Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects

Br J Clin Pharmacol. 2011 Apr;71(4):522-7. doi: 10.1111/j.1365-2125.2010.03845.x.


Aim: The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor.

Methods: This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of C(max) (neratinib+ketoconazole): C(max) (neratinib alone), and AUC(neratinib+ketoconazole): AUC(neratinib alone) were assessed.

Results: Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib C(max) by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median t(max) was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 lh(-1) to 87.1 lh(-1) and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole).

Conclusion: Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib C(max) by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Antifungal Agents / administration & dosage*
  • Antifungal Agents / pharmacokinetics
  • Area Under Curve
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A Inhibitors
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Therapy, Combination
  • Humans
  • Ketoconazole / administration & dosage*
  • Ketoconazole / pharmacokinetics
  • Male
  • Middle Aged
  • Quinolines / administration & dosage
  • Quinolines / pharmacokinetics*
  • Young Adult


  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Quinolines
  • neratinib
  • Ketoconazole