Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration.
In this 2-week, ascending dose study, the pharmacokinetic activity of sirolimus was examined in 40 stable renal transplant patients treated with cyclosporine and prednisone. Nine dose levels (range, 0.5-6.5 mg/m2/12 hr) of sirolimus were studied in a parallel design. Mean values for the pharmacokinetic parameters of sirolimus calculated in all dose groups were as follows: time to peak blood concentration, 1.4 +/- 1.2 hours; terminal half-life, 62 +/- 16 hours; oral dose clearance, 208 +/- 95 mL/h/kg; apparent oral steady-state volume of distribution, 12 +/- 5 L/kg; and blood/plasma ratio, 38 +/- 13. The intersubject variabilities in dose clearance, steady-state volume of distribution, and blood/plasma ratio were 4.5-fold. Preliminary assessments suggests linear dose proportionality. An excellent correlation existed between area under the concentration-time curve and trough blood concentration at steady state. Sirolimus did not produce any significant changes in area under the concentration-time curve of cyclosporine. Preliminary analysis suggested that values for the pharmacokinetic parameters of sirolimus vary among races (black versus nonblack) but not among genders.
Zimmerman
J J
JJ
Wyeth-Ayerst Research, Radnor, Pennsylvania, USA.
Kahan
B D
BD
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011090:Polyenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011241:Prednisone / Q000627:therapeutic use; D020123:Sirolimus
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D011241:Prednisone; D020123:Sirolimus