(Last updated: August 6, 2015; last reviewed: August 6, 2015)
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.
No effect of indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.
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 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 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.
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 (milk-to-plasma ratio 1.26 to 1.45).
Human Studies in Pregnancy
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.1,2 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 have investigated use of indinavir/ritonavir (IDV/r) 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 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% had RNA viral loads <50 copies/mL at delivery.3 In a study of pregnant French women receiving 400 mg indinavir/100 mg ritonavir 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% had HIV RNA level <200 copies/mL at delivery.4 In a small study of 2 patients who received indinavir 800 mg and ritonavir 200 mg twice daily, third-trimester indinavir area under the curve exceeded that for historical non-pregnant controls.5 The available data are insufficient to allow for definitive dosing recommendations for use of IDV/r during pregnancy.
Placental and Breast Milk Passage
In studies of pregnant women receiving unboosted indinavir and their infants, transplacental passage of indinavir was minimal.1,6 In a study of Thai pregnant women receiving IDV/r, median cord blood indinavir concentration 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 0.12.3 It is unknown whether indinavir is excreted in human milk.
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 indinavir.7,8 Among cases of first-trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, defects have been seen in 2.4% (7/289; 95% CI, 1.0% to 4.9%) compared to total prevalence of birth defects in the U.S. population based on Centers for Disease Control and Prevention surveillance of 2.7%.8