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

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.

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Targeted treatment of advanced and metastatic breast cancer with lapatinib

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“…Lapatinib solubility is pH dependent, and decreases with increasing pH. This suggests that absorption may decrease as the drug passes through the gastro-intestinal (GI) tract (Bence et al 2005).…”

“…In general, increasing dose led to increasing serum levels. A drug half-life of 24 hours has been suggested, which lends itself to a once-daily dosing regime (Bence et al 2005).…”

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