Sotrastaurin and cyclosporine drug interaction study in healthy subjects.
BACKGROUND
Sotrastaurin is an immunosuppressant that inhibits protein kinase C and blocks T-lymphocyte activation. The authors determined the effect of combining sotrastaurin with the calcineurin inhibitor cyclosporine on the pharmacokinetics and biomarker responses to both drugs.


METHODS
This was a randomized, 4-period, crossover study in 20 healthy subjects who received single oral doses of (1) sotrastaurin 100 mg, (2) cyclosporine 400 mg, (3) 100 mg sotrastaurin with 100 mg cyclosporine and (4) 100 mg sotrastaurin with 400 mg cyclosporine. Blood samples were collected to measure drug levels and biomarkers of T-lymphocyte activation (interleukin-2 and tumor necrosis factor producing T-cells and interleukin-2 messenger RNA levels) and of T-lymphocyte proliferation (thymidine uptake).


RESULTS
Sotrastaurin did not alter cyclosporine AUC; however, low-dose and high-dose cyclosporine increased sotrastaurin AUC by 1.2-fold [90% confidence interval, 1.1-1.4] and 1.8-fold [1.6-2.1], respectively. Adding high-dose cyclosporine to a low-therapeutic dose of sotrastaurin significantly enhanced the inhibition of cytokine production by 31% [95% confidence interval, 25-36%], of interleukin-2 messenger RNA levels by 13% [7-19%], and of thymidine uptake by 37% [32-42%] compared with sotrastaurin alone. Addition of low-dose cyclosporine elicited slightly lower enhancements in inhibition by 21% [14-28%], 6% [-4-16%], and 26% [21-30%], respectively, compared with sotrastaurin alone.


CONCLUSIONS
Sotrastaurin did not alter the pharmacokinetics of cyclosporine, but cyclosporine increased sotrastaurin AUC up to 1.8-fold. The combined drugs elicited a significantly greater inhibition of T-cell activation and proliferation than sotrastaurin alone.
Kovarik
John M
JM
Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@novartis.com <john.kovarik@novartis.com>
Stitah
Sylvie
S
Slade
Alan
A
Vitaliti
Alessandra
A
Straube
Frank
F
Grenet
Olivier
O
Winter
Serge
S
Sfikas
Nikolaos
N
Seiberling
Michael
M
D000328:Adult; D054316:Biomarkers, Pharmacological / Q000097:blood*; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D054316:Biomarkers, Pharmacological; D004338:Drug Combinations; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D016572:Cyclosporine