The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• Sotrastaurin is an investigational protein kinase C inhibitor. This represents a new mechanism of action for immunosuppression to prevent acute rejection after organ transplantation. In vitro experiments indicate that sotrastaurin is a substrate of CYP3A4. WHAT THIS STUDY ADDS• This study provides clinical pharmacokinetic information to quantify the effect of the strong CYP3A4 inhibitor ketoconazole on sotrastaurin. The susceptibility of sotrastaurin to CYP3A4-related drug interactions is placed in the context of similar information about calcineurin inhibitors (tacrolimus, ciclosporin) and T-cell proliferation inhibitors (everolimus, sirolimus). AIMSSotrastaurin 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. METHODSThis 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. RESULTSCo-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin Cmax by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 Ϯ 128 to 678 Ϯ 189 ng ml -1 and increased AUC by 4.6-fold (4.1, 5.2) from 1666 Ϯ 808 to 7378 Ϯ 3011 ng ml -1 h. Sotrastaurin half-life was nearly doubled from 5.9 Ϯ 1.7 to 10.6 Ϯ 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. CONCLUSIONSThe 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.

Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers

“…The selected study set consisted of 53 separate DDI studies taken from 46 publications between 2005 and 2015, which included 971 subjects with systemic ketoconazole exposure (Table ). A majority of the studies were conducted at study centers in the United States and Germany (Table ).…”

“…In a study investigating the kinetics of sotrastaurin with CYP3A inhibition conducted by Kovarik et al, elevated ALT levels were observed in subject C after completion of the ketoconazole dosing regimen. Treatment consisted of 200 mg oral ketoconazole twice daily for 6 days, along with a single dose of sotrastaurin on study day 4.…”

Pomalidomide: Evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects

“…Food and drink (except water) were withheld for a period of 4 h after dosing. Dosing durations of ketoconazole, fluvoxamine, and carbamazepine to reach approximate steady‐state were based on literature …”

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

“…The daily dose (240 mg) of diltiazem selected for the ticagrelor-diltiazem study was within the approved clinical range (180–480 mg daily19), and was expected to inhibit CYP3A421. The selected dose of ketoconazole (200 mg twice daily) is the maximum clinically approved oral dose23 and is commonly used in phase I drug–drug interaction studies10,25 to inhibit CYP3A4 activity.…”

“…The antifungal agent, ketoconazole22,23, also inhibits CYP3A24 and is considered to be a strong CYP3A inhibitor10. Both of these agents are commonly used in evaluating the effects of CYP3A inhibition on the pharmacokinetic parameters of co-administered drugs10,21,25.…”