Lapatinib

Lapatinib is a 4-anilinoquinazoline kinase inhibitor. It acts on the intracellular tyrosine kinase domains of two receptors: Epidermal Growth Factor Receptor (EGFR [ErbB1]) and Human Epidermal Receptor Type 2 (HER2 [ErbB2]). The estimated Kiapp values are 3nM and 13nM, respectively, and the dissociation half-life is greater than or equal to 300 minutes. In the laboratory and in several animal models, Lapatinib inhibits the growth of ErbB-driven tumor cells. An in vitro study tested Lapatinib together with 5-FU (the active metabolite of Capecitabine) in 4 tumor cell lines, and the combination showed an additive effect. The growth inhibitory effects of Lapatinib were also checked in Trastuzumab-conditioned cell lines. Lapatinib kept significant activity against breast cancer cell lines that had been selected for long-term growth in Trastuzumab-containing medium in vitro. These findings suggest there is no cross-resistance between the two agents. Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that also coexpress HER2 tend to be resistant to established endocrine therapies. In the same way, hormone receptor-positive breast cancer cells that start out lacking EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.

Absorption: When Lapatinib is taken by mouth, absorption is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours), and peak plasma concentrations (Cmax) come about 4 hours after the dose. With daily dosing, steady state is reached within 6 to 7 days, which points to an effective half-life of 24 hours. At a dose of 1,250 mg daily, the steady-state geometric mean [95% confidence interval (CI)] values were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) for Cmax and 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL) for AUC. When the daily dose was divided, exposure at steady state (steady-state AUC) was approximately 2-fold higher than when the same total dose was given once daily. Food raises systemic exposure to Lapatinib. With a lowfat meal (5% fat-500 calories), AUC values were approximately 3-fold higher and Cmax approximately 2.5-fold higher. With a high-fat meal (50% fat-1,000 calories), AUC values were approximately 4-fold higher and Cmax approximately 3-fold higher.

Distribution: Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that it is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.

Metabolism: Lapatinib is extensively metabolised, mainly by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8. This produces several oxidated metabolites. None of them accounts for more than 14% of the dose recovered in the feces or 10% of Lapatinib concentration in plasma.

Elimination: At clinical doses, the terminal phase half-life after a single dose was 14.2 hours, and accumulation with repeated dosing indicates an effective half-life of 24 hours. Lapatinib is cleared mostly by metabolism through CYP3A4/5, and renal excretion is negligible (less than 2%). Unchanged Lapatinib recovered in the feces accounts for a median of 27% (range 3% to 67%) of an oral dose.