Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Protease Inhibitors (PIs)
(Last updated:11/1/2012; last reviewed:11/1/2012)
|Saquinavir (SQV, Invirase)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Hard-gel capsules: 200 mg
Film-coated tablets: 500 mg
- Not approved for use in neonates/infants.
- Not approved for use in children.
Investigational doses in treatment-experienced children:
- SQV must be boosted with ritonavir (RTV):
Aged <2 years:
Aged ≥2 years (conditional dosing based on limited data, see text):
- No dose has been determined.
Aged ≥7 years in combination with lopinavir/ritonavir (LPV/r) for salvage therapy (conditional dosing based on limited data, see text):
SQV + RTV
||SQV 50 mg/kg + RTV 3 mg/kg, both twice daily
||SQV 50 mg/kg + RTV 2.5 mg/kg, both twice daily
||SQV 50 mg/kg + RTV 100 mg, both twice daily
- SQV 750 mg/m2 (max 1600 mg) or SQV
50 mg/kg have been used in combination with LPV/r, both twice daily.
Adolescent (aged ≥16 years)/adult dose:
SQV should only be used in combination with RTV or LPV/r (never unboosted).
- SQV 1000 mg + RTV 100 mg, both twice daily.
- SQV 1000 mg + LPV/r 400/100 mg, both twice daily.
|Selected Adverse Events
- Gastrointestinal intolerance, nausea, and diarrhea
- Elevated transaminases
- Fat maldistribution
- Possible increased bleeding episodes in patients with hemophilia
- PR interval prolongation
- QT interval prolongation and ventricular tachycardia (torsades de pointes) have been reported.
- 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 (ECG) is recommended and SQV is not recommended in patients with a prolonged QT interval.
- 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):
- Metabolism: Saquinavir is both a substrate and inhibitor of the CYP3A4 system, and there is potential for numerous drug interactions.
- Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions.
- More common: Diarrhea, abdominal discomfort, headache, nausea, paresthesias, skin rash, and lipid abnormalities.
- Less common (more severe): Exacerbation of chronic liver disease, fat maldistribution.
- 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 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: Saquinavir is not Food and Drug Administration (FDA)-approved for use in children. Saquinavir has been studied with nucleoside reverse transcriptase inhibitors (NRTIs) and other protease inhibitors (PIs) in HIV-infected children.1-6 Initial studies suggest that saquinavir should not be used without boosting by ritonavir or lopinavir/ritonavir. 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 younger than age 2 years whereas drug exposure was adequate in those ages 2 to 5 years.7 For this reason, saquinavir should not be given to children younger than age 2 years until an appropriate dose is identified. 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 - <15 kg) or 2.5 mg/kg twice daily (patients weighing 15 - 40 kg) resulted in area under the curve and steady state trough concentration (Ctrough) values similar to those in older children8,9 and adults. Because there is no pediatric formulation, in one study saquinavir was formulated by breaking open the 200-mg hard-gel capsules and mixing capsule contents with sugar syrup, jam, or baby formula. Sorbitol syrup was used for patients with diabetes or glucose intolerance.7
Both saquinavir/ritonavir and saquinavir/lopinavir/ritonavir regimens are promising for salvage therapy in children.1,3-6,8-10 In a study evaluating the addition of saquinavir (750 mg/m2 of body surface area every 12 hours, maximum dose 1600 mg) to a regimen containing lopinavir/ritonavir dosed at 400/100 mg/m2 of body surface area twice daily (for patients not concurrently taking a non-nucleoside reverse transcriptase inhibitor [NNRTI]) or lopinavir/ritonavir 480/120 mg/m2 of body surface area twice daily for patients concurrently administered an NNRTI, 18 subjects (median age 14.2 years, range 7.7–17.6 years) were enrolled. The addition of saquinavir at these doses was well tolerated and did not appear to alter lopinavir PKs. Saquinavir dosing was adjusted in four patients (decreased in three, increased in one).10
In a study of 50 Thai children, saquinavir/lopinavir/ritonavir was initiated as second-line therapy based on extensive NRTI resistance. In this group, saquinavir was dosed at 50 mg/m2 of body surface area and lopinavir/ritonavir was dosed at 230/57.5 mg/m2 of body surface area, all twice daily. After 96 weeks of treatment, 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). Median total cholesterol and high-density lipoprotein values increased significantly through 96 weeks from 144 to 196 mg/dL and from 44 to 57 mg/dL, respectively.8,9
In a healthy adult volunteer study, saquinavir/ritonavir use was associated with increases in both QT and PR intervals.11 The degree of QT prolongation was greater than that seen with some other boosted PIs. Rare cases of torsades de pointes and complete heart block have been reported in post-marketing surveillance. Saquinavir/ritonavir 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 electrocardiogram is recommended before initiation of therapy with saquinavir and should be considered during therapy.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. Scandinavian journal of infectious diseases. 2002;34(1):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11874163.
- 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. 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA.
- 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.
- 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.
- 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.
- Food and Drug Administration (FDA). Invirase (package insert). October 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020628s033,021785s010lbl.pdf.