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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

Saquinavir (Invirase [Hard Gel Capsule], SQV)

(Last updated:7/31/2012; last reviewed:7/31/2012)

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Saquinavir (Invirase, SQV) is classified as FDA Pregnancy Category B.

Animal carcinogenicity studies
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 60% of those obtained in humans at the recommended therapeutic dose (rats) and at exposures equivalent to those in humans at the recommended therapeutic dose (mice).

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.

Teratogenicity/developmental toxicity
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 (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.

Too few first-trimester saquinavir exposures have been monitored by the Antiretroviral Pregnancy Registry to be able to accurately calculate the prevalence of birth defects in exposed cases.1

Placental and breast milk transfer
Placental transfer of saquinavir in the rat and rabbit was minimal. In a Phase I study in pregnant women and their infants (PACTG 386, see below), transplacental passage of saquinavir was minimal.2 In addition, in a study of cord blood samples from 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.3 Saquinavir is excreted in the milk of lactating rats; it is not known if it is excreted in human milk.

Human studies in pregnancy
Three studies have evaluated PKs of saquinavir-hard gel capsules (HGC) combined with low-dose ritonavir (saquinavir-HGC 1000 mg/ritonavir 100 mg given twice daily) in a total of 19 pregnant women; trough levels were greater than the target in all but 1 woman.4,5 In a small study of 2 women who received saquinavir-HGC 1200 mg/ritonavir 100 mg given once daily, trough levels were 285 and 684 ng/mL and the AUC0–24 were 28,010 and 16,790 ng hour/mL, greater than the target AUC of 10,000 ng hour/mL.6 Thus, the limited available data suggest that saquinavir-HGC 1000 mg/ritonavir 100 mg given twice daily should achieve adequate trough levels in HIV-infected pregnant women. Data are too limited to recommend once-daily dosing at present. However, a recent analysis of saquinavir HGC administered once daily at 1200 mg/100 mg ritonavir combined with various nucleoside reverse transcriptase inhibitors during 46 pregnancies demonstrated saquinavir levels greater than the target minimum plasma concentration in 46 (93.4%) of pregnancy episodes and undetectable viral load at delivery in 88% of episodes.7 Target levels were achieved in the other 3 women with a dose of 1600 mg/100 mg. The drug was well tolerated.

The PKs of the new 500-mg tablet formulation of saquinavir boosted with ritonavir in a dose of saquinavir 1000 mg/ritonavir 100 mg given twice daily were studied in 37 HIV-infected pregnant women at 20 and 33 weeks’ gestation and 6 weeks postpartum; PK parameters were comparable during pregnancy and postpartum.8 However, in a smaller study of saquinavir tablets boosted with ritonavir given to 14 HIV-infected pregnant women, the saquinavir exposure during the third trimester was reduced by about 50%, yet no woman experienced loss of virologic control and all but 1 maintained adequate trough levels of saquinavir.9 Thus, it does not appear that any adjustment of saquinavir boosted with ritonavir is necessary during pregnancy.

One study of a saquinavir/ritonavir-based combination ARV drug regimen in 42 women during pregnancy 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).10

References

  1. 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.
  2. 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. Jun 2007;51(6):2208-2210. Available at http://www.ncbi.nlm.nih.gov/pubmed/17420209.
  3. 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.
  4. Hanlon M, O'Dea S, Woods S, et al. Evaluation of saquinavir/ritonavir based regimen for prevention of MTCT of HIV. Paper presented at: 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver, CO. Abstract 721.
  5. 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. Paper presented at: XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand.
  6. 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. May-Jun 2003;4(3):227-229. Available at http://www.ncbi.nlm.nih.gov/pubmed/12815561.
  7. 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. Apr 2007;29(2):171-176. Available at http://www.ncbi.nlm.nih.gov/pubmed/17417070.
  8. 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.
  9. 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. Dec 2011;33(6):772-777. Available at http://www.ncbi.nlm.nih.gov/pubmed/22105596.
  10. Hanlon M, O'Dea S, Clarke S, et al. Maternal hepatotoxicity with boosted saquinavir as part of combination ART in pregnancy. Paper presented at: 14th Conference on Retoviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles, CA. Abstract 753.