Pharmacokinetics and tolerability of lapatinib administered once daily in combination with tamoxifen.

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Abstract Abstract #2073 Background: The pharmacokinetics (PK) and tolerability of daily oral dosing with lapatinib (LAP) and tamoxifen (TAM) in patients (pts) with advanced or metastatic breast cancer (MBC) are examined in this study. Optimal dose selection requires characterization of PK to accommodate the potential for a bi-directional PK interaction involving LAP inhibition and TAM induction of CYP3A4 and P-glycoprotein (Pgp).
 Methods: Twenty three previously treated pts with ER and/or PR positive MBC, not ErbB selected, were randomly assigned to one of two groups, to separately assess each direction of the potential PK interaction at steady state during daily dosing of 1250mg LAP and 20mg TAM. In one group, the PK of LAP is assessed on the 14th day of dosing LAP alone, and again on the 28th day dosing of LAP and TAM together. In the other group, the PK of TAM is assessed on the 28th day of dosing TAM alone, and on the 7th day of dosing TAM and LAP together. LAP and TAM are dosed together throughout subsequent 28 day cycles.
 Results: To date 23 pts have been enrolled with a median age of 58 (38-83) and a median PS of 1. Preliminary PK data for LAP from six patients summarized in the table below showing geometric median (95% confidence limits) parameters indicate that LAP plasma concentrations are decreased by TAM. Final PK analysis will be presented at the meeting. To date, the most common adverse events at cycle 1 were: fatigue gr1/2 (100%), diarrhoea gr 1/2 (53%), rash gr 1 (40%), anorexia gr 1 (40 %) and nausea gr1/2 (40 %). Transaminase elevation (SGPT/ALT) increased from 3 pts at baseline to 6 pts at cycle 1 including one gr3.
 
 Conclusions: The preliminary PK results are consistent with data indicating TAM induces hepatic CYP3A, the primary route of LAP elimination. This important information may impact in ongoing adjuvant lapatinib studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2073.