Therapeutic Drug Monitoring and Population Analysis as Applied to Leflunomide and Cyclosporine Therapy in Dogs with Immune-mediated Diseases

Abstract

Two immunomodulator drugs, leflunomide (teriflunomide is its active metabolite) and cyclosporine, are often monitored in veterinary patients in order to support the design of dosing regimens when used to treat immune-mediated diseases. Such information can be complied to offer population-based recommendations. However, while cyclosporine has been well studied in normal animals, leflunomide has not been. This thesis describes the disposition of leflunomide in normal dogs, and an assessment of factors that impact drug concentrations for either drug in patients with clinical disease. For leflunomide, apparently normal, healthy dogs (n=4) were orally dosed with 4 mg/kg and it and teriflunomide were quantified in plasma using HPLC. No leflunomide was detected in any of the samples. Mean pharmacokinetic values for teriflunomide were: Cmax=18.9±8.5 mcg/mL and half-life=25±10 hr. For clinical patients, samples were monitored between January 2012 and May 2014. In animals that responded to treatment, the recommended therapeutic range of teriflunomide is 25-45 mcg/mL. Approximately 77% of dogs on leflunomide were considered responders. The mean dose of leflunomide used to achieve control was 2.8 mg/kg once daily. The correlation (r) between leflunomide dose and teriflunomide plasma concentrations was 0.26. For cyclosporine, clinical samples were monitored between October 2010 and May 2014. Marked variability was seen amongst cyclosporine plasma concentrations. The correlation (r) between cyclosporine dose and plasma concentration ranged from 0.0007-0.32 depending on dosing interval and sample collection time. Half-life also showed marked variability. Approximately 60% of dogs on cyclosporine were considered responders. Covariate analysis revealed the following potentially significant relationships with cyclosporine plasma drug concentrations: breed, disease, ketoconazole, and generic preparations. Covariates with a significant relationship with response were co-treatment of cyclosporine and prednisone or prednisolone, or disease (arthritis, anemia, and inflammatory bowel disease).This study supports the need for monitoring based on the lack of dose-response relationships for either drug. Several cofactors appear to influence concentrations.