title: Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults.
abstract: OBJECTIVE
  Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clinical investigation in solid tumours. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics.
  
  
  METHODS
  This Phase I, single-centre, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers. Three regimens were administered over three periods: Period (P) 1 (Days 1-8), P2 (Days 15-22) and P3 (Days 29-50), with a 14-day (first dose) and 28-day (second dose) washout period after lenvatinib mesylate administration (Day 1, Day 15 and Day 43). In P2, a single oral dose of rifampicin (600 mg) was coadministered with lenvatinib. In P3, rifampicin was administered daily (600 mg) for 21 days (Days 29-49). Serial blood samples were collected, and plasma concentrations of total (protein bound + unbound) and free (unbound) lenvatinib and total metabolites (M1, M2, M3 and M5) were measured by validated high-performance liquid chromatography/tandem mass spectrometry.
  
  
  RESULTS
  Single-dose rifampicin (P-gp inhibition) increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of free and total lenvatinib by 32 and 31 %, respectively. Multiple-dose rifampicin (simultaneous P-gp and CYP3A4 induction) decreased lenvatinib AUC0-∞ (total: 18 %; free: 9 %). Treatment-emergent adverse events were mild or moderate and occurred in 7 subjects (47 %).
  
  
  CONCLUSIONS
  Lenvatinib exposure was increased by P-gp inhibition; however, based on free concentrations, simultaneous P-gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval. Overall, the magnitude of these changes was relatively small, and likely not clinically meaningful.
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA, Robert_shumaker@eisai.com.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Shumaker
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Aluri
authors.forename: Jean
authors.initials: J
authors.lastname: Fan
authors.forename: Gresel
authors.initials: G
authors.lastname: Martinez
authors.forename: Gary A
authors.initials: GA
authors.lastname: Thompson
authors.forename: Min
authors.initials: M
authors.lastname: Ren
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000904:Antibiotics, Antitubercular; D065701:Cytochrome P-450 CYP3A Inducers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C531958:lenvatinib; D012293:Rifampin