Abacavir Pharmacokinetics During Chronic Therapy in HIV-1-Infected Adolescents and Young Adults

Abstract

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and ≥18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults. © 2009 American Society for Clinical Pharmacology and TherapeuticsCorrespondence: EV Capparelli (ecapparelli@ucsd.edu). CONFLICT OF INTEREST G.E.P. is employed by and owns stock in GlaxoSmithKline. E.V.C. has served as a paid consultant to GlaxoSmithKline. The other authors declared no conflict of interest. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAbacavir, in combination with other antiretroviral agents, is currently available for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in children and adults, but there are only limited data regarding its use in adolescents and young adults.1 Similar to other nucleoside analogs, its antiviral activity depends on intracellular metabolization to an active carbovir-triphosphate (carbovir-TP) moiety. Drug clearance occurs primarily through the hepatic pathways of carboxylation and glucuronidation, and the ratios of these metabolites to the parent compound closely correlate with abacavir clearance and area under the plasma concentration-time curve (AUC).2The pharmacokinetic (PK) parameters of abacavir, including the AUC, apparent oral clearance, and half-life have previously been shown to differ significantly between children and adults.3 -8 Clearance in children is approximately twice that in adults when normalized to body weight, with a correspondingly lower AUC at the same dose. This provides the rationale for the difference in currently recommended dose regimens of 300 mg (~4 mg/kg) twice daily for adults vs. 8 mg/kg twice daily for children.1 However, the maximum recommended dose for children is 300 mg twice daily which, for children and adolescents >37.5 kg in body weight, results in per-kilogram doses that are progressively lower on the basis of body weight. In a single-dose pharmacokinetics study of abacav...

Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial

“…However, interestingly, although lamivudine doses received were 17% higher, children in our ARROW Trial PK study had lamivudine AUC 0-24 and C max values that were 33% and 52% higher, respectively, on once-daily dosing compared with those observed in PENTA 13, whereas CL/F/kg values were 10% lower in the ARROW Trial PK study (a similar observation was made for twice-daily dosing; Table 3). PK parameters in the ARROW Trial PK study were also generally more similar to those previously observed in adults (for example, ARROW Trial PK study AUC 0-24 values on twice-daily dosing were only 8% higher than a recent study in Ugandan adults [20], 12% lower than a study in adolescents and young adults [21]; however, findings from two other adult twice-to once-daily studies have been more variable, with results 30% higher [22] and 30% lower [8] than our study). Of note, 14 of 19 children in PENTA 13 were taking lamivudine syrup, dosed at 8 mg/kg daily, whereas all ARROW Trial children were taking scored adult tablets, with a 15-17% higher average dose (32/35 and 29/35 on twice-and once-daily, respectively, achieving ≥8 mg/kg).…”

Lopinavir/Ritonavir plus Lamivudine and Abacavir or Zidovudine dose Ratios for Paediatric Fixed-Dose Combinations

“…These datasets were pooled from nine published studies: therapeutic drug monitoring data from France, the BURKINAME -Agence Française de [15][16][17][18][19][20].…”

“…The data consisted of five pooled studies, that is, four previously published studies: therapeutic drug monitoring from France, Paediatric European Network for Treatment of AIDS (PENTA) protocol PENTA 13 from United Kingdom, IMPAACT/PACTG 1018, 1052 protocols from United States plus PACTG 356 with ABC pharmacokinetic samples obtained pre-dose as well as 1 to 3 h and 4 to 6 h post-dose from the US [15][16][17][18][19][20].…”

Pharmacokinetic Interactions between Lersivirine and Zidovudine, Tenofovir Disoproxil Fumarate/ Emtricitabine and Abacavir/Lamivudine

“…Elimination of abacavir occurs via metabolism by alcohol dehydrogenase (to form 5′-carboxylic acid) and glucuronyl transferase (to form 5′-glucuronide) [11], and in vitro data indicate that abacavir does not inhibit CYP3A4, CYP2D6 or CYP2C9 activity at clinically relevant concentrations [12]. However, abacavir is known to be a substrate for UGT2B7 [13], suggesting that lersivirine has the potential to increase exposures of abacavir via UGT2B7 inhibition. The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion [11]; therefore, the potential for lersivirine to affect lamivudine exposure is low.…”