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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

Protease Inhibitors

Nelfinavir (Viracept, NFV)

(Last updated:3/28/2014; last reviewed:3/28/2014)

Nelfinavir is classified as Food and Drug Administration (FDA) Pregnancy Category B.

Animal Carcinogenicity Studies

Nelfinavir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. However, incidence of thyroid follicular cell adenomas and carcinomas was increased over baseline in male rats receiving nelfinavir dosages of 300 mg/kg/day or higher (equal to a systemic exposure similar to that in humans at therapeutic doses) and female rats receiving 1000 mg/kg/day (equal to a systemic exposure 3-fold higher than that in humans at therapeutic doses).

Reproduction/Fertility

No effect of nelfinavir has been seen on reproductive performance, fertility, or embryo survival in rats at exposures comparable to human therapeutic exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation had no effect on the survival, growth, and development of the offspring to weaning. Maternal exposure to nelfinavir also did not affect subsequent reproductive performance of the offspring.

Teratogenicity/Developmental Toxicity

No evidence of teratogenicity has been observed in pregnant rats at exposures comparable to human exposure and in rabbits with exposures significantly less than human exposure.

In the Antiretroviral Pregnancy Registry (APR), sufficient numbers of first-trimester exposures to nelfinavir have been monitored to be able to detect at least a 1.5-fold increased risk of overall birth defects and a 2-fold increased risk of birth defects in the more common classes of birth defects—the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with nelfinavir. Among cases of first-trimester nelfinavir exposure reported to the APR, prevalence of birth defects was 3.9% (47 of 1,207 births; 95% CI, 2.9% to 5.2%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.1

Placental and Breast Milk Transfer

Transplacental passage of nelfinavir has been minimal to low in humans. In a Phase I study in pregnant women and their infants (PACTG 353, see below), transplacental passage of nelfinavir was minimal.2 In addition, in a study of cord blood samples from 38 women treated with nelfinavir during pregnancy, the cord blood nelfinavir concentration was less than the assay limit of detection in 24 (63%), and the cord blood concentration was low (median, 0.35 µg/mL) in the remaining 14 women.3 Among 20 mother-infant pairs in the Netherlands, the cord to maternal plasma ratio for nelfinavir was 0.14 compared to 0.67 for nevirapine and 0.24 for lopinavir.4 

Nelfinavir also has low breast milk passage. In a pharmacokinetic (PK) study conducted in Kisumu, Kenya, nelfinavir and its active metabolite M8 concentrations were measured in maternal plasma and breast milk from 26 mothers and from their 27 infants at birth, 2, 6, 14, and 24 weeks among women receiving nelfinavir as part of combination antiretroviral therapy.5 Peak nelfinavir concentrations in maternal plasma and breast milk were at Week 2. Median breast milk to plasma ratio was 0.12 for nelfinavir and 0.03 for its active metabolite (i.e., M8). Nelfinavir and M8 concentrations were below the limit of detection in 20/28 (71%) infant plasma dried blood spots tested from nine infants over time points from delivery though Week 24. Overall transfer to breast milk was low and resulted in non-significant exposure to nelfinavir among breastfed infants through age 24 weeks. 

Human Studies in Pregnancy

A Phase I/II safety and PK study (PACTG 353) of nelfinavir in combination with zidovudine and lamivudine was conducted in pregnant HIV-infected women and their infants.2 In the first 9 pregnant HIV-infected women enrolled in the study, nelfinavir administered at a dose of 750 mg three times daily produced drug exposures that were variable and generally lower than those reported in non-pregnant adults with both twice- and three-times-daily dosing. Therefore, the study was modified to evaluate an increased dose of nelfinavir given twice daily (1250 mg twice daily), which resulted in adequate levels of the drug in pregnancy. However, in two other small studies of women given 1250 mg nelfinavir twice daily in the second and third trimesters, drug concentrations in the second and third trimesters were somewhat lower than in non-pregnant women.6,7

In a PK study of combination therapy including the new nelfinavir 625-mg tablet formulation (given as 1250 mg twice daily) in 25 women at 30 to 36 weeks’ gestation (and 12 at 6–12 weeks postpartum), peak levels and area under the curve were lower in the third trimester than postpartum.8 Only 16% (4 of 25) of women during the third trimester and 8% (1/12) women postpartum had trough values greater than the suggested minimum trough of 800 ng/mL; however, viral load was <400 copies/mL in 96% of women in the third trimester and 86% postpartum.

Some nelfinavir manufactured before 2008 may have contained low levels of ethyl methane sulfonate (EMS), a process-related impurity. EMS is teratogenic, mutagenic, and carcinogenic in animals, although no data exist in humans and no increase in birth defects has been observed in the APR. All nelfinavir manufactured and released since March 31, 2008, meets the new final EMS limits established by the FDA for prescribing to all patient populations, including pregnant women and pediatric patients. 

References

  1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2013. 2013. Available at http://www.APRegistry.com. Accessed March 5, 2014.
  2. 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(2):115-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/18474496.
  3. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. 2002;21(9):835-838. Available at http://www.ncbi.nlm.nih.gov/pubmed/12352805.
  4. van Hoog S, Boer K, Nellen J, Scherpbier H, Godfried MH. Transplacental passage of nevirapine, nelfinavir and lopinavir. Neth J Med. 2012;70(2):102-103. Available at http://www.ncbi.nlm.nih.gov/pubmed/22418759.
  5. Weidle PJ, Zeh C, Martin A, et al. Nelfinavir and its active metabolite, hydroxy-t-butylamidenelfinavir (M8), are transferred in small quantities to breast milk and do not reach biologically significant concentrations in breast-feeding infants whose mothers are taking nelfinavir. Antimicrob Agents Chemother. 2011;55(11):5168-5171. Available at http://www.ncbi.nlm.nih.gov/pubmed/21876052.
  6. 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(3):309-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/16934047.
  7. Fang A, Valluri SR, O'Sullivan MJ, et al. Safety and pharmacokinetics of nelfinavir during the second and third trimesters of pregnancy and postpartum. HIV Clin Trials. 2012;13(1):46-59. Available at http://www.ncbi.nlm.nih.gov/pubmed/22306587.
  8. Read JS, Best BM, Stek AM, et al. Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum. HIV Med. 2008;9(10):875-882. Available at http://www.ncbi.nlm.nih.gov/pubmed/18795962.

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