Pharmacokinetics of pimecrolimus, a novel nonsteroid anti-inflammatory drug, after single and multiple oral administration.
OBJECTIVE
To investigate the pharmacokinetics and tolerability of the new nonsteroid anti-inflammatory pimecrolimus (SDZ ASM 981, Elidel) after oral administration.


METHODS
A single-dose, randomised, double-blind, placebo-controlled, dose-rising, parallel-group study in healthy male volunteers, and a multiple-dose, randomised, double-blind, placebo-controlled, dose-rising study in patients with psoriasis.


METHODS
One centre in France (single-dose study) and one centre in Austria (multiple-dose study).


METHODS
The first study investigated the pharmacokinetics and tolerability of ascending single oral doses of pimecrolimus (5-60mg). The 60mg dose was repeated in the same subjects after a fat-rich breakfast. The second study investigated the pharmacokinetics, tolerability, safety and efficacy of rising oral doses administered once daily (5-20mg) or twice daily (20 and 30mg) for 28 days. Only the pharmacokinetic, safety and tolerability data of this study are presented.


RESULTS
Oral administration of pimecrolimus was well tolerated up to the highest dose (60mg). Pimecrolimus was rapidly absorbed (time to maximum blood concentration 0.7-2 hours). A high-fat meal before drug administration delayed the time to peak concentration. Blood concentrations appear to have a long-terminal half-life (30-40 hours after a single dose in fasted subjects, 50-100 hours after the final dose on day 28 in psoriasis patients). After multiple doses, steady state was attained after 6-13 days. Maximum blood concentrations (C(max)) and exposure (area under the concentration-time curve; AUC) were broadly dose proportional. At the highest dose administered in the multiple-dose study (30mg twice daily), a C(max ) of 54.7 microg/L was measured and an AUC(24) of 589.8 microg.h/L was calculated at steady state (day 13).


CONCLUSIONS
The results support further evaluation of the therapeutic potential of oral pimecrolimus for the treatment of inflammatory diseases.
Scott
Graham
G
Novartis Horsham Research Centre, Horsham, West Sussex, UK.
Osborne
Stuart A
SA
Greig
Gerard
G
Hartmann
Stefan
S
Ebelin
Marie-Eve
ME
Burtin
Pascale
P
Rappersberger
Klemens
K
Komar
Michael
M
Wolff
Klaus
K
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018565:Food-Drug Interactions / Q000502:physiology; D006207:Half-Life; D006801:Humans; D008297:Male; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C117268:pimecrolimus; D016559:Tacrolimus