Use of leflunomide in rheumatoid arthritis

Chan, Vivien (2005). Use of leflunomide in rheumatoid arthritis PhD Thesis, School of Pharmacy, The University of Queensland.

       
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Author Chan, Vivien
Thesis Title Use of leflunomide in rheumatoid arthritis
School, Centre or Institute School of Pharmacy
Institution The University of Queensland
Publication date 2005
Thesis type PhD Thesis
Supervisor Tett, Susan E.
Charles, Bruce
Total pages 252
Collection year 2005
Language eng
Subjects L
320503 Clinical Pharmacology and Therapeutics
730199 Clinical health not specific to particular organs, diseases and conditions
Formatted abstract

Leflunomide was the first approved disease modifying anti-rheumatic drug (DMARD) in over 10 years for rheumatoid arthritis (RA). While the probability of clinical success has been reported to increase in proportion to the concentration of its active metabolite A77 1726, use of leflunomide is still limited by fixed dosage regimes and insufficient pharmacokinetic data. Early initiation of DMARD therapy has been advocated to help lessen or prevent joint damage. A better understanding of the role of leflunomide in RA therapy may provide the basis for improving its clinical use. The overall aims of this thesis were to determine the dispensing patterns of DMARD in Australia, in particular the prescribing, dispensing and adverse drug reactions (ADR) reporting of leflunomide, and the elucidation of more comprehensive concentration-effect relationships and pharmacokinetic analyses.

 

Annual dispensing statistics 1992 to 2002 of all DMARD from the Health Insurance Commission's database of Pharmaceutical Benefit Scheme (PBS) medicines were analysed. Drug consumption was calculated as number of defined daily doses (DDD)/1000 inhabitants/day. ADR data were acquired from the Therapeutic Goods Administration's (TGA) national monitoring system, and compared with the World Health Organisation (WHO) Vigibase data for leflunomide. 

 

A simple method for the measurement of A77 1726 in human plasma by high-performance liquid chromatography (HPLC) was developed. Protein precipitation with acetonitrile was used in sample pre-treatment. Chromatographic separation of A77 1726 and the internal standard was achieved using a Ci8 column with ultraviolet detection at 305 nm. This assay was used in the study of the efficacy and population pharmacokinetics of leflunomide. 

 

Data were collected from 23 RA patients on leflunomide for at least 3 months. Main measures were A77 1726 plasma concentrations and disease activity assessments. Using NONMEM, a population estimate was sought for apparent clearance (CL/F). The factors which may influence the CL/F of A77 1726 (weight, age, gender, and estimated creatinine clearance) were analysed. 

 

Consumption of DMARDs in the Australian community increased from 1.5 in 1992 to 3.3 DDD/1000 inhabitants/day in 2002 (128% increase), with methotrexate being the most commonly used (from 0.6 to 1.9 DDD/1000 inhabitants/day). Consumption of gold and penicillamine declined during this time. The inclusion of leflunomide on the PBS in 2000 contributed to an increase in DMARD usage. 

 

Leflunomide use in Australia (dispensing data) rose from 0.2 in 2000 to 0.4 DDD/1000 inhabitants/day in 2002. A similar pattern was observed in the prescribing data obtained from the authority database. Approximately 135 reports, detailing about 371 individual ADR, were generated annually to ADRAC. Gastro-intestinal disorders predominated, accounting for 24% of all reactions reported. Deaths fi-om ADR were rare, attributed to a combination of haematological and gastro-intestinal complications. Trends observed with the reports to the TGA were consistent with those documented in the WHO Vigibase. 

 

The HPLC assay displayed reproducible linearity for A77 1726 with determination coefficients (r2) > 0.997 over the concentration range 0.5 to 60.0 mg/L. The reproducibility (% CV) for intra- and inter-day assays of spiked controls was < 5%. Limit of quantification was 0.8 mg/L, with average absolute recovery approximating 100%. 

 

Significantly higher A77 1726 concentrations were seen in patients with less swollen joints and higher SF-36 mental summary scores (p < 0.05). Statistical analysis of all disease activity measures showed that mean A77 1726 concentrations in groups with greater control of disease activity were significantly higher than those in whom the outcome measures indicated less desirable control (p < 0.05). A steady-state infusion model best described the pharmacokinetic data. Inclusion of age as a covariate decreased inter-individual variability (p < 0.01), but would not be clinically important in terms of dosage changes. The final VII parameter estimate (% CV inter-individual variability) for CL/F was 0.0184 L/h (50%)). Residual (unexplained) variability (% CV) was 8.5%. 

 

Use of DMARDs within the Australian community, in particular leflunomide, has increased in recent years. This coincided with the high level of ADR reported to both the national and international monitoring systems, and the change in philosophy for the treatment of RA, with aggressive drug treatment being adopted progressively earlier. The study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. In addition, the presence of marked variability of CL/F suggests a place for individualised dosing of leflunomide in RA therapy.

Keyword Antirheumatic agents
Rheumatoid arthritis -- Treatment

 
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Created: Fri, 24 Aug 2007, 18:41:02 EST