Population Pharmacokinetics of the Active Metabolite of Leflunomide in Patients with Rheumatoid Arthritis
I. Grabnar (1), T. Trdan (1), P. Bohanec Grabar (2), B. Rozman (3), D. Logar (3), M. Tomsic (3), D. Suput (3), L. Peterlin Masic (1), V. Dolzan (2), A. Mrhar (1)
(1)Faculty of Pharmacy, University of Ljubljana, Slovenia; (2)Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia; (3)Department of Rheumatology, University Medical Centre Ljubljana, Slovenia
Objectives: Leflunomide is a disease-modifying antirheumatic drug. It is converted to the active metabolite A77 1726 with immunosuppressive effects. In the first year of treatment 40 - 70% of patients are withdrawn from therapy due to adverse drug reactions (ADRs) or lack of efficacy [1]. A study on microsomes suggested that CYP1A2, CYP2C19 and CYP3A4 may be involved in the metabolism of leflunomide to A77 1726 [2] and CYP1A2 was associated with leflunomide toxicity [3]. The aim of this study was to assess pharmacokinetics of A77 1726 to evaluate the influence of genetic polymorphisms of CYPs on interpatient variability in A77 1726 concentration and to explore the relationship between drug exposure, efficacy and toxicity.
Methods: Pharmacokinetic analysis was performed using NONMEM 6.2 and PSN 2.3 based on steady-state plasma samples. A one-compartment model and FOCEI were used. The influence of demographic, biochemical and genetic parameters on pharmacokinetics of A77 1726 was investigated. To explore the relationship with clinical effects, Bayesian estimates of CL/F were used to calculate average steady-state concentration (Css) in individual patient. Patients were divided at the median values of the clinical assessments into low and high group and differences in Css were tested by Mann-Whitney U test.
Results: The study enrolled 71 patients who provided 213 concentrations. CL/F was estimated at 0.0302 L/h and an inter-individual CV of 78%, while V/F was estimated at 8.55 L. Residual variability was 7.48% (proportional) and 0.250 mg/L (additive). Absorption rate was fixed at 1 h-1. Inter-individual variability in V/F could not be estimated. Patient's renal function and CYP2C19 polymorphism had an influence on CL/F. In carriers of CYP2C19*2 allele CL/F was 71% higher compared to non-carriers. V/F was affected with patient's gender. Css was associated with the response. Patients with high decrease in C-reactive protein (CRP) had higher Css compared to patients with low decrease in CRP. No association of Css with ADRs was observed.
Conclusions: Our results suggest that genetic variability in CYP2C19 and variability in renal function influence plasma concentration of the active metabolite of leflunomide which is associated with the treatment response.
References:
[1] Rozman B (2002) Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet 41:421-430.
[2] Kalgutkar AS, Nguyen HT, Vaz AD, Doan A, Dalvie DK, McLeod DG and Murray JC (2003) In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes. Drug Metab Dispos 31:1240-1250.
[3] Bohanec Grabar P, Rozman B, Tomsic M, Suput D, Logar D and Dolzan V (2008) Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol 64:871-876.
