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

Abstract

AIMSVoclosporin 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. METHODSVoclosporin 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. RESULTSKetoconazole 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). CONCLUSIONSAdministration 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Calcineurin inhibitors are the gold standard for immunosuppression in transplantation.• Drug-drug interactions with cytochrome P450 inducers, inhibitors and substrates and with P-glycoprotein inhibitors and substrates in these drugs with narrow therapeutic windows may impact both safety and efficacy.• Knowledge of patient and drug factors that influence drug disposition enhances the optimal dosing and successful therapy with the drug. WHAT THIS STUDY ADDS• These results provide a rationale for avoiding the co-administration of voclosporin with strong CYP3A inhibitors and CYP3A inducers.• These results suggest that co-administration of voclosporin with substrates of CYP3A would not result in increased exposure to the substrate.• These results provide a rationale for conducting appropriate concentration and safety monitoring when voclosporin is co-administered with P-glycoprotein substrates and inhibitors.

The Effect of P-Glycoprotein Inhibition and Activation on the Absorption and Serum Levels of Cyclosporine and Tacrolimus in Rats

“…Drugs that inhibit or activate the CYP450 enzymes cause a decrease or increase in the metabolism of other drugs metabolized by the same enzyme, resulting in increased or decreased plasma levels of that drug [28]. Because verapamil and rifampin are also known to inhibit and activate the p450 enzymes [29], and the influence of rifampicin or verapamil was more pronounced on the serum level than on the intestinal absorption of cyclosporine and tacrolimus, it can be suggested that these drugs may have a stronger effect on the P450 enzyme system than on P-gp.…”

Voclosporin: First Approval

“…rifampin) or moderate (e.g. efavirenze) CYP3A inducers decrease voclosporin C max and AUC [ 4 , 15 ]. Coadminstration of voclosporin with strong CYP3A4 inhibitors should be avoided since coadministration can significantly increase voclosporin exposure, potentially increasing the risk of acute and/or chronic nephrotoxicity; dosage adjustment is recommended when voclosporin is coadministered with moderate CYP3A4 inhibitors [ 4 ].…”

Metabolic Drug Interactions with Immunosuppressants

“…Organ Donation and Transplantation -Current Status and Future Challenges inhibitors. Similarly to ciclosporin, voclospiron is a substrate for CYP3A enzymes, anticipating pharmacokinetic/metabolic drug interactions with those agents that interact with ciclosporin as well [60]. However, voclosporin is no longer pursed in transplantation.…”