Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin

Abstract

Aims: Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated.

Methods: Voclosporin 0.4 mg kg(-1) was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (Cmax ) and area under the concentration-time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated.

Results: Ketoconazole increased voclosporin Cmax (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin Cmax (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin Cmax (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold).

Conclusions: Administration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug-drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors.

Keywords: P-glycoprotein; calcineurin inhibitor; cytochrome P450; drug interaction; pharmacokinetics; voclosporin.

© 2013 The British Pharmacological Society.

Figures

Figure 1

Whole blood or plasma concentrations (means ± SD) of voclosporin (VCS) 0.4 mg kg−1 every 12 h (Q12H) alone and with ketoconazole 400 mg once daily (QD; A); VCS 0.4 mg kg−1 alone and following 10 days of rifampin 600 mg QD (B); midazolam 7.5 mg alone and with VCS 0.4 mg kg−1 Q12H (C1); α-hydroxy-midazolam after administration of midazolam 7.5 mg alone and with VCS 0.4 mg kg−1 Q12H (C2); VCS 0.4 mg kg−1 Q12H alone and with verapamil 80 mg every 8 h (D); and digoxin 0.25 mg QD alone and with VCS 0.4 mg kg−1 Q12H (E). (A) , VCS alone; , VCS + ketoconazole. (B) , VCS alone; , VCS + rifampin. (C1) , midazolam alone; , midazolam + VCS. (C2) , midazolam alone; , midazolam + VCS. (D) , VCS alone; , VCS + verapamil. (E) , digoxin alone; , digoxin + VCS

Figure 2

Individual predose concentrations of voclosporin on day 10 [voclosporin (VCS) alone] and day 18 (VCS + ketoconazole) for subjects completing the study and for subjects withdrawn due to elevated serum creatinine levels

Figure 3

Individual subject maximal concentration (Cmax) values of midazolam and α-hydroxy-midazolam after oral administration of midazolam 7.5 mg alone and with voclosporin (VCS) 0.4 mg kg−1 every 12 h

Figure 4

Forest plot presentation of voclosporin drug–drug interaction studies. Point estimate and 90% confidence interval is shown for change in substrate exposure following co-administration of voclosporin with ketoconazole, rifampin and verapamil, where voclosporin is the substrate; and co-administration of voclosporin with midazolam and digoxin, where midazolam and digoxin are the substrates. Abbreviations are as follows: AUC, area under the concentration–time curve; CI, confidence interval; Cmax, maximal whole blood or plasma concentration; PK, pharmacokinetics; TDM, therapeutic drug monitoring