RESEARCH - Influence of genetic polymorphisms on the pharmacokinetics in Arava-treated RA patients

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Drug Metab Dispos. 2009 Oct;37(10):2061-8.

Investigation of the influence of CYP1A2 and CYP2C19 genetic

polymorphism on

2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77

1726) pharmacokinetics in leflunomide-treated patients with rheumatoid

arthritis.

Bohanec Grabar P, Grabnar I, Rozman B, Logar D, Tomsic M, Suput D,

Trdan T, lin Masic L, Mrhar A, Dolzan V.

Faculty of Medicine, Institute of Biochemistry, University of

Ljubljana, 1000 Ljubljana, Slovenia.

Leflunomide is a disease-modifying antirheumatic drug used for the

treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly

CYP1A2 and CYP2C19, may be involved in the transformation of

leflunomide to leflunomide metabolite (A77 1726,

2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim

of this study was to investigate whether genetic polymorphisms in

CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment

response, and the occurrence of adverse drug reactions (ADRs). The

study included 67 patients with RA and 4 patients with polyarthritis

resembling RA and psoriasis treated with leflunomide. A77 1726

steady-state plasma concentrations were determined by validated

high-performance liquid chromatography with UV detection. A population

pharmacokinetic model was developed to estimate the oral clearance

(CL/F) and volume of distribution (V/F). A genotyping approach was

used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as

well as single nucleotide polymorphisms that characterize CYP2C19*2,

*3, *4, and *17 alleles. A large interindividual variability in trough

A77 1726 steady-state plasma concentrations was observed (from 1.9 to

156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2

allele compared with noncarriers. The A77 1726 average steady-state

plasma concentration was associated with the treatment response.

Patients with a greater decrease in C-reactive protein (CRP) had

higher average steady-state plasma A77 1726 concentrations: 49.7 +/-

39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared

with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of <or=8.5 mg/l (p =

0.015). No association of A77 1726 steady-state plasma concentrations

with the occurrence of ADRs was observed. Our results suggest that

genetic variability in leflunomide-metabolizing enzymes influences

leflunomide metabolite concentrations that are associated with the

treatment response but not with leflunomide-induced toxicity.

PMID: 19581389

http://www.ncbi.nlm.nih.gov/pubmed/19581389

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