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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Protease Inhibitors (PIs)
(Last updated: February 12, 2014; last reviewed: March 5, 2015)
Possible increased bleeding episodes in patients with hemophilia
When given in combination with ritonavir, meal restrictions are not necessary.
Adequate hydration is required to minimize risk of nephrolithiasis (≥48 oz of fluid daily in adult patients).
If co-administered with didanosine, give indinavir and didanosine ≥1 hour apart on an empty stomach.
Indinavir capsules are sensitive to moisture; store at room temperature (59–86º F) in original container with desiccant.
Cytochrome P450 3A4 (CYP3A4) inhibitor and substrate
Dosing in patients with hepatic impairment: Decreased dosage should be used in patients with mild-to-moderate hepatic impairment (recommended dose for adults is 600 mg indinavir every 8 hours). No dosing information is available for children with any degree of hepatic impairment or for adults with severe hepatic impairment.
Indinavir has not been approved by the Food and Drug Administration (FDA) for use in the pediatric population. Although indinavir was one of the first protease inhibitors to be studied in children, its use in pediatrics has never been common and is currently very rare.1
Both unboosted and ritonavir-boosted indinavir have been studied in HIV-infected children. Data in children indicate that an unboosted indinavir dose of 500 to 600 mg/m2 body surface area given every 8 hours results in peak blood concentrations and area under the curve slightly higher than those in adults but considerably lower trough concentrations. A significant proportion of children have trough indinavir concentrations less than the 0.1 mg/L value associated with virologic efficacy in adults.2-5 Studies in small groups of children of a range of ritonavir-boosted indinavir doses have shown that indinavir 500 mg/m2 body surface area plus ritonavir 100 mg/m2 body surface area twice daily is probably too high,6 that indinavir 234 to 250 mg/m2 body surface area plus low-dose ritonavir twice daily is too low,7,8 and that indinavir 400 mg/m2 body surface area plus ritonavir 100 to 125 mg/m2 body surface area twice daily results in exposures approximating those seen with 800 mg indinavir/100 mg ritonavir twice daily in adults, albeit with considerable inter-individual variability and high rates of toxicity.8-10
The cumulative frequency of nephrolithiasis is substantially higher in children (29%) than in adults (12.4%, range across clinical trials 4.7%–34.4%).11 This is likely due to the difficulty in maintaining adequate hydration in children. Finally, a large analysis of more than 2,000 HIV-infected children from PACTG 219 demonstrated a hazard ratio of 1.7 for risk of renal dysfunction in children receiving combination antiretroviral therapy with indinavir.12
Van Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr. 2011;57(2):165-173. Available at http://www.ncbi.nlm.nih.gov/pubmed/21407086.
Burger DM, van Rossum AM, Hugen PW, et al. Pharmacokinetics of the protease inhibitor indinavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. 2001;45(3):701-705. Available at http://www.ncbi.nlm.nih.gov/pubmed/11181346.
Fletcher CV, Brundage RC, Remmel RP, et al. Pharmacologic characteristics of indinavir, didanosine, and stavudine in human immunodeficiency virus-infected children receiving combination therapy. Antimicrob Agents Chemother. 2000;44(4):1029-1034. Available at http://www.ncbi.nlm.nih.gov/pubmed/10722507.
Gatti G, Vigano A, Sala N, et al. Indinavir pharmacokinetics and parmacodynamics in children with human immunodeficiency virus infection. Antimicrob Agents Chemother. 2000;44(3):752-755. Available at http://www.ncbi.nlm.nih.gov/pubmed/10681350.
Mueller BU, Sleasman J, Nelson RP, Jr., et al. A phase I/II study of the protease inhibitor indinavir in children with HIV infection. Pediatrics. 1998;102(1 Pt 1):101-109. Available at http://www.ncbi.nlm.nih.gov/pubmed/9651421.
van Rossum AM, Dieleman JP, Fraaij PL, et al. Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with indinavir. Pediatrics. 2002;110(2 Pt 1):e19. Available at http://www.ncbi.nlm.nih.gov/pubmed/12165618.
Plipat N, Cressey TR, Vanprapar N, Chokephaibulkit K. Efficacy and plasma concentrations of indinavir when boosted with ritonavir in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis J. 2007;26(1):86-88. Available at http://www.ncbi.nlm.nih.gov/pubmed/17195716.
Curras V, Hocht C, Mangano A, et al. Pharmacokinetic study of the variability of indinavir drug levels when boosted with ritonavir in HIV-infected children. Pharmacology. 2009;83(1):59-66. Available at http://www.ncbi.nlm.nih.gov/pubmed/19052483.
Bergshoeff AS, Fraaij PL, van Rossum AM, et al. Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. 2004;48(5):1904-1907. Available at http://www.ncbi.nlm.nih.gov/pubmed/15105157.
Fraaij PL, Bergshoeff AS, van Rossum AM, Hartwig NG, Burger DM, de Groot R. Changes in indinavir exposure over time: a case study in six HIV-1-infected children. J Antimicrob Chemother. 2003;52(4):727-730. Available at http://www.ncbi.nlm.nih.gov/pubmed/12917234.
Crixivan [package insert]. Food and Drug Administration. 2010. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020685s073lbl.pdf. Accessed December 22, 2014.
Andiman WA, Chernoff MC, Mitchell C, et al. Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J. 2009;28(7):619-625. Available at http://www.ncbi.nlm.nih.gov/pubmed/19561425.