Rodman JH, Cross SJ, D'Angelo LJ, Rose C, Robbins BL, Yuen GK; International Conference on AIDS.
Int Conf AIDS. 2002 Jul 7-12; 14: abstract no. MoPpB2010.
St. Jude Children's Research Hosp, Memphis, United States
BACKGROUND: Abacavir (ABC) systemic clearance (CLabc) is primarily determined by the extent of formation of glucuronide (GLU) and carboxylate (CAR) metabolites. Defining ABCs metabolic profile may offer insights into known differences in dose requirements and pharmacokinetics between children and adults. Additionally variable metabolite formation may be relevant for patients at risk for hypersensitivity reactions. METHODS: The pharmacokinetics of ABC, GLU, and CAR were determined after administration of 8 mg/kg of ABC given to HIV infected pediatric patients stratified based on Tanner stage and gender. Plasma concentrations (n=9) of ABC, GLU, and CAR were determined by HPLC. A pharmacokinetic model for parent and metabolites was fit to each patients data and a metabolite phenotype was defined by ratio of GLU and CAR to ABC. RESULTS: Mean weight and age were 54.9 kg and 14.8 years. ABC and metabolites were well described by the PK model (r2 >0.9). CLabc varied > 5 fold with median (range) of 523 (245-1360) ml/min/m2. The GLU/ABC ratio ranged from 1.1 to 9.8 with a bimodal distribution. Subjects with a GLU/ABC ratio >4 (4.1-9.5) had a mean CLABC of 1118 ml/min/m2 while those with a GLU/ABC ratio <4 (1.1-2.6) had a mean CLABC of 411 ml/min/m2. CAR/ABC ratios were less variable (range 0.4-1.3), normally distributed and did not discriminate low and high CLabc as well. CONCLUSIONS: CLabc is highly variable and glucuronidation an important determinant. A single blood sample is informative for glucuronidation phenotype and distinguishes among patients with low or high CLABC. CAR metabolite profiles were less informative but further studies may identify subjects with important differences in this metabolic pathway. Genotypic studies in progress will clarify the basis for the phenotypic differences in CLABC. ABC glucuronidation phenotype warrants further study to identify patients with high CLABC and patients who experience ABC hypersensitivity reactions.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Adult
- CD4 Lymphocyte Count
- Child
- Dideoxynucleosides
- Glucose
- Government Agencies
- HIV Infections
- HIV Seropositivity
- Humans
- Laboratory Techniques and Procedures
- Metabolic Clearance Rate
- Phenotype
- abacavir
- genetics
- pharmacokinetics
Other ID:
UI: 102255818
From Meeting Abstracts