Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs

Abstract

Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling.

Cisplatin nephrotoxicity in male beagle dogs: next-generation protein kidney safety biomarker tissue expression and related changes in urine

“…9 CDDP has been recognized as a regulatorapproved priority standard of care therapeutic for human oncological diseases where specialized diagnostic or monitoring is needed. 11 However, CDDP is seldom used in veterinary practice because dose-limiting nephrotoxicity is a common side effect of therapeutically needed dose levels. 11 However, CDDP is seldom used in veterinary practice because dose-limiting nephrotoxicity is a common side effect of therapeutically needed dose levels.…”

“…10 CDDP is not approved by the United States Food and Drug Administration (FDA) for use in companion animals. 11 However, dogs (Canis familiaris) represent the most commonly used nonrodent model for both preclinical drug safety and efficacy testing of candidate drugs intended for use in humans and veterinary indications despite consideration of the sometimes limited translational value of selected toxicity data, which is oftentimes revealed from beagle dogs. 11 However, dogs (Canis familiaris) represent the most commonly used nonrodent model for both preclinical drug safety and efficacy testing of candidate drugs intended for use in humans and veterinary indications despite consideration of the sometimes limited translational value of selected toxicity data, which is oftentimes revealed from beagle dogs.…”