title: Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies.
abstract: BACKGROUND
  Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of fostamatinib, R406, is primarily metabolized by CYP3A4.
  
  
  OBJECTIVE
  The aim of this study was to characterize hepatic microsomal metabolism of R406 and confirm the role of CYP3A4 in R406 metabolism, determining whether co-administration of CYP3A4 inhibitors (ketoconazole, verapamil) or inducers (rifampicin) affects R406 pharmacokinetics.
  
  
  METHODS
  R406 stability was determined using human hepatic microsomes. The CYP450 isoforms responsible for R406 metabolism in humans were identified using expressed CYP450 isoforms and specific chemical inhibitors. The ketoconazole interaction study (double-blind, randomized, placebo-controlled, two-period crossover) involved fostamatinib administration (single 80-mg dose), alone and with ketoconazole (200 mg twice daily). The verapamil and rifampicin interaction studies (open-label, two-period, fixed-sequence) involved fostamatinib administration (single 150-mg dose), alone and with immediate-release verapamil (80 mg three times daily) or rifampicin (600 mg once daily). Standard pharmacokinetic parameters were calculated in all studies.
  
  
  CONCLUSIONS
  Hepatic microsomes showed time-dependent loss of R406 and formation of para-O-demethylated R406. Microsomal metabolism of R406 was markedly inhibited by CYP3A4 inhibitors and, in the expressed CYP450 studies, the rate of R406 disappearance was greatest with CYP3A4. In the clinical studies, co-administration of ketoconazole caused a 2-fold (CI 1.77-2.30) increase in R406 exposure. Verapamil increased R406 exposure (39% increase, CI 8-80), whereas rifampicin co-administration decreased exposure by 75% (CI 68-81). Fostamatinib was well tolerated.
  
  
  CONCLUSIONS
  The oxidative metabolism of R406 is predominantly catalyzed by CYP3A4. In clinical studies, exposure to R406 is affected by concomitant administration of CYP3A4 inducers/inhibitors. These findings should be taken into account when considering co-prescription of fostamatinib with such agents.
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK. paul.martin@astrazeneca.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca, Gaithersburg, MD, USA. michael.gillen@astrazeneca.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Former AstraZeneca, Macclesfield, UK.
authors.forename: David
authors.initials: D
authors.lastname: Millson
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.affiliation: Former AstraZeneca, Macclesfield, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Brealey
authors.affiliation: Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA.
authors.forename: Elliott B
authors.initials: EB
authors.lastname: Grossbard
authors.affiliation: Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baluom
authors.affiliation: Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lau
authors.affiliation: Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sweeny
authors.affiliation: Quintiles Drug Research Unit at Guy's Hospital, London, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Mant
authors.affiliation: Quintiles Phase I Unit, Overland Park, KS, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Craven
mesh_terms: D000328:Adult; D000631:Aminopyridines; D018592:Cross-Over Studies; D065701:Cytochrome P-450 CYP3A Inducers / Q000627:therapeutic use*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines; D010078:Oxazines / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D011743:Pyrimidines; D012293:Rifampin / Q000627:therapeutic use*; D014700:Verapamil / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D014700:Verapamil; D007654:Ketoconazole; C523665:fostamatinib; D012293:Rifampin