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Effect of Intraperitoneal Injection Volume and Antibody Protein Dose on the Pharmacokinetics of Intraperitoneally Administered IgG2a Murine Monoclonal Antibody in the Rat¹

Division of Nuclear Medicine, Department of Internal Medicine [J. S. B., R. L. W., S. J. F.], UpJohn Center for Clinical Pharmacology [J. S. B., J. G. W.], and Department of Diagnostic Radiology [R. L. W.], University of Michigan Medical Center, Ann Arbor, Michigan 48109

The i.p. route of antibody administration offers a regional delivery advantage to the peritoneal cavity. In an effort to optimize this method of delivery, the volume of i.p. injection and total protein dose were examined for their effect on the absorption and disposition of an IgG2a murine monoclonal antibody, 5G6.4, administered i.p. Normal rats (Sprague-Dawley) were given one of two protein doses (1–2 or 100 µg) of ₁₂₅I-5G6.4 in a 2.0-ml i.p. injection volume. In both cases the same radiation dose (approximately 20 µCi/rat) was administered since only the tracer level (1–2 µg) was labeled. Hence, the 100-µg dose consisted of approximately 2 µg of labeled antibody with 98 µg of unlabeled antibody. In a separate experiment, two i.p. injection volumes (2.0 or 20.0 ml) of ¹²⁵I-5G6.4 (approximately 20 µCi/rat) were administered to normal Sprague-Dawley rats. Pharmacokinetic modeling of the whole blood radioactivity levels was undertaken for both groups. The liver, kidney, muscle, lung, diaphragm, and anterior mediastinal lymph nodes were excised upon sacrifice and tissue levels at sacrifice were recorded. The volume of i.p. injection is shown to be a significant factor with respect to i.p. transport. Maximum concentration in the blood, C_max, was reduced (P < 0.1) and time of maximum concentration, t_Cmax was prolonged (P < 0.05) from 8.4 h (in the 2-ml group) to 14.5 h (in the 20-ml group). Both contribute to a modest reduction in AUC₍₀₎ (P < 0.15) in which AUC is the area under the concentration-time curve. The increase in blood clearance, Cl_b, at the higher injection volume (0.287 ml/h for the 20-ml volume and 0.194 ml/h for the 2-mol volume) is presumably due to increased diuresis resulting from autoregulation of fluid removal via lymphatic drainage. Volume of distribution, V_d, is increased since V_d and Cl_b are functionally proportionate and elimination is assumed constant. Tissue levels at sacrifice, except for the thyroid and anterior mediastinal lymph nodes, were the same. Mean thyroid levels were reduced in the 20-ml group (P < 0.05) by 22.5%, likely as a result of increased diuresis. Increased nodal uptake (P < 0.01) can be attributed to the dilution effect of the bolus injection. The rate of mass transfer is greater for the 2-ml group up to 4 h postinjection. Subsequently, the mass transfer rate is greater for the 20-ml group. While peritoneal concentrations are maintained at 10-fold greater in the 2-ml group for the duration of the absorption phase, the lymphatic flow rate, F_i.p.·liter, eventually compensates for the concentration difference. Hence, larger bolus i.p. volumes increase lymphatic flow from the peritoneal cavity. Protein dose effects appear to be minimal. Mean blood levels were higher in the high dose (100-µg) group albeit there was no statistical difference in the AUC₍₀₎ or in the general shape of the blood level curves. V_d tended to be smaller in the high dose group and Cl_b of the high dose group was generally slower than the tracer dose rats (0.159 versus 0.185 ml/h). Also, mean tissue levels at sacrifice were slightly smaller for the low dose group. Likewise, thyroid levels were higher for the high dose group, increased tissue uptake suggesting increased extrahepatic deiodination. These findings suggest that higher injection volumes will enhance the delivery advantage to the peritoneal cavity and minimize systemic antibody exposure, and that coadministration of unlabeled antibody may be unnecessary inasmuch as it appears to increase the extent to which the labeled antibody is exposed to the circulation, although these manipulations will need testing in a system with tumor present.

¹ Paper 2 in the series, "Investigations into the Route of Uptake and Pharmacokinetics of Intraperitoneally Administered Monoclonal Antibodies." Supported by Grants CA 41531 and POI CA 42537 awarded by the USPHS.

² H. Helfman Pharmacy Student Aid Fellow. Present address: Drug Metabolism Department, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.

³ To whom requests for reprints should be addressed, at University of Michigan Medical Center, Division of Nuclear Medicine, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0028.

Received 4/17/90. Accepted 4/22/91.

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