Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

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Protease Inhibitors

Saquinavir (Invirase, SQV)

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

Saquinavir is classified as Food and Drug Administration Pregnancy Category B.

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 administered saquinavir for approximately 2 years at plasma exposures approximately 29% (rat) and 65% (mouse) of those obtained in humans at the recommended clinical dose boosted with ritonavir.1

Reproduction/Fertility
No effect of saquinavir has been seen on reproductive performance, fertility, or embryo survival in rats. Because of limited bioavailability of saquinavir in animals, the maximal plasma exposures achieved in rats were approximately 26% of those obtained in humans at 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 limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (area under the curve [AUC] values) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir.1

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

Human Studies in Pregnancy

Pharmacokinetics
Studies of saquinavir pharmacokinetics (PK) in pregnancy with 800 to 1200 mg of the original hard-gel capsule formulation and 100 mg ritonavir demonstrated reduced saquinavir exposures compared with nonpregnant adults, but adequate Cmin in the majority of subjects.2-4 The PK of saquinavir with the current 500-mg tablets boosted with ritonavir at a dose of 1000 mg saquinavir/100 mg ritonavir given 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 in the third trimester compared to postpartum, no subject experienced loss of virologic control and all but one maintained adequate third-trimester trough levels of saquinavir.7 In an observational study of saquinavir concentrations collected as part of clinical care between 11 and 13 hours after dosing with the tablet formulation (1000 mg saquinavir/100 mg ritonavir) 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 the usual trough drug concentration target for saquinavir of 0.1 mg/L 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 women.9 It is not known whether saquinavir is excreted in human milk.

Teratogenicity/Adverse Pregnancy Outcomes
The 182 first-trimester saquinavir exposures monitored by the Antiretroviral Pregnancy Registry are too few to be able to accurately calculate the prevalence of birth defects in exposed cases.10

Other Safety Information
One study of 42 pregnant women receiving 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, Grade 3 in 1 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, neurological outcomes. Late language emergence was more likely among saquinavir-exposed infants at 1 year (OR 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

Excerpt from Table 9a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Saquinavir
(SQV)
Invirase

Note:
Must be combined with low-dose RTV for PK boosting
Tablet:
  • 500 mg
Capsule:
  • 200 mg
Standard Adult Dose:
  • SQV 1000 mg plus RTV 100 mg twice a day with food or within 2 hours after a meal

PK in Pregnancy:
  • Based on limited data, SQV exposure may be reduced in pregnancy but not sufficient to warrant a dose change.

Dosing in Pregnancy:
  • No change in dose indicated.
Low placental transfer to fetus.b

Insufficient data to assess for teratogenicity in humans. No evidence of teratogenicity in rats or rabbits.

Must be boosted with low-dose RTV.

Baseline ECG recommended before starting because PR and/or QT interval prolongations have been observed. Contraindicated in patients with preexisting cardiac conduction system disease.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 7).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic hepatitis B virus infection in adults
e Generic formulation available
f WHO recommends maximum dose of 30 mg twice daily regardless of weight.

Key to Acronyms: ECG = electrocardiogram; EFV = efavirenz; PK = pharmacokinetic; RTV = ritonavir; SQV = saquinavir; WHO = World Health Organization

References 

  1. Saquinavir (Invirase) [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. Medecine et Maladies Infectieuses. 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 2017. Wilmington, NC: Registry Coordinating Center. 2017. Available at http://www. apregistry.com/.
  11. Hanlon M, O'Dea S, Clarke S, et al. 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.

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