Postural effects on peritoneal transport and systemic uptake of radiolabeled monoclonal antibodies.
To optimize the regional delivery advantage with i.p. administration of monoclonal antibody (mAb) for radioimmunotherapy, it may be possible to delay the rate and extent of mAb absorption from the peritoneal cavity by simply altering the position of a patient after radioantibody administration. It has been shown that the hydrostatic pressure against the diaphragm plays a major role in the rate of egress of radioantibodies from the peritoneal cavity and that fluid removal from the peritoneal cavity can be altered by posture. The current study examined postural effects in normal rats following the i.p. injection of 125I-5G6.4 murine IgG2a anticarcinoma antibody (45 microCi). A 10-ml injection volume of the radioantibody solution was administered to rats restrained in either a supine or inclined (reverse Trendelenburg; feet down at a 45 degrees angle) position. Pharmacokinetic analysis confirmed that the appearance of the radioantibody into the systemic circulation was delayed in the inclined group. The time to peak blood concentration was prolonged from 14.7 (supine) to 19.2 (inclined) hours (P = 0.005). All other pharmacokinetic parameters were equivalent across the treatment groups. The mean half-life of 166 h, mean blood clearance of 9 ml/min, and mean steady-state volume of distribution of 36 ml were consistent with previous experience with this radioantibody in the rat. The intrinsic absorption profile indicated that the mean percentage absorption from the peritoneal cavity to the blood stream was greater in the supine animals from 4 h after i.p. injection until absorption was complete. By 10 h after injection, absorption from the peritoneal cavity was essentially complete in the supine-dosed animals, while those restrained in an inclined position had cleared only 50% of the total absorbed dose. Hence, the regional delivery advantage afforded by intraperitoneal administration of the radioantibody may be further exploited by maintaining an inclined position throughout the absorption phase, a strategy that may be applicable to radioimmunotherapy of patients.
Barrett
J S
JS
DuPont Merck Pharmaceuticals, Department of Drug Metabolism and Pharmacokinetics, Newark, Del., USA.
Fisher
S J
SJ
Wahl
R L
RL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D016499:Radioimmunotherapy; D051381:Rats; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm