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Purpose: This phase II study evaluated the pharmacokinetics and safety of trastuzumab and paclitaxel given every 3 weeks to women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer., Patients and Methods: Thirty-two patients received a loading dose of trastuzumab 8 mg/kg intravenously (day 1) and paclitaxel 175 mg/m2 (day 0). Thereafter, trastuzumab 6 mg/kg was administered on the same day as paclitaxel 175 mg/m2 every 3 weeks for seven cycles. In responding patients, trastuzumab monotherapy every 3 weeks was then continued until disease progression or patient withdrawal., Results: Trastuzumab trough levels were more than 20 mug/mL by the end of cycle 1. The half-life of trastuzumab was estimated to be 18 to 27 days, although this may be an underestimate. The combination of paclitaxel and trastuzumab was generally well tolerated, with no unexpected toxicities and no pharmacokinetic interaction. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue. Events associated with trastuzumab included infusion-related reactions and cardiac dysfunction. Ten patients had a > or = 15% decrease in ejection fraction, but only one had symptomatic heart failure. The investigator-assessed objective response rate was 59% (four complete and 15 partial responses) and seven patients (22%) had stable disease. The median duration of response was 10.5 months and median time to progression was 12.2 months., Conclusion: Additional investigation of trastuzumab administered every 3 weeks is warranted. In combination with paclitaxel, it is generally well tolerated. Plasma trastuzumab trough levels and clinical response rates compare favorably with those achieved with the standard weekly trastuzumab regimen plus chemotherapy. The presence of trastuzumab does not alter exposure to paclitaxel.