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

Archived Drugs

Saquinavir (Invirase, SQV)

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

Animal Studies

Carcinogenicity
Saquinavir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Carcinogenicity studies found no indication of carcinogenic activity in rats and mice given saquinavir for approximately 2 years at doses that produced plasma exposures approximately 29% (in rats) and 65% (in mice) of those obtained in humans who received the recommended clinical dose boosted with ritonavir.¹

Reproduction/Fertility
Saquinavir has had no observable effects on reproductive performance, fertility, or embryo survival in rats. Because of the limited bioavailability of saquinavir in animals, the maximum plasma exposures achieved in rats were approximately 26% of those obtained in humans who received the recommended clinical dose boosted with ritonavir.¹

Teratogenicity/Adverse Pregnancy Outcomes
No evidence of embryotoxicity or teratogenicity of saquinavir has been found in rabbits or rats. Because of the limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (measured as area under the curve [AUC] values) were approximately 29% (in rats) and 21% (in rabbits) of those obtained in humans who received the recommended clinical dose boosted with ritonavir.¹

Placental and Breast Milk Passage
Placental transfer of saquinavir in rats and rabbits was minimal. Saquinavir is excreted in the milk of lactating rats.¹

Human Studies in Pregnancy

Pharmacokinetics
Studies have investigated saquinavir pharmacokinetics (PK) during pregnancy using 800 mg to 1200 mg of the original hard-gel capsule formulation and ritonavir 100 mg. Saquinavir exposures were reduced in pregnant adults compared to nonpregnant adults, but the majority of subjects achieved adequate C_min.^2-4 The PKs of saquinavir when using the current 500-mg tablets at a dose of saquinavir/ritonavir 1000 mg/100 mg twice daily have been studied in pregnant women in two studies.^5,6 One study performed intensive sampling on pregnant women with HIV at 20 weeks’ gestation (n = 16), 33 weeks’ gestation (n = 31), and 6 weeks postpartum (n = 9). PK parameters were comparable during pregnancy and postpartum.⁵ The second study performed intensive sampling in 14 pregnant women at 24 and 34 weeks’ gestation and 6 weeks postpartum. Saquinavir AUC was similar during the second trimester and postpartum. Although there was a 50% reduction in saquinavir AUC during the third trimester compared to postpartum, no participant experienced loss of virologic control and all but one maintained adequate third-trimester trough levels of saquinavir.⁷ An observational study analyzed saquinavir concentrations in samples that were collected as part of clinical care between 11 and 13 hours after dosing with the tablet formulation (saquinavir/ritonavir 1000 mg/100 mg) in pregnant women with HIV during the third trimester (n = 20) and at delivery (n = 5). Saquinavir plasma concentrations averaged around 1.15 mg/L and exceeded 0.1 mg/L, the usual trough drug concentration target for saquinavir, in all but one subject.⁶

Placental and Breast Milk Passage
In a Phase 1 study in pregnant women and their infants (PACTG 386), transplacental passage of saquinavir was minimal.⁸ In addition, in a study of eight women treated with saquinavir during pregnancy, the cord blood concentration of saquinavir was less than the assay limit of detection in samples from all of the women in the study.⁹ It is not known whether saquinavir is excreted in human milk.

Teratogenicity/Adverse Pregnancy Outcomes
Only 182 cases of first-trimester saquinavir exposure have been reported to the Antiretroviral Pregnancy Registry. Without more data, the prevalence of birth defects among infants exposed to saquinavir cannot be accurately calculated.¹⁰

Other Safety Information
One study of 42 pregnant women who received antiretroviral therapy that included saquinavir/ritonavir reported abnormal transaminase levels in 13 women (31%) within 2 to 4 weeks of treatment initiation, although the abnormalities were mild (toxicity Grade 1–2 in most women, Grade 3 in one woman).¹¹ In a study of 62 pregnant women on a regimen that included saquinavir/ritonavir, one severe adverse event occurred (maternal Grade 3 hepatotoxicity).⁶

In the U.S. PHACS/SMARTT cohort study, after adjusting for birth cohort and other factors, maternal use of saquinavir led to no increase in the likelihood of adverse metabolic, growth/development, cardiac, or neurological outcomes. Late language emergence was more likely among saquinavir-exposed infants at 1 year (odds ratio 2.72; 95% CI, 1.09–6.91, P = 0.03), but not at 2 years. No significant differences were observed for other neurodevelopmental outcomes.¹²

References

1. Saquinavir [package insert]. Food and Drug Administration. 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020628s041,021785s017lbl.pdf.
2. Khan W, Hawkins DA, Moyle G, et al. Pharmacokinetics (PK), safety, tolerability and efficacy of saquinavir hard-gel capsules/ritonavir (SQV/r) plus 2 nucleosides in HIV-infected pregnant women. Presented at: XV International AIDS Conference. 2004. Bangkok, Thailand.
3. Lopez-Cortes LF, Ruiz-Valderas R, Pascual R, Rodriguez M, Marin Niebla A. Once-daily saquinavir-hgc plus low-dose ritonavir (1200/100 mg) in HIV-infected pregnant women: pharmacokinetics and efficacy. HIV Clin Trials. 2003;4(3):227-229. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12815561.
4. Lopez-Cortes LF, Ruiz-Valderas R, Rivero A, et al. Efficacy of low-dose boosted saquinavir once daily plus nucleoside reverse transcriptase inhibitors in pregnant HIV-1-infected women with a therapeutic drug monitoring strategy. Ther Drug Monit. 2007;29(2):171-176. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17417070.
5. van der Lugt J, Colbers A, Molto J, et al. The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women. Antivir Ther. 2009;14(3):443-450. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19474478.
6. Brunet C, Reliquet V, Jovelin T, et al. Effectiveness and safety of saquinavir/ritonavir in HIV-infected pregnant women: INEMA cohort. Med Mal Infect. 2012;42(9):421-428. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22938775.
7. Martinez-Rebollar M, Lonca M, Perez I, et al. Pharmacokinetic study of saquinavir 500 mg plus ritonavir (1000/100 mg twice a day) in HIV-positive pregnant women. Ther Drug Monit. 2011;33(6):772-777. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22105596.
8. Zorrilla CD, Van Dyke R, Bardeguez A, et al. Clinical response and tolerability to and safety of saquinavir with low-dose ritonavir in human immunodeficiency virus type 1-infected mothers and their infants. Antimicrob Agents Chemother. 2007;51(6):2208-2210. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17420209.
9. 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.
10. 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/.
11. Hanlon M, O'Dea S, Clarke S, al e. Maternal hepatotoxicity with boosted saquinavir as part of combination ART in pregnancy. Presented at: 14th Conference on Retoviruses and Opportunistic Infections. 2007. Los Angeles, CA.
12. Van Dyke RB, Chadwick EG, Hazra R, Williams PL, Seage GR, 3rd. The PHACS SMARTT study: assessment of the safety of In utero exposure to antiretroviral drugs. Front Immunol. 2016;7:199. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27242802.