Cytochrome P450 3A and P‐glycoprotein drug–drug interactions with voclosporin

• Published in: British journal of clinical pharmacology Vol. 77; no. 6; pp. 1039 - 1050
• Main Authors: Ling, Spencer Y., Huizinga, Robert B., Mayo, Patrick R., Larouche, Richard, Freitag, Derrick G., Aspeslet, Launa J., Foster, Robert T.
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.06.2014
• Subjects: Adolescent; Adult; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; calcineurin inhibitor; Calcineurin Inhibitors - pharmacokinetics; Cyclosporine - pharmacokinetics; Cyclosporine - pharmacology; Cytochrome P-450 CYP3A - physiology; Cytochrome P-450 CYP3A Inhibitors - pharmacology; cytochrome P450; Digoxin - pharmacokinetics; drug interaction; Drug Interactions; Female; Humans; Ketoconazole - pharmacokinetics; Ketoconazole - pharmacology; Male; Midazolam - pharmacokinetics; Midazolam - pharmacology; Middle Aged; pharmacokinetics; P‐glycoprotein; Verapamil - pharmacokinetics; Verapamil - pharmacology; voclosporin; P-glycoprotein; pharmacokinetics; cytochrome P450; calcineurin inhibitor; voclosporin; drug interaction
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12309

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.