Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite

Br J Clin Pharmacol. 2019 Sep;85(9):2108-2117. doi: 10.1111/bcp.14022. Epub 2019 Jul 23.

Abstract

Aims: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors.

Methods: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed.

Results: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred.

Conclusions: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.

Keywords: CYP3A; FLT3; acute myeloid leukaemia; drug interaction; quizartinib.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics*
  • Area Under Curve
  • Benzothiazoles / administration & dosage
  • Benzothiazoles / pharmacokinetics*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors / administration & dosage
  • Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • Fluconazole / administration & dosage
  • Fluconazole / pharmacokinetics
  • Healthy Volunteers
  • Humans
  • Invasive Fungal Infections / drug therapy
  • Invasive Fungal Infections / immunology
  • Ketoconazole / administration & dosage
  • Ketoconazole / pharmacokinetics
  • Leukemia, Myeloid, Acute / complications
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / immunology
  • Male
  • Middle Aged
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacokinetics*
  • Young Adult
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Antifungal Agents
  • Benzothiazoles
  • Cytochrome P-450 CYP3A Inhibitors
  • Phenylurea Compounds
  • quizartinib
  • Fluconazole
  • Cytochrome P-450 CYP3A
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Ketoconazole