To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA).Design.
Open-label, staggered trial conducted in conjunction with a phase III clinical trial.Setting.
Government research hospital.Patients.
Twenty-six patients with refractory RA. 'Intervention.
Fludarabine 20 or 30 mg/mVday was administered as a 0.5-hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo).Measurements and Main Results.
Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two-compartment model. There were no differences in pharmacokinetics betweenthe low- and high-dose groups. The mean ± SD total clearance, volume of distribution at steady state, and β-half-life were 13.68 ±5.1 IVhour, 170.08 ± 86.5 L, and 10.9 ±3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters.Conclusion.
Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate-length distribution phase (˜ 40 min), terminal half-life of 10.9 hours, and significant amount of tissue distribution.