The pharmacokinetics and pharmacodynamics of fludarabine in rheumatoid arthritis.
OBJECTIVE
To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA).


METHODS
Open-label, staggered trial conducted in conjunction with a phase I-II clinical trial.


METHODS
Government research hospital.


METHODS
Twenty-six patients with refractory RA.


METHODS
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).


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.


CONCLUSIONS
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.
Knebel
W
W
Clinical Pharmacokinetics Research Laboratory and Clinical Section, Clinical Center, Pharmacy Department, National Institutes of Health, Bethesda, Maryland 20892-1196, USA.
Davis
J C
JC
Sanders
W D
WD
Fessler
B
B
Yarboro
C
C
Pucino
F
F
Boumpas
D T
DT
D000328:Adult; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012044:Regression Analysis; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D014740:Vidarabine; C024352:fludarabine