Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects

Invest New Drugs. 2005 Jan;23(1):39-49. doi: 10.1023/B:DRUG.0000047104.45929.ea.

Abstract

GW572016 is a dual EGFR-ErbB2 inhibitor that has promise as an anticancer agent. Two phase I studies were conducted to determine the safety, tolerability and pharmacokinetics of single and multiple doses given to healthy subjects. The single dose study evaluated two groups of eight subjects in an ascending dose, 4-way cross-over, while the multiple dose study evaluated twenty-seven healthy volunteers in an ascending dose, double-blind, randomized, placebo-controlled, staggered parallel design. No serious adverse events were seen in either study. The most common adverse events for subjects receiving GW572016 were headache, diarrhea, rash, cold symptoms, gastrointestinal symptoms, and elevated LFTs, which were similar between treatment and placebo groups. Absorption of single doses of GW572016 was slightly delayed, with median t(lag) of 15 minutes (range 0-90 minutes) and achieved peak serum concentrations at a median of three hours (range 1.5-6 hours) post-dose. Serum concentrations after multiple doses of GW572016 demonstrated no significant accumulation at the 25 mg dose, and approximately 50% accumulation at the 100 mg and 175 mg doses, achieving steady state in six to seven days. A modest time-dependent increase in serum concentrations also was detected with multiple doses of GW572016. Single and multiple oral doses of GW572016 were well tolerated in healthy subjects, and resulted in dose-related systemic exposure of GW572016.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Area Under Curve
  • Cross-Over Studies
  • Double-Blind Method
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Lapatinib
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacokinetics*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Safety

Substances

  • Quinazolines
  • Lapatinib
  • ErbB Receptors
  • Receptor, ErbB-2