Transcript Poster #710 Adequate Lopinavir (LPV) Exposure Achieved with a Higher Dose During the 3rd Trimester of Pregnancy 13th Conference on Retroviruses and Opportunistic Infections February 5

Poster #710
Adequate Lopinavir (LPV) Exposure Achieved with a
Higher Dose During the 3rd Trimester of Pregnancy
13th Conference on
Retroviruses and
Opportunistic Infections
February 5 – 8, 2006
Denver, CO, USA
M Mirochnick1, A Stek2, EV Capparelli3, B Best3, D Holland3, J Connor3, SK Burchett4, C Hu5, E Smith6, JS Read7, and PACTG 1026s Protocol Team
Univ, Boston, MA; 2Univ of Southern California, Los Angeles, CA; 3UC San Diego, San Diego, CA; 4Children’s Hospital, Boston, MA; 5Harvard Sch of Public Health, Boston, MA; 6NIAID, Bethesda, MD; 7NICHD, Bethesda, MD
AUC and Cmin were significantly lower in 3rd trimester compared to PP (p<0.005). Mean cord blood LPV concentration was 1.1 +
0.7 mcg/mL and the mean ratio of cord blood/maternal delivery LPV concentration was 0.24 + 0.12 (n=15).
Conclusions: The higher LPV/r dose (533mg/133mg) provided adequate LPV exposure during the 3rd trimester but resulted in
excessive AUC at 2 weeks PP. LPV AUC was low with standard dosing (400mg/100mg) during the 2nd trimester. These data suggest
that the higher LPV/r dose should be used in 3rd trimester pregnant women, that it should be considered in 2nd trimester pregnant
women, especially those who are protease inhibitor experienced, and that postpartum LPV/r dosing can be reduced to standard
dosing by 2 weeks after delivery.
Introduction
• The physiologic changes of pregnancy may have a profound effect on drug
disposition. We have previously shown that dosing during pregnancy with the
standard lopinavir/ritonavir (LPV/r) regimen of 400 mg/100 mg twice daily
results in serum concentrations ~50% lower than postpartum.1
Median (± SE) LPV concentrations
Standard Dose, 3rd Trimester and Postpartum
Study Methods
• All subjects were enrolled in P1025: “PACTG Perinatal Core Protocol” and its substudy
P1026s: “Pharmacokinetic Properties of Antiretroviral Drugs During Pregnancy”
• 26 pregnant HIV-infected women receiving LPV/r twice daily as part of routine
clinical care were studied
• After at least 2 weeks of stable therapy, PK evaluations were performed:
• During the second trimester with LPV/r dosing of 400 mg/100 mg twice daily
(n=8 subjects)
• During the third trimester with LPV/r dosing of 533 mg/133 mg twice daily
(n=26 subjects)
• At 2 weeks postpartum with LPV/r dosing of 533 mg/133 mg twice daily
(n=22 subjects)
• Plasma samples collected pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose
• Cord blood and maternal samples collected at delivery from 23 mother-infant pairs
• Samples were assayed for LPV/r by a validated HPLC assay with a lower limit of
quantitation of 0.047 mcg/mL
• Area under the curve (AUC0-12) was calculated with the trapezoidal rule
• Pharmacokinetic results were reported to their primary care givers within 2 weeks
Clinical Characteristics
15
AUC and Cpre-dose Comparisons
Lopinavir AUC Ante- and Postpartum
Lopinavir Cpre-dose Ante- and Postpartum
250
0
0
2
4
6
8
10
12
Tim e Afte r Dos e (hours )
3rd Tri. n=17
400/100 mg
6-12 W ks PP, n=12
400/100 mg
• Optimal antiretroviral exposure during pregnancy is critical for prevention of HIV
mother to child transmission and for maintenance of maternal health.
• LPV pharmacokinetics with a higher dose during pregnancy have not been
evaluated previously.
1. Stek A, Mirochnick M, Capparelli1 E, Best B, Burchett S, Hu C, Gardella J, Elgie C, Schiffhauer J, Smith E, Read J, Tuomala R.. Reduced lopinavir
exposure during pregnancy: preliminary pharmacokinetic results from PACTG 1026. XV International AIDS Conference, Bangkok, Thailand, July,
2004.
Age at delivery (years)
Weight at delivery (kg)
CD4+ at delivery (cells/uL)
Concomitant ARV’s at delivery
Ethnicity
Median
Range
31.2
18.6 – 40.9
80.6
60.4 – 121.8
517
190 - 1339
17 Combivir, 6 Trizivir, 6 Other
11 Hispanic, 8 Black, 6 White, 1 Unknown
•All subjects tolerated LPV/r well, with only 3 grade III or IV toxicities noted 1 each of hypoglycemia, pedal edema and elevated amylase
•Viral load at delivery was <400 copies/mL in 23/24
Third Trimester
Lopinavir (mcg/mL)
30
10
1
0
2
4
6
8
533m g/133m g bid (n=26)
10
10
1
12
0
2
4
Tim e Pos t Dos e (hours )
6
8
10
12
Tim e Pos t Dos e (hours )
50 th percentile, non-pregnant
50 th percentile, non-pregnant
Median (± SE) LPV Concentrations
Two Weeks Postpartum
533m g/133m g bid (n=22)
30
10
10
20
1
200
150
50th percentile
on 400/100 mg
100
(Non-pregnant)
50
0
2nd Trim e s te r
400/100 mg
3rd Trim e s te r 2 Wk s Pos tpartum
533/133 mg
533/133 mg
0
1
15
2
4
6
8
10
12
Time Post Dose (hours)
0
2
4
6
8
10
Tim e Pos t Dos e (hours )
12
2nd Tri. n=8
400/100 mg
3rd Tri. n=26
533/133 mg
Post. n=24
533/133 mg
50 th percentile, non-pregnant
10
Conclusions
typical trough
5
1 mcg/mL
0
2nd Trim e s te r
400/100 mg
3rd Trim e s te r 2 Wk s Pos tpartum
533/133 mg
533/133 mg
• The higher LPV/r dose (533mg/133mg) was tolerated well and provided adequate LPV
exposure during the 3rd trimester but resulted in excessive AUC at 2 weeks PP.
• LPV AUC was low with standard dosing (400mg/100mg) during the 2nd trimester.
• LPV placental transport is poor, with a median cord blood to maternal ratio of 23%.
Cord Blood and Delivery Concentrations
10
5
30
30
25
20
Second Trimester
400m g/100m g bid (n=8)
Median (±SE) Lopinavir (mcg/mL)
Results: As of Sept 2005, LPV PK data were available for 23 women (7 Black, 10 Hispanic, 5 White, 1 other; median age = 31.9 yrs,
median delivery weight = 79.1 kg).
2nd Trimester
3rd Trimester
2wk Postpartum
LPV/r dose
400/100 BID
533/133 BID
533/133 BID
Mean AUC + SD (mcg*hr/mL)
57.9 + 21.6
85 + 28.2
145.8 + 50.0
Met AUC target/Total
5/8
20/23
17/18
Mean Cmin + SD (mcg/mL)
2.4 + 1.6
4.5 + 2.4
8.7 + 4.5
Postpartum
533 mg/133 mg bid
n=22
151.7
(49.1 - 228.4)
11.0
(0.05 - 20.0)
15.0
(6.0 - 23.2)
8.6
(2.4 - 16.5)
Lopinavir (mcg/mL)
k
2nd Trimester
3rd Trimester
400 mg/100 mg bid 533 mg/133 mg bid
n=8
n=26
AUC
57.3
87.5
(mcg*hr/mL)
(30.2 - 101.9)
(32 - 153.5)
Cpredose
2.8
6.4
(mcg/mL)
(1.2 - 8.2)
(BDL - 13.3)
Cmax
8.0
9.7
(mcg/mL)
(3.8 - 12.9)
(4.4 - 15.2)
C12 hour
2.5
4.6
(mcg/mL)
(1.3 - 7.6)
(0.8 - 9.8)
Median (range)
Lopinavir (mcg/mL)
Methods: PACTG 1026s is an on-going, prospective, non-blinded study of ARV pharmacokinetics (PK) in HIV-infected pregnant
women that includes a cohort receiving LPV/r 400mg/100mg twice daily during the 2nd trimester and 533mg/133mg twice daily
during the 3rd trimester through 2 weeks postpartum. Intensive steady-state 12-hour PK profiles were performed during the 3rd
trimester and at 2 weeks PP, and were optional during the 2nd trimester. Maternal and umbilical cord blood samples were obtained at
delivery. LPV was measured by reverse-phase HPLC with a detection limit of 0.05 mcg/mL. Target LPV AUC was > estimated 10th
percentile LPV AUC (>52mcg*hr/mL) in non-pregnant historical controls taking the standard dose (mean AUC=80mcg*hr/mL).
Primary Objective:
• To describe the pharmacokinetics of LPV during the 2nd and 3rd
trimesters of pregnancy and postpartum
Secondary Objective:
• To compare LPV concentrations in plasma from cord blood with
those in maternal plasma at time of delivery
Lopinavir C pre-dose (mcg/mL)
Background: Use of standard adult lopinavir/ritonavir (LPV/r) dosing (400mg/100mg) during the 3rd trimester of pregnancy
results in reduced LPV exposure. Optimal antiretroviral (ARV) exposure during pregnancy is critical for prevention of HIV mother
to child transmission (MTCT) and for maternal health. The goal of this analysis was to determine LPV exposure during the 3rd
trimester of pregnancy and 2 weeks postpartum (PP) with a higher LPV/r dose.
LPV Concentration – Time Figures
Pharmacokinetic Parameters
Objectives
Lopinavir AUC (mcg*hr/mL)
1Boston
Original Abstract
Median (+SE) Lopinavir (mcg/mL)
Mark Mirochnick, MD
91 East Concord St
Boston, MA 02118
Phone: 617-414-3754
Fax: 617-414-7297
Email: [email protected]
• Cord blood and maternal samples at delivery were obtained from 23 mother-infant
pairs
• Both cord blood and maternal LPV concentrations were below the assay limit of
detection in 2 mother-infant pairs
• LPV was measurable in cord blood and maternal samples from 21 mother-infant
pairs:
Median (range)
Cord blood LPV concentration (mcg/mL)
0.9 (0.1 - 11.2)
Maternal LPV concentration at delivery (mcg/mL) 4.9 (0.4 - 10.1)
Cord blood/maternal ratio
0.23 (0.08 – 1.11)
• We suggest that:
• The higher LPV/r dose should be used in 3rd trimester pregnant women and that it
should be considered in 2nd trimester pregnant women, especially those who are
protease inhibitor experienced.
• Postpartum LPV/r dosing can be reduced to standard dosing by 2 weeks after
delivery.
• Since this study was performed using the recently phased out soft gel formulation
(133mg/33mg per capsule), a follow up study of the new 200mg/50mg film coated tablet
formulation during pregnancy is under development.
Acknowledgements:
The authors wish to thank the women that participated in the protocol and the staff of the participating
PACTG centers. Supported by the Pediatric AIDS Clinical Trials Group funded by the National Institute of
Allergy and Infectious Diseases, National Institutes of Health, U01 AI41110 and by the Pediatric/Perinatal
HIV Clinical Trials Network funded by the National Institute of Child Health and Human Development,
National Institutes of Health, HD-3-3345.