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Pharmacokinetics of the Mouse Monoclonal Antibody 17-1A in Cancer Patients Receiving Various Treatment Schedules¹

Department of Oncology (Radiumhemmet) [J-E. F., H. M.] and Immunologic Research Laboratory [J-E. F., A-K. L., H. M.], Karolinska Hospital, Stockholm, Sweden

Twenty-four patients with metastatic colorectal carcinoma were treated with repeated doses (200–500 mg) of the mouse monoclonal antibody (MAb) 17-1A. Four different treatment schedules were used. The total dose was 1, 3.6, 7.6, and 12 g, respectively. Altogether, 263 infusions were administered. The interindividual variations in the maximum serum concentration at 2 h (max_{2 h}) were large. The mean max_{2 h} value after an infusion of 200 mg was 55 ± 5 µg/ml and after 500 mg, 132 ± 7 µg/ml. Max_{2 h} concentration correlated inversely with the half-life of MAb 17-1A (P < 0.001). The t _ß for 200 mg was 25.9 ± 1.4 h and after the administration of 500 mg, 19.8 ± 1.0 h. The total area under the concentration versus time curve increased when high doses were administered on a continuous basis, in comparison with spaced infusions, thus increasing the exposure of the tumor tissues to MAb 17-1A. The pharmacokinetics of mouse MAb 17-1A are best described by a one-compartment model. All patients developed anti-mouse IgG antibodies and most also IgM antibodies. In the more intensive treatment schedules, the IgG antibody response was suppressed. Induction of high titers of antimouse antibodies did not cause clinical problems. Neither did they affect the pharmacokinetics of MAb 17-1A at these dose levels. Therapy was tolerated well. The side effects were mild and of short duration. The gastrointestinal adverse reactions were dose dependent and correlated to serum max_{2 h} concentration. Allergic reactions were rare and easily clinically manageable.

¹ The study was approved by the Ethical Committee of the Karolinska Institute. The study was supported by grants from the Swedish Cancer Society, the Cancer Society in Stockholm, the King Gustav V Jubilee Fund, the Karolinska Institute Foundation, and the Alex and Eva Wallerströms Foundation.

² To whom requests for reprints should be addressed; at Department of Oncology (Radiumhemmet), Karolinska Hospital, S-104 01 Stockholm, Sweden.

Received 12/29/89. Revised 3/28/90.

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