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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Abacavir

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

Abacavir (ABC, Ziagen)
Abacavir (ABC, Ziagen)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Pediatric Oral Solution
: 20 mg/mL
Tablets: 300 mg (scored)
Fixed-Dose Combination (FDC) Tablets

With Lamivudine (3TC): 

  • ABC 600 mg + 3TC 300 mg (Epzicom)

With Zidovudine (ZDV) and 3TC: 

  • ABC 300 mg + ZDV 300 mg + 3TC 150 mg (Trizivir)
Dosing Recommendations
Neonate/Infant Dose:
  • Not approved for infants aged <3 months.
Pediatric Dose:

Oral Solution (Aged ≥3 Months): 

  • 8 mg/kg (maximum 300 mg) twice daily. 

Weight Band Dosing (Weight ≥14 kg)
Scored 300-mg tablet. 

Weight (kg) Twice-Daily Dosage Regimen
AM Dose PM Dose Total
Daily Dose
 14–21 kg  ½ tablet
(150 mg)
½ tablet
(150 mg)
300 mg
>21 to <30 kg  ½ tablet
(150 mg)
1 tablet
(300 mg)
450 mg
≥30 kg  1 tablet
(300 mg)
1 tablet
(300 mg)
600 mg

In clinically stable patients with undetectable viral load and stable CD4 T lymphocyte (CD4) counts for more than 24 weeks, changing from twice-daily to once-daily dosing at 16–20 mg/kg/day to a maximum of 600 mg once daily is recommended if part of a once-daily regimen (see text below).

Adolescent (Aged ≥16 years)/Adult Dose:
  • 300 mg twice daily or 600 mg once daily.
Trizivir
  • Adolescent (Weight ≥40 kg)/Adult Dose:
    One tablet twice daily.
Epzicom
  • Adolescent (Aged ≥16 years)/Adult Dose:
    One tablet once daily.
Selected Adverse Events
  • Hypersensitivity reactions (HSRs) can be fatal. HSRs usually occur during the first few weeks of starting therapy. Symptoms may include fever, rash, nausea, vomiting, malaise or fatigue, loss of appetite, and respiratory symptoms (e.g., cough and shortness of breath).
  • Several observational cohort studies suggest increased risk of myocardial infarction in adults with recent or current use of ABC; however, other studies have not substantiated this finding, and there are no data in children.
Special Instructions
  • Test patients for the HLA-B*5701 allele before starting therapy to predict risk of HSR. Patients positive for the HLA-B*5701 allele should not be given ABC. Patients with no prior HLA-B*5701 testing who are tolerating ABC do not need to be tested. 
  • Warn patients and parents about risk of serious potentially fatal HSR. Occurrence of HSRs requires immediate and permanent discontinuation of ABC. Do not re-challenge.
  • ABC can be given without regard to food. Oral solution does not require refrigeration.
Metabolism
  • Systemically metabolized by alcohol dehydrogenase and glucuronyl transferase 
  • Intracellularly metabolized to carbovir triphosphate (CBV-TP). 
  • Active metabolite is 82% renally excreted.
  • ABC requires dosage adjustment in hepatic insufficiency.
  • Do not use fixed-dose combinations such as Trizivir and Epzicom in patients with impaired hepatic function because the dose of abacavir cannot be adjusted.
  • Do not use Trizivir and Epzicom in patients with creatinine clearance (CrCl) <50 mL/min and patients on dialysis (because of the fixed dose of lamivudine).

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

  • Abacavir does not inhibit, nor is it metabolized by hepatic cytochrome P (CYP) 450 enzymes. Therefore, it does not cause changes in clearance of agents metabolized through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (see more information in Drug Interaction section below under Pediatric Use).
  • Through interference with alcohol dehydrogenase and glucuronyl transferase, alcohol increases abacavir levels by 41%.

Major Toxicities

  • More common: Nausea, vomiting, fever, headache, diarrhea, rash, and anorexia.
  • Less common (more severe): Serious and sometimes fatal hypersensitivity reactions (HSRs) observed in approximately 5% of adults and children (rate varies by race/ethnicity) receiving abacavir. HSR to abacavir is a multi-organ clinical syndrome usually characterized by rash or signs or symptoms in two or more of the following groups: 
    • Fever 
    • Constitutional, including malaise, fatigue, or achiness 
    • Gastrointestinal, including nausea, vomiting, diarrhea, or abdominal pain 
    • Respiratory, including dyspnea, cough, or pharyngitis. 
  • Laboratory and radiologic abnormalities include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, lymphopenia, and pulmonary infiltrates. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have also been reported. Pancreatitis can occur. This reaction generally occurs in the first 6 weeks of therapy, but has also been reported after a single dose. If an HSR is suspected, abacavir should be stopped immediately and not restarted—hypotension and death may occur upon re-challenge. The risk of abacavir HSR is associated with the presence of HLA-B*5701 allele; it is greatly reduced by testing patients for HLA-B*5701 prior to the initiation of therapy and by not using abacavir in those who test positive for the HLA-B*5701.
  • Rare: Increased liver enzymes, elevated blood glucose, elevated triglycerides, and possible increased risk of myocardial infarction (in observational studies in adults). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Pancreatitis can occur.
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/ABC.html).

Pediatric Use
Approval 
Abacavir is Food and Drug Administration (FDA)-approved for use in HIV-infected children as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy. 

Efficacy 
Abacavir used either twice daily or once daily has demonstrated durable antiviral effectiveness in pediatric trials.1-3

Pharmacokinetics 
Pharmacokinetics in Children 
Pharmacokinetic (PK) studies of abacavir in children aged <12 years have demonstrated that children have more rapid clearance of abacavir than adults and that pediatric doses approximately twice the directly scaled adult dose are necessary to achieve similar systemic exposure.4,5 Metabolic clearance of abacavir in adolescents and young adults (aged 13–25 years) is slower than that observed in younger children and approximates clearance seen in older adults.6 

Exposure-Response Relationship 
Plasma area under the drug-concentration-by-time curve (AUC) correlates with virologic efficacy of abacavir, although the association is weak.7,8 Intracellular concentrations of NRTIs are most strongly associated with antiviral effectiveness, and the active form of abacavir is the intracellular metabolite carbovir triphosphate (CBV-TP).9,10 Measurement of intracellular CBV-TP is more difficult than measurement of plasma AUC, so the abacavir plasma AUC is frequently considered as a proxy measurement for intracellular concentrations. However, this relationship is not sufficiently strong that changes in plasma AUC can be assumed to reflect true changes in intracellular active drug.11 Intracellular CBV-TP concentrations are affected by gender and have been reported to be higher in females than in males.11-13 This effect of gender and the interactions with PIs (see Drug Interactions section below) on abacavir PK further complicate linking clinically available plasma abacavir concentrations with more difficult to obtain—but pharmacodynamically more important—intracellular CBV-TP concentrations. 

Drug Interactions 
Abacavir plasma AUC has been reported to be decreased by 17% and 32% with concurrent use of the boosted PIs atazanavir/ritonavir and lopinavir/ritonavir, respectively.14 In a study comparing PK parameters of abacavir in combination with either lopinavir/ritonavir or nevirapine, abacavir plasma AUC was decreased 40% by concurrent use of lopinavir/ritonavir; however, the CBV-TP concentrations appeared to be increased in the lopinavir/ritonavir cohort.13 The mechanism and the clinical significance of these drug interactions with the PIs are unclear. No dose adjustment for abacavir or PIs is recommended. 

Dosing
Frequency of Administration
Abacavir 600 mg is administered once daily in adults; however, once-daily use in children remains controversial. The PENTA-13 crossover trial compared abacavir exposure at 16 mg/kg once daily with 8 mg/kg twice daily in 24 children aged 2 to 13 years who had undetectable or low, stable viral loads. This study showed equivalent AUC0-24 for both dosing regimens and improved acceptability of therapy in the once-daily dosing arm.15,16 However, trough abacavir plasma concentrations were lower in younger children (aged 2–6 years) receiving the once-daily regimen.16 The PENTA-15 crossover trial studied 18 children aged 3 to 36 months, again comparing abacavir 16 mg/kg once daily versus 8 mg/kg twice daily in children with viral loads <400 copies/mL or with stable viral loads on twice-daily abacavir at baseline. ABC AUC0-24 and clearance were similar in children on the once- and twice-daily regimens. After the change from twice-daily to once-daily abacavir, viral load remained <400 copies/mL in 16 of 18 participants through 48 weeks of monitoring.17 A study of 41 children (aged 3 to 12 years in Uganda who were stable on twice-daily fixed-dose co-formulation of abacavir/lamivudine) also showed equivalent AUC0-24 and stable clinical outcome (i.e., disease stage and CD4 T lymphocyte [CD4] cell count) after the switch to once-daily abacavir during a median follow-up of 1.15 years. Virologic outcome was not evaluated in this study.18 

Abacavir Steady-State Pharmacokinetics with Once-Daily or Twice-Daily Dosing
Study
(Reference)
Pediatric
PENTA 1517
Pediatric
PENTA 1316
Pediatric
Arrow18
Adult6 Adult11
Location Europe Europe Uganda United States United States
N of Subjects 18 14 36 15 15 27
Mean Age
Years
2 5 7 16 22 45
Sex
% Male
56% 43% 42% 53% 53% 70%
Body weight
kg
11 19 19 63a 72a N/A
Subjects Using PI(s) 8 1 0 9 0 N/A
Dosing interval
Hours
12 24 12 24 12 24 12 12 12 24
Dose
mg
8a 16a 8a 16a 19b 19b 300 300 300 600
Dose Range
mg/kg
7.7-8.3c 15.5-16.3c 5.0-8.4 15.6-17.1 15.4-23.1c 14.6-23.1 N/A
 N/A  N/A  N/A
AUC0-24
mg*hr/L
10.85d 11.57b 9.91d 13.37b 15.6b 15.28b 7.01 6.59 7.90d 8.52d
Cmax 
mg/L
1.38d 4.68 2.14d 4.80d 4.18d 6.84d 2.58 2.74 1.84d 3.85d
Cmin
mg/L
0.03d <0.02d 0.025d <0.015d 0.02d 0.016d N/A
N/A
N/A
N/A
Cl/F/kg
L/hr/kg
1.47d 1.38d 1.58d 1.16d 1.23d 1.24d 9.80e 12.10e N/A
N/A
Data are medians except as noted.
a mg/kg
b total daily dose in mg/kg (divided doses were given but sometimes in unequal amounts morning and evening)
c interquartile range
d geometric mean
e mL/min/kg

Key to Acronyms: AUC = area under the curve; Cmax = maximal (peak) concentration; Cmin = minimal (trough) concentration; PI = protease inhibitor


Most recently, a pediatric PK model was developed based on data from 69 children in the PENTA trials (13 and 15) and ARROW study.19 Irrespective of age, body weight was identified as the most significant factor influencing the oral clearance of abacavir in children. Predicted steady state peak (Cmax) and AUC0-12 abacavir concentrations on standard twice-daily dosing were lower in toddlers and infants aged 0.4 to 2.8 years when compared with children aged 3.6 to 12.8 years. Model-based predictions showed that equivalent systemic plasma abacavir exposure was achieved after once- or twice-daily dosing regimens. The model did not include information on ethnicity and other potentially important demographic factors. No clinical trials have been conducted involving children who initiated therapy with once-daily dosing of abacavir. None of the pediatric clinical trials evaluated the pharmacodynamically most important intracellular CBV-TP concentrations. All three pediatric studies presented in the table above enrolled only patients who had low viral loads or were clinically stable on twice-daily abacavir before changing to once-daily dosing. Recent data from 48-week follow-up in the ARROW trial demonstrated clinical non-inferiority of once-daily (336 children) versus twice-daily abacavir (333 children) in combination with a once- or twice-daily lamivudine-based regimen.3 Therefore, as part of a once-daily regimen, the Panel suggests a switch from twice-daily to once-daily dosing of abacavir (at a dose of 16 to 20 mg/kg/dose [maximum of 600 mg] once daily) for clinically stable patients with undetectable viral loads and stable CD4 cell counts for more than 6 months.

Toxicity 
Abacavir has less of an effect on mitochondrial function than zidovudine, stavudine, or didanosine.1,2 

References

  1. 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.
  2. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. AIDS. May 11 2007;21(8):947-955. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457088.
  3. Musiime V, Kasirye P, al e. Randomised comparison of once versus twice daily abacavir and lamivudine among 669 HIV-infected children in the ARROW trial. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2013; Atlanta, GA.
  4. Hughes W, McDowell JA, Shenep J, et al. Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. Mar 1999;43(3):609-615. Available at http://www.ncbi.nlm.nih.gov/pubmed/10049275.
  5. Cross SJ, Rodman JH, Lindsey JC, et al. Abacavir and metabolite pharmacokinetics in HIV-1-infected children and adolescents. J Acquir Immune Defic Syndr. May 1 2009;51(1):54-59. Available at http://www.ncbi.nlm.nih.gov/pubmed/19282779.
  6. Sleasman JW, Robbins BL, Cross SJ, et al. Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults. Clin Pharmacol Ther. Apr 2009;85(4):394-401. Available at http://www.ncbi.nlm.nih.gov/pubmed/19118380.
  7. McDowell JA, Lou Y, Symonds WS, Stein DS. Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. Aug 2000;44(8):2061-2067. Available at http://www.ncbi.nlm.nih.gov/pubmed/10898676.
  8. Weller S, Radomski KM, Lou Y, Stein DS. Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. Aug 2000;44(8):2052-2060. Available at http://www.ncbi.nlm.nih.gov/pubmed/10898675.
  9. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS. Oct 17 2003;17(15):2159-2168. Available at http://www.ncbi.nlm.nih.gov/pubmed/14523272.
  10. Fletcher CV, Kawle SP, Kakuda TN, et al. Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons. AIDS. Sep 29 2000;14(14):2137-2144. Available at http://www.ncbi.nlm.nih.gov/pubmed/11061655.
  11. Moyle G, Boffito M, Fletcher C, et al. Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. Apr 2009;53(4):1532-1538. Available at http://www.ncbi.nlm.nih.gov/pubmed/19188387.
  12. Harris M, Back D, Kewn S, Jutha S, Marina R, Montaner JS. Intracellular carbovir triphosphate levels in patients taking abacavir once a day. AIDS. May 24 2002;16(8):1196-1197. Available at http://www.ncbi.nlm.nih.gov/pubmed/12004286.
  13. Pruvost A, Negredo E, Theodoro F, et al. Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir. Antimicrob Agents Chemother. May 2009;53(5):1937-1943. Available at http://www.ncbi.nlm.nih.gov/pubmed/19273671.
  14. Waters LJ, Moyle G, Bonora S, et al. Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients. Antivir Ther. 2007;12(5):825-830. Available at http://www.ncbi.nlm.nih.gov/pubmed/17713166.
  15. LePrevost M, Green H, Flynn J, et al. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. Jun 2006;25(6):533-537. Available at http://www.ncbi.nlm.nih.gov/pubmed/16732152.
  16. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Available at http://www.ncbi.nlm.nih.gov/pubmed/15865218.
  17. Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. Antivir Ther. 2010;15(3):297-305. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20516550.
  18. Musiime V, Kendall L, Bakeera-Kitaka S, et al. Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-1124. Available at http://www.ncbi.nlm.nih.gov/pubmed/21149918.
  19. Zhao W, Piana C, Danhof M, Burger D, Pasqua OD, Jacqz-Aigrain E. Population pharmacokinetics of abacavir in infants, toddlers and children. Br J Clin Pharmacol. Nov 5 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/23126277.

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