Effect of Intraperitoneal Injection Volume and Antibody Protein Dose on the Pharmacokinetics of Intraperitoneally Administered IgG2ak Murine Monoclonal Antibody in the Rat

Jeffrey S. Barrett, Susan J. Fisher, Richard L. Wahl

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The i.p. route of antibody administration offers a regional delivery advantage to the peritoneal cavity. In an effort to optimize this methodof delivery, the volume of i.p. injection and total protein dose were examined for their effect on the absorption and disposition of an IgG2ak 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]25I-5G6.4 in a 2.0-ml i.p. injection volume. In both cases the same radiationdose (approximately 20 Ci/rat) was administered since only the tracer level (1-2 μig)was labeled. Hence, the 100-Mg dose consisted of approximately 2 UKof labeled antibody with 98 Mgof unlabeled antibody. In aseparate experiment, two i.p. injection volumes (2.0 or 20.0 ml) of 125I-5G6.4 (approximately 20 Ci/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 uponsacrifice 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, Cmax9 was reduced (P < 0.1) and time of maximum concentration, rC|najwas prolonged (P < 0.05) from 8.4h (in the 2-ml group) to 14.5 h (in the 20-ml group). Both contribute toa modest reduction in AUC(0→∞c)(P < 0.15) in which AUC is the areaunder the concentration-time curve. The increase in blood clearance, Clt: at the higher injection volume (0.287 ml/h for the 20-ml volume and0.194 ml/h for the 2-ml volume) is presumably due to increased diuresisresulting from autoregulation of fluid removal via lymphatic drainage. Volume of distribution, I', is increased since I', and (/, are functionally proportionate and elimination is assumed constant. Tissue levels atsacrifice, 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 nodaluptake (/' < 0.01) can be attributed to the dilution effect of the bolusinjection. The rate of mass transfer is greater for the 2-ml group up to 4h postinjection. Subsequently, the mass transfer rate is greater for the20-ml group. While peritoneal concentrations are maintained at 10-foldgreater in the 2-ml group for the duration of the absorption phase, thelymphatic flow rate, Fi.p.liter, meventually compensates for the concentrationdifference. Hence, larger bolus i.p. volumes increase lymphatic flow fromthe peritoneal cavity. Protein dose effects appear to be minimal. Meanblood levels were higher in the high dose (100-Mg) group albeit there wasno statistical difference in the AUC(0→∞) or in the general shape of theblood level curves. I', tended to be smaller in the high dose group and Clb, 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 werehigher for the high dose group, increased tissue uptake suggesting increased extrahepatic deiodination. These findings suggest that higherinjection volumes will enhance the delivery advantage to the peritonealcavity and minimize systemic antibody exposure, and that coadministrationof unlabeled antibody may be unnecessary inasmuch as it appears to increase the extent to which the labeled antibody is exposed to thecirculation, although these manipulations will need testing in a systemwith tumor present.

Original languageEnglish
Pages (from-to)3434-3444
Number of pages11
JournalCancer research
Issue number13
StatePublished - Jul 1 1991


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