Skip to main content
SpringerLink
Log in

Antiretroviral Pharmacokinetics in the Paediatric Population

A Review

  • Review Articles
  • Special Populations
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Characteristics unique to paediatric pharmacotherapy should be considered when treating children infected with human immunodeficiency virus (HIV). Processes of growth and development in the paediatric patient can significantly affect drug absorption and disposition. Immature renal function, altered hepatic enzyme activity and differences in drug absorption lead to variations in systemic exposure of antiretrovirals among children. Paediatric patients are also subject to unique circumstances that may prevent adherence to antiretroviral regimens.

The pharmacokinetics of nucleoside reverse transcriptase inhibitors differ significantly among preterm infants, full-term infants and older children. Decreased hepatic glucuronidation activity in neonates results in pharmacokinetic differences in zidovudine disposition when compared with older children. Didanosine, stavudine and lamivudine are renally eliminated, thus resulting in differences among young children with immature renal function. Pharmacokinetic data for non-nucleoside reverse transcriptase inhibitors in children are limited. Decreased elimination of nevirapine among neonates has been observed, primarily due to decreased enzymatic activity. Pharmacokinetic differences across age groups have been noted for efavirenz, but no formal assessments have been conducted in children weighing less than 10kg. Protease inhibitors are metabolised by the cytochrome P450 enzyme system, which is not fully developed in younger children. Decreased metabolism can result in elevated plasma concentrations, thereby increasing the chance of toxicity.

Unfortunately, few studies exist evaluating the pharmacokinetics of anti-retrovirals in children. As a result, dosage selection of antiretrovirals in children often occurs without adequate data. As the life expectancy of HIV-infected children increases, use of antiretrovirals to prevent disease progression also increases. If prevention of treatment failure continues to be the goal of antiretroviral therapy, the pharmacokinetics of antiretrovirals in children need to be assessed early in the drug development process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II

Similar content being viewed by others

References

  1. Elsberry VA. Principles of rational drug use in children. Clin Trends Pharm Prac 1995; 9(5): 77–83

    Google Scholar 

  2. Yaffe SJ, Aranda JV, editors. Pediatric pharmacology: therapeutic principles in practice. 2nd ed. Philadelphia (PA): WB Saunders Company, 1992: 16

    Google Scholar 

  3. Taketomo CK, Hodding JH, Kraus DM. Pediatric dosage handbook. 6th ed. Hudson (OH): Lexi-Comp Inc, 1998

    Google Scholar 

  4. Kearns GL. Meeting the needs of the modernization act: challenges in developing pediatric therapies. J Allergol Clin Immunol 2000; 106: S128–38

    Article  CAS  Google Scholar 

  5. Jospe N, Forbes G. Fluids and electrolytes-clinical aspects. Pediatr Rev 1996; 17: 395–402

    PubMed  CAS  Google Scholar 

  6. Evans WE, Schentag JJ, Jusko WJ, editors. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3rd ed. Vancouver (WA): Applied Therapeutics, 1992

    Google Scholar 

  7. Shingadia D, Viani R, Rolando M, et al. Gastrostomy tube insertion for improvement of adherence to highly active anti-retroviral therapy in pediatric patients with human immunodeficiency virus [abstract]. Pediatrics 2000; 105(6): 1326

    Article  Google Scholar 

  8. Gao WY, Shirasaka T, Johns DG, et al. Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J Biol Chem 1993; 91: 2326–33

    CAS  Google Scholar 

  9. Havlir DV, Tierney C, Friedland GH, et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis 2000; 182: 321–5

    Article  PubMed  CAS  Google Scholar 

  10. Faletto MB, Miller WH, Garvey EP, et al. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother 1997; 41: 1099–107

    PubMed  CAS  Google Scholar 

  11. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection [online]. Available from URL: http://www.hivatis.org/ [Accessed 2002 Sep 03]

  12. Zidovudine (Retrovir) [package insert]. Research Triangle Park (NC): Glaxo Wellcome, 1998

  13. Didanosine (Videx) [package insert]. Princeton (NJ): Bristol-Myers Squibb, 2000

  14. Stavudine (Zerit) [package insert]. Princeton (NJ): Bristol-Myers Squibb, 2000

  15. Lamivudine (Epivir) [package insert]. Research Triangle Park (NC): Glaxo Wellcome, 1999

  16. Abacavir (Ziagen) [package insert]. Research Triangle Park (NC): Glaxo Wellcome, 1998

  17. Nevirapine (Viramune) [package insert]. Columbus (OH): Roxane, 2000

  18. Delavirdine (Rescriptor) [package insert]. La Jolla (CA): Agouron, 2000

  19. Efavirenz (Sustiva) [package insert]. Wilmington (DE): DuPont, 2000

  20. Saquinavir (Fortovase) [package insert]. Nutley (NJ): Roche, 2000

  21. Brundage RC, Kline MW, Lindsey JC, et al. Pharmacokinetics (PK) of saquinavir (SQV) and nelfinavir (NFV) in a twice-daily (BID) regimen in HIV-infected children [abstract 718]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retorvirology and Human Health, 2000: 209

    Google Scholar 

  22. Ritonavir (Norvir) [package insert]. North Chicago (IL): Abbott, 2000

  23. Indinavir (Crixivan) [package insert]. West Point (PA): Merck, 2000

  24. Gatti G, Vigano A, Sala N, et al. Indinavir pharmacokinetics and pharmacodynamics in children with human immunodeficiency virus infection. Antimicrob Agents Chemother 2000; 44: 752–5

    Article  PubMed  CAS  Google Scholar 

  25. Nelfinavir (Viracept) [package insert]. La Jolla (CA): Agouron, 2000

  26. Acosta EP, Nachman S, Wiznia A, et al. Pharmacokinetic (PK) evaluation of nelfinavir (NFV) in combination with nevirapine (NVP) or ritonavir (RTV) in HIV-infected children-PACTG 403 [abstract 1642]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto. Washington, DC: Society for Microbiology, 2000: 334

    Google Scholar 

  27. Amprenavir (Agenerase) [package insert]. Research Triangle Park (NC): Glaxo Wellcome, 1999

  28. Lopinavir/Ritonavir (Kaletra) [package insert]. North Chicago (IL): Abbott Laboratories, 2000

  29. Gibb D, Barry M, Ormesher S, et al. Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in children with HIV infection. Br J Clin Pharmacol 1995; 39: 527–30

    Article  PubMed  CAS  Google Scholar 

  30. Kline MW, Dunkle LM, Church JA, et al. A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection. Pediatrics 1995; 96: 247–52

    PubMed  CAS  Google Scholar 

  31. Veldkamp A, Van Heeswyk RPG, Scherpbier HJ, et al. The steady-state plasma pharmacokinetics of lamivudine and stavudine in HIV-1 infected children [abstract WePeB4124]. 13th International AIDS Conference; 2000; Durban, South Africa

    Google Scholar 

  32. Hughes W, McDowell JA, Shenep J, et al. Safety and singledose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother 1999; 43: 609–15

    PubMed  CAS  Google Scholar 

  33. Luzuriaga K, Byrson Y, McSherry G, et al. Pharmacokinetics, safety, and activity of nevirapine in human immunodeficiency virus type 1-infected children. J Infect Dis 1996; 174: 713–21

    Article  PubMed  CAS  Google Scholar 

  34. Willoughby R, Watson D, Welliver R, et al. Phase I evaluation of delavirdine in HIV-1-infected pediatric patients [abstract 1995]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco. Washington, DC: American Society for Microbiology, 1999: 522

    Google Scholar 

  35. Brundage RC, Fletcher CV, Fiske WD, et al. Pharmacokinetics of an efavirenz suspension in children [abstract 424]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 1999: 147

    Google Scholar 

  36. Fletcher CV, Kline MW, Brundage RC, et al. Pharmacologic characteristics of saquinavir soft gelatin capsules (SQV-SGC) given with nucleoside antiretroviral agents (NRTIs) with and without nelfinavir (NLV) in HIV infected children [abstract 223]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago. Alexandria (VA): Foundation for Retrovirology and Human Health, 1998: 121

    Google Scholar 

  37. Mueller BU, Nelson RP, Sleasman J, et al. A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection. Pediatrics 1998; 101: 335–43

    Article  PubMed  CAS  Google Scholar 

  38. 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: 1029–34

    Article  PubMed  CAS  Google Scholar 

  39. 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 1999; 28: 1109–18

    Article  PubMed  CAS  Google Scholar 

  40. Balis FM, Pizzo PA, Eddy J, et al. Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. J Pediatr 1989; 114: 880–4

    Article  PubMed  CAS  Google Scholar 

  41. Klecker RW, Collins JM, Yarchoan R, et al. Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxy-thymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 1987; 41: 407–12

    Article  PubMed  Google Scholar 

  42. Boucher FD, Modlin JF, Weller S, et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr 1993; 122: 137–44

    Article  PubMed  CAS  Google Scholar 

  43. Mirochnick M, Capparelli E, Dankner W, et al. Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother 1998; 42: 808–12

    PubMed  CAS  Google Scholar 

  44. Balis FM, Pizzo PA, Murphy RF, et al. The pharmacokinetics of zidovudine administered by continuous infusion in children. Ann Intern Med 1989; 110: 279–85

    PubMed  CAS  Google Scholar 

  45. Stevens RC, Rodman JH, Yong FH, et al. Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. AIDS Res Hum Retroviruses 2000; 16: 415–21

    Article  PubMed  CAS  Google Scholar 

  46. King JR, Nachman S, Wiznia A, et al. Pharmacokinetics (PK) of enteric-coated didanosine (ddI EC) in HIV-infected pediatric patients [abstract 106]. Pharmacotherapy 2001; 21: 1272

    Google Scholar 

  47. Balis FM, Pizzo PA, Butler KM, et al. Clinical pharmacology of 2′,3′-dideoxyinosine in human immunodeficiency virus-infected children. J Infect Dis 1992; 165: 99–104

    Article  PubMed  CAS  Google Scholar 

  48. Mueller BU, Butler KM, Stocker VL, et al. Clinical and pharmacokinetic evaluation of long-term therapy with didanosine in children with HIV infection. Pediatrics 1994; 94: 724–31

    PubMed  CAS  Google Scholar 

  49. Capparelli E. Pharmacokinetics of didanosine in HIV-infected infants [abstract A-63]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; Washington (DC): American Society of Microbiology, 1998: 20

    Google Scholar 

  50. Lewis LL, Venzon D, Church J, et al. Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. J Infect Dis 1996; 174: 16–25

    Article  PubMed  CAS  Google Scholar 

  51. Mueller BU, Lewis LL, Yuen GJ, et al. Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother 1998; 42: 3187–92

    PubMed  CAS  Google Scholar 

  52. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 1998; 178: 1327–33

    Article  PubMed  CAS  Google Scholar 

  53. Kumar PN, Sweet DE, McDowell JA, et al. Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency type 1-infected adults. Antimicrob Agents Chemother 1999; 43: 603–8

    PubMed  CAS  Google Scholar 

  54. Johnson GM, Rodman JH, McDowell J, et al. Preliminary analysis of abacavir succinate (ABC) pharmacokinetics in neonates differs from adults and young children [abstract 720]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2000: 209

    Google Scholar 

  55. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998; 178: 368–74

    Article  PubMed  CAS  Google Scholar 

  56. Musoke P, Guay L, Bagenda D, et al. A phase I/II study of safety and pharmacokinetics of nevirapine in HIV-1 infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999; 13: 479–86

    Article  PubMed  CAS  Google Scholar 

  57. Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. N Engl J Med 1999; 341: 1874–81

    Article  PubMed  CAS  Google Scholar 

  58. Debouck C. The HIV-1 protease as a therapeutic target for AIDS. AIDS Res Hum Retroviruses 1992; 8: 153–64

    Article  PubMed  CAS  Google Scholar 

  59. Kohl NE, Emini EA, Schleif WA, et al. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci USA 1988; 85: 4686–90

    Article  PubMed  CAS  Google Scholar 

  60. Breilh D, Thuret I, Dumon C, et al. Population pharmacokinetic of ritonavir in 31 HIV-infected infants [abstract 1202]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sept 25–29; San Francisco. Washington, DC: American Society for Microbiology, 1999: 35

    Google Scholar 

  61. Burger DM, van Rossum AMC, Hugen PW, et al. Pharmacokinetics of the protease inhibitor indinavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother 2001; 45: 701–5

    Article  PubMed  CAS  Google Scholar 

  62. van Rossum AMC, de Groot R, Hartwig NG, et al. Pharmacokinetics of indinavir and low-dose ritonavir in children with HIV-1 infection. AIDS 2000; 14: 2209–19

    Article  PubMed  Google Scholar 

  63. Litalien C, Ciaquinto C, Faye A, et al. Nelfinavir doses should be increased in infants less than 3 months [abstract MoPeB2213]. 13th International AIDS Conference; 2000 Jul 9–14; Durban, South Africa. Fairfield (MN): Marathon Multimedia, 2000

    Google Scholar 

  64. Brundage RC, Fletcher CV, Fenton T, et al. Efavirenz (EFV) and nelfinavir (NFV) pharmacokinetics (PK) in HIV-infected children under 2 years of age [abstract 719]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2000: 209

    Google Scholar 

  65. Capparelli E, Sullivan J, Mofenson L, et al. Pharmacokinetics (PK) of nelfinavir in HIV infected infants [abstract 1658]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto. Washington, DC: American Society for Microbiology, 2000: 338

    Google Scholar 

  66. Capparelli E, Burchett S, Kovacs A, et al. Nelfinavir (NFV) pharmacokinetics in combination with ritonavir (RTV) in infants and children with advanced HIV disease [abstract 661]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco. Alexandria (VA): Foundation for Retrovirology and Human Health, 2000: 199

    Google Scholar 

  67. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing. Antimicrob Agents Chemother 2001; 45: 30–7

    Article  PubMed  CAS  Google Scholar 

  68. Wintergerst U, Engelhorn C, Kurowski M, et al. Pharmacokinetic interaction of amprenavir in combination with efavirenz or delavirdine in HIV-infected children. AIDS 2000; 14: 1866–7

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Supported in part by grant U01-AI 41089 from the National Institutes of Allergy and Infectious Diseases and by grants from the General Clinical Research Center Program (RR-032). The authors have no potential conflicts of interest related to this manuscript.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 116, Birmingham, Alabama, 35294-0019, USA

    Jennifer R. King &  Edward P. Acosta

  2. Department of Pediatric Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA

    David W. Kimberlin & Grace M. Aldrovandi

Authors
  1. Jennifer R. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David W. Kimberlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Grace M. Aldrovandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward P. Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward P. Acosta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

King, J.R., Kimberlin, D.W., Aldrovandi, G.M. et al. Antiretroviral Pharmacokinetics in the Paediatric Population. Clin Pharmacokinet 41, 1115–1133 (2002). https://doi.org/10.2165/00003088-200241140-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200241140-00001

Keywords

Search

Navigation