In 7 infant cord blood samples, the mean (SD) umbilical cord APV blood concentration was 0.11 (0.07) μg/mL. The maternal plasma concentration at delivery was 0.43 (0.29) μg/mL. APV GLS mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration was 0.267 (0.241, 0.297).
FPV, the phosphoester prodrug of the PI amprenavir (APV), is approved for use in treatment-naive and treatment experienced HIV-infected individuals. APV is predominantly eliminated by the hepatic microsomal enzyme CYP3A4 and a substrate for an inducer of the efflux transporter P-glycoprotein.21,22 To date, little data have been published about the pharmacokinetics or safety of FPV during pregnancy.23–26 Second-trimester pharmacokinetics of APV after FPV administration have never been investigated.
The mean ratio of cord blood/maternal APV concentration was 0.27, suggesting that transplacental transfer of APV is higher than that reported for other PI.8,12,13,19,27,28 The mean umbilical cord blood concentration of 0.11 μg/mL seen in our study is within the range of the mean protein binding-adjusted IC50 for wild-type HIV (0.146 μg/mL), suggesting that APV cord concentrations may contribute to the prevention of HIV transmission to the fetus.
The FPV/RTV was well tolerated by both mother and infant consistent with the results of a previous study.26 There has been no association with FPV use in pregnancy and an increased risk of birth defects.29 The rate of birth defects for infants exposed to FPV in utero is 2.42%, similar to that of the general population of 2.72% reported by the Centers for Disease Control and Prevention.30
Our limited study demonstrated that the standard twice-daily FPV/RTV 700/100-mg regimen provided adequate APV exposure during the second and third trimesters of pregnancy. The observed reduction in APV concentrations seemed not to be clinically significant because all women remained virologically suppressed during the study, and no cases of vertical HIV transmission occurred. Transplacental passage of APV with the FPV/RTV regimen was relatively high compared with that reported for most other PIs. The regimen was well tolerated in both mothers and infants, with no reports of drug-related adverse events. The pharmacokinetics, safety, and efficacy results we observed suggest that dose adjustment is not required for FPV/RTV twice-daily administration during pregnancy. Close virologic monitoring is suggested with the use of FPV, as with the use of any PI, for p-MTCT in women with significant PI mutations.
The authors thank the study participants for their participation. GlaxoSmithKline contributed to protocol development, serum drug concentration determination, and statistical analysis and had no influence on interpretation of data. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Government. The authors give special thanks to outreach coordinator Luis A. Vargas for his contributions to the success of this study.
2. Massad LS, Springer G, Jacobson L, et al.. Pregnancy
rates and predictors of conception, miscarriage and abortion in US women with HIV
. AIDS. 2004;18:281–286.
3. Chen JL, Philips KA, Kanouse DE, et al.. Fertility desires and intentions of HIV
-positive men and women. Fam Plann Perspect. 2001;33:144–152.
4. Aberg JA, Kaplan JE, Libman H, et al.. Primary care guidelines for the management of persons infected with human immunodeficiency virus. Clin Infect Dis. 2009;49:651–681.
5. Centers for Disease Control and Prevention (CDC). Achievements in public health. reduction in perinatal transmission of HIV
infection-United States, 1985–2005. MMWR Morb Mortal Wkly Rep. 2006;55:592–597.
6. Panel on Treatment of HIV
-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV
-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV
Transmission in the United States. 2011:1–207. Available at: http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf.
Accessed February 16, 2012.
7. Capparelli E, Rakhmanina N, Mirochnick M. Pharmacotherapy of perinatal HIV
. Sem Fetal Neonat Med. 2005;10:161–175.
8. Best BM, Stek AM, Mirochnick M, et al.. Lopinavir tablet pharmacokinetics
with an increased dose during pregnancy
. J Acquir Immune Defic Syndr. 2010;54:381–388.
9. Stek AM, Mirochnick M, Capparelli E, et al.. Reduced lopinavir exposure during pregnancy
. AIDS. 2006;20:1931–1939.
10. Scott G, Rodman J, Scott W, et al.. Pharmacokinetic and virologic response to ritonavir (RTV) in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV
-1 infected pregnant women and their infants. Paper presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24–28, 2002; Seattle, WA; Abstract/poster 794.
11. Mirochnick M, Best BM, Stek AM, et al.. Atazanavir pharmacokinetics
with and without tenofovir during pregnancy
. J Acquir Immune Defic Syndr. 2011;56:412–419.
12. Conradie F, Zorilla C, Josipovic D, et al.. Safety and exposure of once-daily ritonaivr-boosted atazanavir in HIV
-infected pregnant women. HIV
13. Acosta EP, Bardeguez A, Zorilla CD, et al.. Pharmacokinetics
of saquinavir plus low-dose ritonavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2004;48:430–436.
14. Van der Lugt J, Colbers A, Molto J, et al.. The pharmacokinetics
, safety and efficacy of boosted saquinavir tablets in HIV
type-1-infected pregnant women. Antivir Ther. 2009;14:443–450.
15. Burger DM, Eggink A, van der Ende I, et al.. The pharmacokinetics
of saquinavir new tablet formulation + ritonavir (1000/100mg BID) in HIV
-1-infected pregnant women. Paper presented at: Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, CA; Abstract/poster 741.
16. Nellin J, Schillevoort I, Wit F, et al.. Nelfinavir plasma concentrations are low during pregnancy
. Clin Infect Dis. 2004;39:736–740.
17. Villani P, Floridia M, Pirillo MF, et al.. Pharmacokinetics
of nelfinavir in HIV
-1-infected pregnant and nonpregnant women. Br J Clin Pharmacol. 2006;62:309–315.
18. Read JS, Best BM, Stek AM, et al.. Pharmacokinetics
of new 625 mg nelfinavir formulation during pregnancy
and postpartum. HIV
19. Capparelli EV, Best BM, Stek A, et al.. Pharmacokinetics
of darunavir once or twice daily during pregnancy
and postpartum. Paper presented at: 3rd International Workshop on HIV
Pediatrics; July 15–18, 2011; Rome, Italy; Abstract/poster P72.
20. Levey A, Bosch J, Lewis JB, et al.. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461–470.
21. Wire MB, Shelton MJ, Studenberg S. Fosamprenavir
: clinical pharmacokinetics
and drug interactions of the amprenavir prodrug. Clin Pharmacokinet. 2006;45:137–168.
22. Huang L, Wring SA, Woolley JL, et al.. Induction of P-glycoprotein and cytochrome P450 3A by HIV
protease inhibitors. Drug Metab Dispos. 2001;29:754–760.
23. Luber AD, Condoluci DV, Slowinski PD, et al.. Steady-state amprenavir and tenofovir pharmacokinetics
after coadministration of unboosted or ritonavir-boosted fosamprenavir
with tenofovir disoproxil fumarate in healthy volunteers. HIV
24. Capparelli E, Stek A, Best B, et al.. Boosted fosamprenavir pharmacokinetics
. Paper presented at: 17th Conference on Retroviruses and Opportunistic Infections; February 16–19, 2010; San Francisco, CA; Abstract 908/Poster T-110.
25. Pacanowski J, Bollens D, Poirier J-M, et al.. Efficacy of darunavir despite low plasma trough levels during late pregnancy
in an HIV
-hepatitis C virus-infected patient. AIDS. 2009;23:1923–1924.
26. Martorell C, Theroux E, Bermudez A, et al.. Safety and efficacy of fosamprenavir
in human immunodeficiency virus-infected pregnant women. Pediatr Infect Dis J. 2010;29:985.
27. Bryson YJ, Mirochnick M, Stek A, et al.. Pharmacokinetics
and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV
-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353. HIV
Clin Trials. 2008;9:115–125.
28. Yeh RF, Rezk NL, Kashuba ADM, et al.. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy
in human immunodeficiency virus type 1-infected women. Antimicrob Agents Chemother. 2009;53:2367–2374.
29. Antiretroviral Pregnancy
Registry Steering Committee. Antiretroviral Pregnancy
Registry International Interim Report for 1 January 1989 through 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2011. Available from URL: www.APRegistry.com.
Accessed July 5, 2012.
30. Correa A, Cragan J, Kucik J, et al. Metropolitan Atlanta Congenital Defects Program surveillance report reporting birth defects surveillance data 1968–2003. Birth Defects Res (Part A). 79:65–93:2007.