Abstract
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 ΔCRP of more than 8.5 mg/l compared with 24.8 ± 13.7 mg/l in patients with ΔCRP of ≤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.
- RA, rheumatoid arthritis
- A77 1726, leflunomide metabolite, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
- MTX, methotrexate
- ADR, adverse drug reaction
- V/F, volume of distribution
- CL/F, oral clearance
- SNP, single nucleotide polymorphism
- ESR, erythrocyte sedimentation rate
- CRP, C-reactive protein
- ALT, alanine aminotransferase
- anti-CCP, anti-citrullinated peptide antibodies
- GFR, glomerular filtration rate
- DAS28, disease activity score of 28 joint count
- VAS, visual analog scale
- BSA, body surface area
- PCR, polymerase chain reaction
- HPLC, high-performance liquid chromatography
- NSAID, nonsteroidal anti-inflammatory drug
- ΔOFV, decrease of objective function value relative to the base model.
Footnotes
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This work was supported by the Slovenian Research Agency [ARRS Grants PO-0503-0381 and P1-0189-0787].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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P.B.G. and I.G. equally contributed to this work.
- Received March 14, 2009.
- Accepted June 29, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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