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.

• Authors: Spencer Y Ling, Robert B Huizinga, Patrick R Mayo, Richard Larouche, Derrick G Freitag, Launa J Aspeslet, Robert T Foster
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 77 Issue 6 Pg. 1039-50 (Jun 2014) ISSN: 1365-2125 [Electronic] England
• PMID: 24330024 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Calcineurin Inhibitors
• Cytochrome P-450 CYP3A Inhibitors
• voclosporin
• Digoxin
• Cyclosporine
• Verapamil
• Cytochrome P-450 CYP3A
• Midazolam
• Ketoconazole

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, physiology)
• Adolescent
• Adult
• Calcineurin Inhibitors (pharmacokinetics)
• Cyclosporine (pharmacokinetics, pharmacology)
• Cytochrome P-450 CYP3A (physiology)
• Cytochrome P-450 CYP3A Inhibitors (pharmacology)
• Digoxin (pharmacokinetics)
• Drug Interactions
• Female
• Humans
• Ketoconazole (pharmacokinetics, pharmacology)
• Male
• Midazolam (pharmacokinetics, pharmacology)
• Middle Aged
• Verapamil (pharmacokinetics, pharmacology)