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

Archived Drugs

Tipranavir (Aptivus, TPV)

Tipranavir is classified as Food and Drug Administration Pregnancy Category C. Tipranavir should not be used during pregnancy.

Animal Studies

Carcinogenicity
Tipranavir was neither mutagenic nor clastogenic in a battery of five screening tests, both in vitro and, in animals, in vivo. Long-term carcinogenicity studies of tipranavir have been conducted in mice and rats. Mice were administered tipranavir doses ranging from 30 to 300 mg/kg/day, with or without ritonavir 40 mg/kg/day; all doses resulted in systemic exposures below those seen in humans receiving the recommended dose. Incidence of benign hepatocellular adenomas, combined adenomas/carcinomas, and hepatocellular carcinoma was increased in both male and female mice receiving tipranavir/ritonavir (TPV/r). The clinical relevance of the carcinogenic findings in mice is unknown. Rats were administered doses ranging from 30 to 300 mg/kg/day tipranavir, with or without ritonavir. No drug-related findings were observed in male rats. At the highest dose of tipranavir (approximately equivalent to exposure in humans at the recommended therapeutic dose), an increased incidence of benign follicular cell adenomas of the thyroid gland was observed in female rats. This finding is probably not relevant to humans, because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction.¹

Reproduction/Fertility
Tipranavir had no effect on fertility or early embryonic development in rats at exposure levels that are similar to human exposure levels at the recommended clinical dose (TPV/r 500 mg/200 mg administered twice daily).¹

Teratogenicity/Adverse Pregnancy Outcomes
No teratogenicity was detected in studies of pregnant rats and rabbits at exposure levels approximately 1.1-fold and 0.1-fold human exposure. Fetal toxicity (decreased ossification and body weights) was observed in rats exposed to 400 mg/kg/day or more of tipranavir (~0.8-fold human exposure). Fetal toxicity was not seen in rats and rabbits at levels of 0.2-fold and 0.1-fold human exposures. In rats, no adverse effects on development were seen at levels of 40 mg/kg/day (~0.2-fold human exposure), but at 400 mg/kg/day (~0.8-fold human exposure).¹

Placental and Breast Milk Passage
No animal studies of placental or breast milk passage of tipranavir have been reported.

Human Studies in Pregnancy

Pharmacokinetics
No studies of tipranavir have been completed in pregnant women or neonates.

Placental and Breast Milk Passage
It is unknown if passage of tipranavir through the placenta or breast milk occurs in humans. A single case report described relatively high levels of tipranavir in the third trimester and relatively high placental transfer (0.41), as measured by cord blood.²

Teratogenicity/Adverse Pregnancy Outcomes
The five first-trimester exposures to tipranavir that have been monitored to date in the Antiretroviral Pregnancy Registry are insufficient to allow conclusions to be drawn regarding risk of birth defects.³

References

1. Tipranavir [package insert]. Food and Drug Administration. 2016. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021814s016,022292s009lbl.pdf.
2. Weizsaecker K, Kurowski M, Hoffmeister B, Schurmann D, Feiterna-Sperling C. Pharmacokinetic profile in late pregnancy and cord blood concentration of tipranavir and enfuvirtide. Int J STD AIDS. 2011;22(5):294-295. Available at http://www.ncbi.nlm.nih.gov/pubmed/21571982.
3. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2018. Wilmington, NC: Registry Coordinating Center. 2018. Available at http://www.apregistry.com.