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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Saquinavir

(Last updated:2/12/2014; last reviewed:2/12/2014)

Saquinavir (SQV, Invirase)

Saquinavir (SQV, Invirase)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Formulations

Hard-Gel Capsules:
200 mg
Film-Coated Tablets: 500 mg

Dosing Recommendations

Neonate/Infant Dose:
  • Not approved for use in neonates/infants.
Pediatric Dose:
  • Not approved for use in children.
Investigational Doses in Treatment-Experienced Children:
  • Saquinavir must be boosted with ritonavir.
Aged <2 years:
  • No dose has been determined.
Aged ≥2 Years (Conditional Dosing Based on Limited Data, See Text):
Weight (kg) Dose
Saquinavir plus Ritonavir
5 to <15 kg saquinavir 50 mg/kg plus ritonavir 3 mg/kg, both twice daily
15 to 40 kg  saquinavir 50 mg/kg plus ritonavir 2.5 mg/kg, both twice daily
≥40 kg  saquinavir 50 mg/kg plus ritonavir 100 mg, both twice daily

Aged ≥7 Years in Combination with Ritonavir-Boosted Lopinavir for Salvage Therapy (Conditional Dosing Based On Limited Data, See Text):

  • Saquinavir 750 mg/m2 (max 1600 mg) and saquinavir 50 mg/kg each have been used in combination with ritonavir-boosted lopinavir, both twice daily.
Adolescent (Aged ≥16 years)/Adult Dose:
  • Saquinavir should only be used in combination with ritonavir or ritonavir-boosted lopinavir (never unboosted). 
  • Saquinavir 1000 mg + ritonavir 100 mg, both twice daily
  • Saquinavir 1000 mg + ritonavir-boosted lopinavir 400/100 mg, both twice daily

Selected Adverse Events

  • Gastrointestinal intolerance, nausea, and diarrhea
  • Headache
  • Elevated transaminases
  • Hyperlipidemia
  • Hyperglycemia
  • Fat maldistribution
  • Increased bleeding episodes in patients with hemophilia 
  • PR interval prolongation, QT interval prolongation and ventricular tachycardia (torsades de pointes) have been reported.

Special Instructions

  • Administer within 2 hours after a full meal.
  • Sun exposure can cause photosensitivity reactions; advise patients to use sunscreen or protective clothing.
  • Pre-therapy electrocardiogram is recommended and saquinavir is contraindicated in patients with a prolonged QT interval.

Metabolism

  • Cytochrome P450 3A4 (CYP3A4) substrate and inhibitor, 90% metabolized in the liver.
  • Use in patients with hepatic impairment: Use with caution.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents)

  • Saquinavir is both a substrate and inhibitor of the CYP3A4 system. Potential exists for multiple drug interactions. Co-administration of saquinavir is contraindicated with drugs that are highly dependent on the CYP3A clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. 
  • Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions.

Major Toxicities

  • More common: Diarrhea, abdominal discomfort, headache, nausea, paresthesia, skin rash, and lipid abnormalities.
  • Less common (more severe): Exacerbation of chronic liver disease, lipodystrophy.
  • Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, pancreatitis, and elevation in serum transaminases. The combination of saquinavir and ritonavir could lead to prolonged PR and/or QT intervals with potential for heart block and ventricular tachycardia (torsades de pointes).

Resistance

The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/SQV.html).

Pediatric Use

Approval
Saquinavir is not Food and Drug Administration (FDA)-approved for use in children. 

Efficacy
Saquinavir has been studied with nucleoside reverse transcriptase inhibitors (NRTIs) and other protease inhibitors in HIV-infected children.1-6 Ritonavir-boosted saquinavir and saquinavir/lopinavir/ritonavir regimens were considered for salvage therapy in children prior to the emergence of the new classes of antiretroviral medications.1,3-9

Pharmacokinetics
Studies suggest that saquinavir should not be used without boosting by ritonavir or ritonavir-boosted lopinavir. A pharmacokinetic (PK) analysis of 5 children aged younger than 2 years and 13 children aged 2 to 5 years using a dose of 50 mg/kg twice daily with boosting ritonavir demonstrated that drug exposure was lower in children aged <2 years whereas drug exposure was adequate in those aged 2 to 5 years.10 For this reason, saquinavir should not be administered to children aged <2 years. In children aged ≥2 years, a dose of 50 mg/kg twice daily (maximum dose = 1000 mg) boosted with ritonavir 3 mg/kg twice daily (patients weighing 5 to <15 kg) or 2.5 mg/kg twice daily (patients weighing 15–40 kg) resulted in area under the curve and steady-state trough plasma concentration (Ctrough) values similar to those in older children7,8 and adults. 

In a study of 18 children (median age 14.2 years, range 7.7–17.6 years) evaluating the addition of saquinavir (750 mg/m2 body surface area every 12 hours, maximum dose 1600 mg) to a regimen containing ritonavir-boosted lopinavir dosed at 400/100 mg/m2 body surface area twice daily (for patients not concurrently taking a non-nucleoside reverse transcriptase inhibitor [NNRTI]) or ritonavir-boosted lopinavir 480/120 mg/m2 body surface area twice daily for patients concurrently administered an NNRTI, the addition of saquinavir was well tolerated and did not appear to alter lopinavir PKs. Saquinavir required dose adjustment in four patients (decreased in three, increased in one).9

In a study of 50 Thai children, saquinavir/lopinavir/ritonavir was initiated as second-line therapy based on extensive NRTI resistance (saquinavir was dosed at 50 mg/m2 body surface area and ritonavir-boosted lopinavir was dosed at 230/57.5 mg/m2 body surface area, all twice daily). After 96 weeks, 74% of the children achieved an undetectable plasma RNA load at <50 copies/mL. Therapeutic drug monitoring was used to establish adequate minimum plasma concentration (Cmin) values and to aid with alterations in drug dosage based upon toxicity. Most Cmin values for saquinavir were above the desired trough value of 0.1 mg/L. The average Cmin throughout 96 weeks for saquinavir was 1.37 mg/L, and when saquinavir doses were adjusted, most were decreased by an average of 21% (8 mg/kg).7,8

Toxicity
In a healthy adult volunteer study, ritonavir-boosted saquinavir use was associated with increases in both QT and PR intervals.11,12 Rare cases of torsades de pointes and complete heart block have been reported in post-marketing surveillance. Ritonavir-boosted saquinavir is not recommended for patients with any of the following conditions: documented congenital or acquired QT prolongation, pretreatment QT interval of >450 milliseconds, refractory hypokalemia or hypomagnesemia, complete atrioventricular block without implanted pacemakers, at risk of complete AV block, or receiving other drugs that prolong QT interval. An ECG is recommended before initiation of therapy with saquinavir and should be considered during therapy.

References

  1. Ananworanich J, Kosalaraksa P, Hill A, et al. Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children. Pediatr Infect Dis J. Oct 2005;24(10):874-879. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220084.
  2. De Luca M, Miccinesi G, Chiappini E, Zappa M, Galli L, De Martino M. Different kinetics of immunologic recovery using nelfinavir or lopinavir/ritonavir-based regimens in children with perinatal HIV-1 infection. Int J Immunopathol Pharmacol. Oct-Dec 2005;18(4):729-735. Available at http://www.ncbi.nlm.nih.gov/pubmed/16388722.
  3. Grub S, Delora P, Ludin E, et al. Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection. Clin Pharmacol Ther. Mar 2002;71(3):122-130. Available at http://www.ncbi.nlm.nih.gov/pubmed/11907486.
  4. Hoffmann F, Notheis G, Wintergerst U, Eberle J, Gurtler L, Belohradsky BH. Comparison of ritonavir plus saquinavir- and nelfinavir plus saquinavir-containing regimens as salvage therapy in children with human immunodeficiency type 1 infection. Pediatr Infect Dis J. Jan 2000;19(1):47-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/10643850.
  5. Kline MW, Brundage RC, Fletcher CV, et al. Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection. Pediatr Infect Dis J. Jul 2001;20(7):666-671. Available at http://www.ncbi.nlm.nih.gov/pubmed/11465838.
  6. Palacios GC, Palafox VL, Alvarez-Munoz MT, et al. Response to two consecutive protease inhibitor combination therapy regimens in a cohort of HIV-1-infected children. 
  7. Scand J Infect Dis. 2002;34(1):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11874163.
  8. Bunupuradah T, van der Lugt J, Kosalaraksa P, et al. Safety and efficacy of a double-boosted protease inhibitor combination, saquinavir and lopinavir/ritonavir, in pretreated children at 96 weeks. Antivir Ther. 2009;14(2):241-248. Available at http://www.ncbi.nlm.nih.gov/pubmed/19430099.
  9. Kosalaraksa P, Bunupuradah T, Engchanil C, et al. Double boosted protease inhibitors, saquinavir, and lopinavir/ritonavir, in nucleoside pretreated children at 48 weeks. Pediatr Infect Dis J. Jul 2008;27(7):623-628. Available at http://www.ncbi.nlm.nih.gov/pubmed/18520443.
  10. Robbins BL, Capparelli EV, Chadwick EG, et al. Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors. Antimicrob Agents Chemother. Sep 2008;52(9):3276-3283. Available at http://www.ncbi.nlm.nih.gov/pubmed/18625762.
  11. Haznedar J, Zhang A, Labriola-Tompkins E, et al. A pharmacokinetic study of ritonavir-boosted saquinavir in HIV-infected children 4 months to <6 years old. Paper presented at: 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA.
  12. Food and Drug Administration (FDA). Invirase (package insert). October 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020628s033,021785s010lbl.pdf.
  13. Zhang X, Jordan P, Cristea L, et al. Thorough QT/QTc study of ritonavir-boosted saquinavir following multiple-dose administration of therapeutic and supratherapeutic doses in healthy participants. J Clin Pharmacol. Apr 2012;52(4):520-529. Available at http://www.ncbi.nlm.nih.gov/pubmed/21558456.