Abacavir and Metabolite Pharmacokinetics in HIV-1-Infected Children and Adolescents

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 51; no. 1; pp. 54 - 59
• Main Authors: Cross, Shane J, Rodman, John H, Lindsey, Jane C, Robbins, Brian L, Rose, Charles H, Yuen, Geoffrey J, DʼAngelo, Lawrence J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins, Inc 01-05-2009; Lippincott Williams & Wilkins; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Abacavir; Administration, Oral; Adolescence; Adolescent; Age; Age Factors; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacokinetics; Antiretroviral drugs; antiretroviral therapy; Biological and medical sciences; Body size; Child; Children; Children & youth; Data processing; Dideoxynucleosides - administration & dosage; Dideoxynucleosides - metabolism; Dideoxynucleosides - pharmacokinetics; Drug therapy; Female; Fundamental and applied biological sciences. Psychology; High-performance liquid chromatography; HIV; HIV Infections - drug therapy; HIV Infections - metabolism; HIV-1; Human immunodeficiency virus; Human immunodeficiency virus 1; Human viral diseases; Humans; Infection; Infectious diseases; Male; Medical sciences; Metabolic Clearance Rate; Metabolism; Metabolites; Microbiology; Miscellaneous; Pediatrics; Pharmacokinetics; Pharmacology; Puberty; Sex; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virology; Human; Immunopathology; Microbiology; HIV-1 virus; Metabolite; adolescents; Retroviridae; AIDS; Immune deficiency; Lentivirus; Virology; Infection; Virus; HIV; children; Viral disease; Abacavir; Adolescent; pharmacokinetics; Antiviral; Human immunodeficiency virus; Child
• ISSN: 1525-4135; 1944-7884
• DOI: 10.1097/QAI.0b013e31819a2257

OBJECTIVES:Abacavir (ABC) oral clearance, adjusted for body size, is approximately 2 times higher for children than adults with a corresponding difference in dose regimens. However, there are limited data available in the adolescent population. The pharmacokinetics (PKs) of ABC and primary metabolites were determined in HIV-1-infected children and adolescents to evaluate age and patient characteristics as a basis for adjusting ABC dose regimens and to assess the influence of metabolite formation on PK parameters.
METHODS:Pediatric subjects 9-18 years of age receiving antiretroviral therapy for HIV-1 infection were stratified by Tanner stage and given a single 8 mg/kg dose of ABC oral solution. Blood samples (n = 10) were obtained over 8 hours and measured for ABC, glucuronide, and carboxylate metabolites using high-performance liquid chromatography. PK parameters for children (Tanner stages 1-2; TS1) and adolescents (Tanner stages 3-5; TS2) were compared.
RESULTS:Twenty-five subjects were enrolled. ABC mean (range) maximum concentration (Cmax; μg/mL), area under the curve (μg·hr/mL), half-life (hours), and apparent clearance (CL/F; mL/min per kg) for TS1 and TS2 were 3.5 (1.2-5.6) vs 3.4 (1.8-5.9), 8.0 (2.1-18.6) vs 8.9 (3.1-17.2), 1.3 (0.7-2.5) vs 1.4 (0.9-1.9), and 22.1 (7.0-59.2) vs 18.4 (7.7-42.9) and not significantly different. Age, Tanner stage, and sex were not correlated with ABC clearance by univariate analysis. The ratios of metabolites to ABC area under the curve were correlated with ABC clearance as were the ratios of metabolites to ABC concentrations at the 6-hour time point.
CONCLUSIONS:ABC oral clearance in HIV-1-infected pediatric patients does not change during puberty, is similar to younger children, and is higher than previously published in adults. Therefore, dosing adolescents as adults should be reexamined. Intersubject PK variability is substantial and is not correlated with body size or age but more likely due to differences in metabolite formation that may be genetic in origin.