Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Archived Drugs

Indinavir (Crixivan, IDV)

Indinavir is classified as Food and Drug Administration Pregnancy Category C. Given the availability of effective alternative antiretroviral (ARV) drugs, indinavir is not recommended for use in pregnant women.

Animal Studies

Carcinogenicity
Indinavir is neither mutagenic nor clastogenic in both in vitro and in vivo assays. No increased incidence of any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640 mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid adenomas were seen in male rats.¹

Reproduction/Fertility
No effect of indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.¹

Teratogenicity/Adverse Pregnancy Outcomes
There has been no evidence of teratogenicity or treatment-related effects of indinavir on embryonic/fetal survival or fetal weights in rats, rabbits, or dogs at exposures comparable to, or slightly greater than, therapeutic human exposure. Developmental toxicity in rats, which manifested as an increase in supernumerary and cervical ribs, was observed at doses comparable to those administered to humans. No treatment-related external or visceral changes were observed in rats. No treatment-related external, visceral, or skeletal changes were seen in rabbits (fetal exposure was limited, approximately 3% of maternal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to rhesus monkeys during the third trimester (at doses up to 160 mg/kg twice daily) and to neonatal rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir caused an exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately four-fold greater than those seen in controls receiving indinavir 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester. In rhesus monkeys, fetal plasma drug levels were approximately 1% to 2% of maternal plasma drug levels approximately 1 hour after maternal dosing with indinavir at 40, 80, or 160 mg/kg twice daily.¹

Placental and Breast Milk Passage
Significant placental passage of indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels.¹

Human Studies in Pregnancy

Pharmacokinetics
The optimal dosing regimen for use of indinavir in pregnant patients has not been established. Two studies of the pharmacokinetics (PKs) of unboosted indinavir (800 mg 3 times/day) during pregnancy demonstrated significantly lower indinavir plasma concentrations during pregnancy than postpartum.^2,3 Use of unboosted indinavir is not recommended in pregnant patients with HIV because of the substantially lower antepartum concentrations observed in these studies and the limited experience in this patient population.

Several studies have investigated the use of indinavir/ritonavir (IDV/r) during pregnancy. In an intensive PK study of 26 pregnant Thai women receiving IDV/r 400/100 mg twice daily, indinavir plasma concentrations were significantly lower during pregnancy than postpartum. The median trough indinavir concentration was 0.13 µg/mL; 24% of subjects had trough concentrations below 0.10 µg/mL, the target trough concentration used in therapeutic drug monitoring programs; and 81% of subjects had RNA viral loads <50 copies/mL at delivery.⁴ In a study of pregnant French women receiving IDV/r 400 mg/100 mg twice a day, the median indinavir trough concentration was 0.16 µg/mL, 18% of subjects had trough concentrations below 0.12 µg/mL, and 93% of subjects had HIV RNA levels <200 copies/mL at delivery.⁵ In a small study of two patients who received IDV/r 800 mg/200 mg twice daily, third-trimester indinavir area under the curve exceeded that for historical non-pregnant controls.⁶ The available data are insufficient to allow for definitive dosing recommendations for use of IDV/r during pregnancy.

Placental and Breast Milk Passage
Transplacental passage of indinavir was minimal in studies of pregnant women who received unboosted indinavir. In a study of pregnant Thai women receiving IDV/r, median indinavir concentration in cord blood was 0.12 µg/mL, median maternal plasma delivery concentration was 0.96 µg/mL, and the median ratio between indinavir concentrations in cord blood and maternal plasma at delivery was 0.12.⁴ In one woman taking IDV/r 600 mg/200 mg twice daily, indinavir concentrations in breast milk were 90% to 540% of plasma concentrations over the first 5 days after delivery.⁷

Teratogenicity/Adverse Pregnancy Outcomes
Although the French Perinatal Cohort reported an association of head and neck birth defects with first trimester exposure to indinavir (3 defects in 350 first-trimester exposures, 0.9%), the Antiretroviral Pregnancy Registry has not observed an increase in birth defects with use of indinavir.^8,9 Among cases of first-trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, prevalence of birth defects was 2.4% (7 of 289 births; 95% CI, 1.0% to 4.9%) compared with a total prevalence of 2.76% in the U.S. population, according to Centers for Disease Control and Prevention surveillance. ⁹ 

References

1. Indinavir [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020685s077lbl.pdf.
2. Unadkat JD, Wara DW, Hughes MD, et al. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2007;51(2):783-786. Available at http://www.ncbi.nlm.nih.gov/pubmed/17158945.
3. Hayashi S, Beckerman K, Homma M, Kosel BW, Aweeka FT. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS. 2000;14(8):1061-1062. Available at http://www.ncbi.nlm.nih.gov/pubmed/10853990.
4. Cressey TR, Best BM, Achalapong J, et al. Reduced indinavir exposure during pregnancy. Br J Clin Pharmacol. 2013;76(3):475-483. Available at http://www.ncbi.nlm.nih.gov/pubmed/23305215.
5. Ghosn J, De Montgolfier I, Cornelie C, et al. Antiretroviral therapy with a twice-daily regimen containing 400 milligrams of indinavir and 100 milligrams of ritonavir in human immunodeficiency virus type 1-infected women during pregnancy. Antimicrob Agents Chemother. 2008;52(4):1542-1544. Available at http://www.ncbi.nlm.nih.gov/pubmed/18250187.
6. Kosel BW, Beckerman KP, Hayashi S, Homma M, Aweeka FT. Pharmacokinetics of nelfinavir and indinavir in HIV-1-infected pregnant women. AIDS. 2003;17(8):1195-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/12819521.
7. Colebunders R, Hodossy B, Burger D, et al. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk. AIDS. 2005;19(16):1912-1915. Available at http://www.ncbi.nlm.nih.gov/pubmed/16227801.
8. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781315.
9. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report 1 January 1989–31 January 2018. Wilmington, NC: Registry Coordinating Center. 2018. Available at http://www.apregistry.com/