Sotrastaurin and everolimus pharmacokinetics after single-dose coadministration.
BACKGROUND
Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4.


METHODS
This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment.


RESULTS
Coadministration of everolimus decreased sotrastaurin C(max) from 638 +/- 295 to 539 +/- 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 - 1.00). Sotrastaurin total AUC was not altered by everolimus with values of 3660 +/- 1853 versus 3630 +/- 2006 ng*h/ml and a ratio of 1.00 (0.88 - 1.13). Sotrastaurin increased everolimus C(max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased everolimus total AUC from 114 +/- 50 to 137 +/- 56 ng*h/ml yielding a ratio of 1.20 (1.05 - 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels cannot be excluded.


CONCLUSIONS
Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.
Kovarik
J M
JM
Novartis Pharmaceuticals, 4002 Basel, Switzerland. john.kovarik@novartis.com
Bartlett
M
M
Rordorf
C
C
Antunes
M C
MC
Winter
S
S
Marbach
P
P
van Marle
S
S
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D000068338:Everolimus; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011493:Protein Kinase C; D020123:Sirolimus