Investigational New Drugs 23: 39–49, 2005. 39 C  2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands. Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects Aimee K. Bence 1 , Eric B. Anderson 2 , Maqbool A. Halepota 2 , Michael A. Doukas 2 , Phillip A. DeSimone 2 , George A. Davis 1 , Deborah A. Smith 3 , Kevin M. Koch 3 , Andrew G. Stead 3 , Steve Mangum 3 , Carolyn J. Bowen 3 , Neil L. Spector 3 , Showchien Hsieh 3 and Val R. Adams 1,2 1 Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; 2 Markey Cancer Center, University of Kentucky Medical Center, Lexington, KY 40536, USA; 3 GlaxoSmithKline Inc., Research Triangle Park, NC 27709, USA Key words: tyrosine kinase inhibitor, GW572016, signal transduction, phase I Summary 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. Introduction GW572016, an oral, reversible, dual inhibitor of epider- mal growth factor receptor (EGFR) and ErbB2 tyrosine kinase receptors, has recently entered clinical develop- ment as a potential therapeutic agent in the treatment of cancer. The epidermal growth factor receptor and the ErbB2 receptor are members of the Type I family of ty- rosine kinase receptors. The family comprises four ho- mologous members, EGFR or ErbB1, ErbB2, ErbB3 and ErbB4, regulated by a family of peptide ligands including epidermal growth factor (EGF) and transforming growth factor α (TGF-α). Upon ligand binding, the ErbB recep- tors form homo- or heterodimers resulting in tyrosine au- tophosphorylation and activation of signal transduction pathways. The signaling pathways controlled by these re- ceptors regulate cell cycle progression, apoptosis, angio- genesis and cell adhesion [1–6]. These include the ras- and shc-activated mitogen activated protein kinase (MAPK) pathway, and the phosphoinositol 3-kinase-activated AKT pathway [5]. Although ErbB2 has no known ligand, it is an important signalling partner for other ErbB family mem- bers. Heterodimers that include ErbB2 have an increased affinity for the ligand leading to an enhanced biological response [7]. The dysregulation of the signaling pathways controlled by these receptors, either through overexpression of the receptors or mutations resulting in constitutively active receptors, has been linked to the initiation and spread of many human tumors [5]. Moreover, in certain can- cer patient populations, the dysregulation of EGFR or ErbB2 signalling has been associated with advanced dis- ease, metastasis, recurrence, poor prognosis, and reduced overall survival [4, 6, 8–12]. Some patients with tumors that overexpress both EGFR and ErbB2 also have been shown to have a poorer prognosis; tumors overexpressing