Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients.
BACKGROUND
Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (Certican, RAD) is currently in clinical development to address this issue.


METHODS
The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose-escalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus.


RESULTS
Fifty-four subjects were randomized for 4 weeks treatment with everolimus (n = 44) or placebo (n = 10). Dose levels of everolimus between 0.75 and 5 mg daily were well tolerated, permitting dose escalation to the highest everolimus dose of 10 mg daily. At this dose, everolimus was associated with a higher incidence and severity of adverse events, most notably thrombocytopenia. Pharmacodynamic assessment showed a relationship between drug exposure and thrombocytopenia. Notable reversible elevations of cholesterol were also observed at the 10 mg/day dose. Other changes in laboratory evaluations, including triglycerides, were minor, reversible and did not appear to be dose dependent. The bioavailability of the tablet formulation was 2.6-fold higher compared with the capsule, with evidence for dose proportionality over the dose range tested. Within-subject pharmacokinetic variability was low (coefficient of variation: 10-19%); however, between-subject variability ranged from 34 to 60% for AUC and C(max).


CONCLUSIONS
These results indicate that up to 5 mg/day everolimus results in a dose-proportional exposure, and is adequately well tolerated in renal transplant recipients receiving cyclosporin and steroids.
Department of Nephrology, Charité University Hospital, Schumannstrasse 20-21, D-10117 Berlin, Germany. klemens.budde@charite.de
Klemens
K
Budde
Hans-Hellmut
HH
Neumayer
Gustav
G
Lehne
Michael
M
Winkler
Ingeborg Anni
IA
Hauser
Arno
A
Lison
Lutz
L
Fritsche
Jean-Paul
JP
Soulillou
Per
P
Fauchald
Jaques
J
Dantal
D000328:Adult; D000368:Aged; D001682:Biological Availability; D002214:Capsules; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013256:Steroids / Q000627:therapeutic use; D013607:Tablets
D002214:Capsules; D007166:Immunosuppressive Agents; D013256:Steroids; D013607:Tablets; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus