Sotrastaurin and tacrolimus coadministration: effects on pharmacokinetics and biomarker responses.
Sotrastaurin is an immunosuppressant that inhibits protein kinase C. In the prevention of acute rejection in organ transplantation, sotrastaurin might be combined with tacrolimus. A drug interaction study was performed in 18 healthy subjects who received single oral doses of sotrastaurin 400 mg, tacrolimus 7 mg, and the drug combination. Drug blood levels and lymphocyte activation and proliferation were measured. Tacrolimus did not alter the pharmacokinetics of sotrastaurin; however, sotrastaurin increased tacrolimus area under the concentration-time curve by 2.0-fold (90% confidence interval, 1.8-2.1). Production of interleukin-2 and tumor necrosis factor by T cells activated via calcium-independent pathways was inhibited by 75% ± 22% from baseline by sotrastaurin. Interleukin-2 messenger RNA levels were decreased by 90% ± 9% from baseline by sotrastaurin. Addition of tacrolimus to sotrastaurin had minimal or no effect on these biomarkers, consistent with tacrolimus' mechanism of action. Lymphocyte proliferation induced via calcium-dependent pathways was decreased from baseline by 82% ± 9% by sotrastaurin, 76% ± 11% by tacrolimus, and 96% ± 2% for the drug combination. How sotrastaurin and tacrolimus could be partnered in an immunosuppressive regimen will need to be established in the context of controlled clinical trials in organ transplant patients, taking into account the pharmacokinetic interaction on tacrolimus and the potentially enhanced immunosuppressive activity of this drug combination.
Kovarik
John M
JM
Novartis Pharma, Building WSJ 210.427, 4002 Basel, Switzerland. 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; D019540:Area Under Curve; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
D015415:Biomarkers; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011758:Pyrroles; D011799:Quinazolines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C543528:sotrastaurin; D011493:Protein Kinase C; D002118:Calcium; D016559:Tacrolimus