The pharmacokinetics and pharmacodynamics of fludarabine in rheumatoid arthritis.

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 I-II clinical trial.

SETTING

Government research hospital.

PATIENTS

Twenty-six patients with refractory RA.

INTERVENTION

Fludarabine 20 or 30 mg/m2/day 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 between the low- and high-dose groups. The mean+/-SD total clearance, volume of distribution at steady state, and beta-half-life were 13.68+/-5.1 L/hour, 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 (approximately 40 min), terminal half-life of 10.9 hours, and significant amount of tissue distribution.