitoring target of a trough
concentration of 800 ng/mL. The decreased third trimester M8/NFV ratio is consistent
with a reduction of CYP2C19 activity during pregnancy.
|
|
NFV AUC
|
NFV C0
|
NFV C12
|
NFV CMax
|
M8 AUC
|
M8/NFV AUC ratio
|
|
Third
Trimester (n = 25)
median
(range)
|
18.7
(3.6- 53.7)
|
0.9
(0.1-4.4)
|
0.5
(0.04-1.5)
|
3.1
(0.9-6.5)
|
1.5
(0.0-12.4)
|
0.06
(0.00-0.3)
|
|
Post-partum (n = 12)
median
(range)
|
30.8
(18.5-52.6)
|
1.8
(0.0-4.8)
|
0.6
(0.2-2.3)
|
4.9
(2.6-6.5)
|
10.1
(0.2-43.7)
|
0.3
(0.01-0.8)
|
|
Third
Trimester vs
Post-partum (n = 12)
Geometric
mean (90%CI)
p
value
|
0.7
(0.5-0.9)
0.09
|
1.4
(0.5-4.2)
0.68
|
0.6
(0.3-1.2)
0.34
|
0.7
(0.5-0.9)
0.03
|
0.2
(0.1-0.5)
0.002
|
0.4
(0.2-0.6)
0.002
|
|
