The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole.
OBJECTIVE
Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.


METHODS
This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration.


RESULTS
Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C(max) by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 +/- 128 to 678 +/- 189 ng ml(-1) and increased AUC by 4.6-fold (4.1, 5.2) from 1666 +/- 808 to 7378 +/- 3011 ng ml(-1) h. Sotrastaurin half-life was nearly doubled from 5.9 +/- 1.7 to 10.6 +/- 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations.


CONCLUSIONS
The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.
Kovarik
John M
JM
Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@novartis.com
Huang
Hsun-Lun A
HL
Slade
Alan
A
Sfikas
Nikos
N
Chandler
Patricia A
PA
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole