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
Indinavir (Crixivan, IDV)
(Last updated:7/31/2012; last reviewed:7/31/2012)
Indinavir (Crixivan, IDV) is classified as FDA Pregnancy Category C.
Animal carcinogenicity studies
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.
Reproduction/fertility
No effect of indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.
Teratogenicity/developmental toxicity
There has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival or fetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to or slightly greater than therapeutic human exposure. In rats, developmental toxicity manifested by 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 limited, approximately 3% of maternal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to pregnant 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 exacerbated the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately 4-fold greater than controls at 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 at 40, 80, or 160 mg/kg twice daily.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposure to indinavir in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with indinavir. Among cases of first-trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.1% (6 of 286 births; 95% CI, 0.8%–4.5%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance.1
Placental and breast milk passage
Significant placental passage of indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. In studies of pregnant women receiving unboosted indinavir and their infants, transplacental passage of indinavir was minimal.2,3 In a study of Thai pregnant women receiving indinavir boosted with ritonavir, median cord blood indinavir concentration was 0.12 mcg/mL, median maternal plasma delivery concentration was 0.96 mcg/mL, and the median ratio between indinavir concentrations in cord blood and maternal plasma at delivery was 12%.4 Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels (milk-to-plasma ratio 1.26–1.45); it is not known if indinavir is excreted in human milk.
Human studies in pregnancy
The optimal dosing regimen for use of indinavir in pregnant patients has not been established. Two studies of the PKs of unboosted indinavir (800 mg 3 times a day) during pregnancy demonstrated significantly lower indinavir plasma concentrations during pregnancy than postpartum.2,5 Use of unboosted indinavir is not recommended in HIV-infected pregnant patients because of the substantially lower antepartum exposures observed in these studies and the limited experience in this patient population.
Several reports investigate the use of indinavir with ritonavir boosting during pregnancy. In an intensive PK study of 26 Thai pregnant women receiving 400 mg indinavir/100 mg ritonavir twice a day, indinavir plasma concentrations were significantly lower during pregnancy than postpartum. The median trough indinavir concentration was 0.13 mcg/mL; 24% of subjects had trough concentrations below 0.10 mcg/mL, the target trough concentration used in therapeutic drug monitoring (TDM) programs; and 81% had RNA viral loads <50 copies/mL at delivery.4 In a study of French pregnant women receiving 400 mg indinavir/100 mg ritonavir twice a day, the median indinavir trough concentration was 0.16 mcg/mL, 18% of subjects had trough concentrations below 0.12 mcg/mL, and 93% had HIV RNA level < 200 copies/mL at delivery.6 In a small study of 2 women who received indinavir 800 mg and ritonavir 200 mg twice daily, third-trimester indinavir AUC exceeded that for historical non-pregnant controls.7 Based on these data, indinavir can be used in pregnancy with ritonavir boosting. Given the limited data on appropriate dosing, HIV RNA levels and trough indinavir concentrations should be monitored during indinavir use in pregnancy.
References
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available at http://www.APRegistry.com.
- Unadkat JD, Wara DW, Hughes MD, et al. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. Feb 2007;51(2):783-786. Available at http://www.ncbi.nlm.nih.gov/pubmed/17158945.
- Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. Sep 2002;21(9):835-838. Available at http://www.ncbi.nlm.nih.gov/pubmed/12352805.
- Cressey TR, Kreitchman R, et al. Effect of pregnancy on pharmacokinetics of indinavir boosted ritonavir. Paper presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona, Spain. Abstract P37.
- Hayashi S, Beckerman K, Homma M, Kosel BW, Aweeka FT. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS. May 26 2000;14(8):1061-1062. Available at http://www.ncbi.nlm.nih.gov/pubmed/10853990.
- 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. Apr 2008;52(4):1542-1544. Available at http://www.ncbi.nlm.nih.gov/pubmed/18250187.
- Kosel BW, Beckerman KP, Hayashi S, Homma M, Aweeka FT. Pharmacokinetics of nelfinavir and indinavir in HIV-1-infected pregnant women. AIDS. May 23 2003;17(8):1195-1199. Available at http://www.ncbi.nlm.nih.gov/pubmed/12819521.