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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Nelfinavir

(Last updated: February 12, 2014; last reviewed: February 12, 2014)

Nelfinavir (NFV, Viracept)
Nelfinavir (NFV, Viracept)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Formulations

Tablets:
250 mg and 625 mg

Dosing Recommendations

Neonate/Infant Dose:
  • Nelfinavir should not be used for treatment in children aged <2 years.
Pediatric Dose (Aged 2–13 Years):
  • 45–55 mg/kg twice daily
Adolescent/Adult Dose:
  • 1250 mg (five 250-mg tablets or two 625-mg tablets) twice daily
  • Some adolescents require higher doses than adults to achieve equivalent drug exposures. Consider using therapeutic drug monitoring to guide appropriate dosing.



Selected Adverse Events

  • Diarrhea
  • Hyperlipidemia
  • Hyperglycemia
  • Fat maldistribution
  • Possible increase in bleeding episodes in patients with hemophilia
  • Serum transaminase elevations

Special Instructions

  • Administer nelfinavir with meal or light snack.
  • If co-administered with didanosine, administer nelfinavir 2 hours before or 1 hour after didanosine.
  • Patients unable to swallow nelfinavir tablets can dissolve the tablets in a small amount of water. Once tablets are dissolved, patients should mix the cloudy mixture well and consume it immediately. The glass should be rinsed with water and the rinse swallowed to ensure that the entire dose is consumed. Tablets can also be crushed and administered with pudding or other nonacidic foods.

Metabolism

  • CYP2C19 and 3A4 substrate
  • Metabolized to active M8 metabolite
  • CYP3A4 inhibitor

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

  • Metabolism: Cytochrome P (CYP) 2C19 and 3A4 substrate. Metabolized to active M8 metabolite. CYP3A4 inhibitor. However, ritonavir boosting does not significantly increase nelfinavir concentrations and co-administration of nelfinavir with ritonavir is not recommended.
  • There is potential for multiple drug interactions with nelfinavir.
  • Before administering nelfinavir, carefully review a patient’s medication profile for potential drug interactions.

Major Toxicities

  • More common: Diarrhea (most common), asthenia, abdominal pain, rash, and lipid abnormalities.
  • Less common (more severe): Exacerbation of chronic liver disease, fat redistribution.
  • Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, and elevations in transaminases.

Resistance

The International Antiviral 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/NFV.html).

Pediatric Use

Approval
Nelfinavir is a protease inhibitor (PI) approved for use in combination with 2 nucleoside reverse transcriptase inhibitors in children aged >2 years. Nelfinavir is not recommended for treatment of children aged <2 years (see the Perinatal Guidelines).

Efficacy in Pediatric Clinical Trials
Nelfinavir in combination with other antiretroviral drugs has been extensively studied in HIV-infected children.1-8 In randomized trials of children aged 2 to 13 years receiving nelfinavir as part of triple combination antiretroviral therapy (cART), the proportion of patients with HIV RNA <400 copies/mL through 48 weeks of therapy has been quite variable, ranging from 26% to 69%. In clinical studies, virologic and immunologic response to nelfinavir-based therapy has varied according to the patient’s age or prior history of ART, the number of drugs included in the combination regimen, and dose of nelfinavir used. 

Pharmacokinetics: Exposure-Response Relationships
The relatively poor ability of nelfinavir to control plasma viremia in infants and children in clinical trials may be related to lower potency compared with other PIs or non-nucleoside reverse transcriptase inhibitors, as well as highly variable drug exposure, metabolism, and poor patient acceptance of available formulations.9-11

Administration of nelfinavir with food increases nelfinavir exposure (area under the curve increased by as much as five fold) and decreases pharmacokinetic (PK) variability relative to the fasted state. Drug exposure may be even more unpredictable in pediatric patients than in adults because of increased clearance of nelfinavir observed in children, and difficulties in taking nelfinavir with sufficient food to improve bioavailability. A pediatric powder formulation, no longer available, was poorly tolerated when mixed with food or formula. In the PENTA-7 trial, 35% (7 of 20) of infants started on powder at initiation of therapy were switched from the powder to crushed tablets because of difficulty administering the oral formulation to the infants.1 A slurry made by dissolving nelfinavir tablets in water or other liquids can be administered to children who are unable to swallow tablets. The bioavailability of dissolved nelfinavir tablets is comparable to that of tablets swallowed whole.12 

Nelfinavir is metabolized by multiple CYP-450 enzymes including CYP3A4 and CYP2C19. M8, the major oxidative metabolite, has in vitro antiviral activity comparable to the parent drug. The variability of drug exposure at any given dose is much higher for children than adults,13 which has been attributed at least in part to differences in the diets of children and adults. Two population PK studies of nelfinavir and its active metabolite, M8, describe the large intersubject variability observed in children.14,15 Analysis of data from PACTG 377 and PACTG 366 showed that CYP2C19 genotypes altered nelfinavir PKs and the virologic responses to combination therapy in HIV-1-infected children. These findings suggest that CYP2C19 genotypes are important determinants of nelfinavir PKs and virologic response in HIV-1-infected children.9

Several studies have demonstrated a correlation between nelfinavir trough concentrations and virologic response. In both children and adults, an increased risk of virologic failure was associated with low nelfinavir drug exposure, particularly with a nelfinavir minimum plasma concentration (Cmin) <1.0 mcg/mL.16-18

The antiviral response to nelfinavir is significantly less in children younger than age 2 years than in older children.6,8,19 Infants have even lower drug exposures and higher variability in plasma concentrations than children with body weights <25 kg; the presence of lower peak drug concentrations and higher apparent oral clearance suggests that both poor absorption and more rapid metabolism may be contributing factors.20,21 In a study of 32 children treated with nelfinavir 90 mg/kg/day divided into 2 or 3 doses a day, 80% of children with morning trough nelfinavir plasma concentration >0.8 mcg/mL had Week 48 HIV RNA concentrations <50 copies/mL, compared with only 29% of those with morning trough <0.8 mcg/mL.22 It is of note that the median age of the group with Ctrough <0.8 mcg/mL was 3.8 years, while the median age of the group with Ctrough >0.8 mcg/mL was 8.3 years.22 Therapeutic drug monitoring (TDM) of nelfinavir plasma concentrations, with appropriate adjustments for low drug exposure, results in improved outcome in adults treated with nelfinavir.16,23 Similarly, better virologic responses were demonstrated in two pediatric trials in which TDM was used to guide dosing;15,24 doses higher than those recommended in adults may be required in some patients. Given the higher variability of nelfinavir plasma concentrations in infants and children, nelfinavir is not recommended for use in children younger than age 2 years. 

References

  1. Aboulker JP, Babiker A, Chaix ML, et al. Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome. AIDS. Jan 23 2004;18(2):237-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/15075541.
  2. King JR, Nachman S, Yogev R, et al. Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403. Pediatr Infect Dis J. Oct 2005;24(10):880-885. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220085.
  3. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. Apr 1 2002;34(7):991-1001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880966.
  4. Krogstad P, Wiznia A, Luzuriaga K, et al. Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect Dis. May 1999;28(5):1109-1118. Available at http://www.ncbi.nlm.nih.gov/pubmed/10452644.
  5. Luzuriaga K, McManus M, Mofenson L, et al. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med. Jun 10 2004;350(24):2471-2480. Available at http://www.ncbi.nlm.nih.gov/pubmed/15190139.
  6. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet. 2002;359(9308):733-740. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11888583&query_hl=42.
  7. Resino S, Larru B, Maria Bellon J, et al. Effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to nelfinavir in children. BMC Infect Dis. 2006;6:107. Available at http://www.ncbi.nlm.nih.gov/pubmed/16834769.
  8. Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JM, Kuijpers TW. Long-term experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years in a pediatric cohort. Pediatrics. Mar 2006;117(3):e528-536. Available at http://www.ncbi.nlm.nih.gov/pubmed/16481448.
  9. Saitoh A, Capparelli E, Aweeka F, et al. CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. Jul 2010;54(3):285-289. Available at http://www.ncbi.nlm.nih.gov/pubmed/19890215.
  10. Wu H, Lathey J, Ruan P, et al. Relationship of plasma HIV-1 RNA dynamics to baseline factors and virological responses to highly active antiretroviral therapy in adolescents (aged 12-22 years) infected through high-risk behavior. J Infect Dis. 2004;189(4):593-601. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14767811&query_hl=31.
  11. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. Jun 27 2002;346(26):2039-2046. Available at http://www.ncbi.nlm.nih.gov/pubmed/12087139.
  12. Regazzi MB, Seminari E, Villani P, et al. Nelfinavir suspension obtained from nelfinavir tablets has equivalent pharmacokinetic profile. J Chemother. Oct 2001;13(5):569-574. Available at http://www.ncbi.nlm.nih.gov/pubmed/11760223.
  13. Gatti G, Castelli-Gattinara G, Cruciani M, et al. Pharmacokinetics and pharmacodynamics of nelfinavir administered twice or thrice daily to human immunodeficiency virus type 1-infected children. Clin Infect Dis. Jun 1 2003;36(11):1476-1482. Available at http://www.ncbi.nlm.nih.gov/pubmed/12766843.
  14. Hirt D, Urien S, Jullien V, et al. Age-related effects on nelfinavir and M8 pharmacokinetics: a population study with 182 children. Antimicrob Agents Chemother. Mar 2006;50(3):910-916. Available at http://www.ncbi.nlm.nih.gov/pubmed/16495250.
  15. Crommentuyn KM, Scherpbier HJ, Kuijpers TW, Mathot RA, Huitema AD, Beijnen JH. Population pharmacokinetics and pharmacodynamics of nelfinavir and its active metabolite M8 in HIV-1-infected children. Pediatr Infect Dis J. Jun 2006;25(6):538-543. Available at http://www.ncbi.nlm.nih.gov/pubmed/16732153.
  16. Burger DM, Hugen PW, Aarnoutse RE, et al. Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations. Ther Drug Monit. 2003;25(1):73-80. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12548148&query_hl=15.
  17. Gonzalez de Requena D, Nunez M, de Mendoza C, Jimenez-Nacher I, Soriano V. Nelfinavir plasma concentrations in patients experiencing early failure with nelfinavir-containing triple combinations. AIDS. Feb 14 2003;17(3):442-444. Available at http://www.ncbi.nlm.nih.gov/pubmed/12556700.
  18. Pellegrin I, Breilh D, Montestruc F, et al. Virologic response to nelfinavir-based regimens: pharmacokinetics and drug resistance mutations (VIRAPHAR study). AIDS. Jul 5 2002;16(10):1331-1340. Available at http://www.ncbi.nlm.nih.gov/pubmed/12131209.
  19. Food and Drug Administration (FDA). Nelfinavir (Viracept®) product label.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020778s035,020779s056,021503s017lbl.pdf.
  20. Capparelli EV, Sullivan JL, Mofenson L, et al. Pharmacokinetics of nelfinavir in human immunodeficiency virus-infected infants. Pediatr Infect Dis J. Aug 2001;20(8):746-751. Available at http://www.ncbi.nlm.nih.gov/pubmed/11734735.
  21. Mirochnick M, Stek A, Acevedo M, et al. Safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life. J Acquir Immune Defic Syndr. Jun 1 2005;39(2):189-194. Available at http://www.ncbi.nlm.nih.gov/pubmed/15905735.
  22. Burger DM, Bergshoeff AS, De Groot R, et al. Maintaining the nelfinavir trough concentration above 0.8 mg/L improves virologic response in HIV-1-infected children. J Pediatr. Sep 2004;145(3):403-405. Available at http://www.ncbi.nlm.nih.gov/pubmed/15343199.
  23. Burger D, Hugen P, Reiss P, et al. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS. May 23 2003;17(8):1157-1165. Available at http://www.ncbi.nlm.nih.gov/pubmed/12819517.
  24. Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial. Clin Pharmacol Ther. Feb 2008;83(2):300-306. Available at http://www.ncbi.nlm.nih.gov/pubmed/17609682.

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