The Pharmacokinetics and Pharmacodynamics of Fludarabine in Rheumatoid Arthritis

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Abstract

Study Objective.

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.

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