title: Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin.
abstract: OBJECTIVE
  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: Isotechnika Pharma Inc., Edmonton, Alberta, Canada.
authors: Spencer Y
authors: SY
authors: Ling
authors: Robert B
authors: RB
authors: Huizinga
authors: Patrick R
authors: PR
authors: Mayo
authors: Richard
authors: R
authors: Larouche
authors: Derrick G
authors: DG
authors: Freitag
authors: Launa J
authors: LJ
authors: Aspeslet
authors: Robert T
authors: RT
authors: Foster
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D065095:Calcineurin Inhibitors / Q000493:pharmacokinetics*; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004077:Digoxin / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D014700:Verapamil / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; C484071:voclosporin; D004077:Digoxin; D016572:Cyclosporine; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole
keywords: P-glycoprotein; calcineurin inhibitor; cytochrome P450; drug interaction; pharmacokinetics; voclosporin