Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Abstract

Objective To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. Animals 5 healthy purpose-bred hounds. Procedures The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and non-compartmental analyses. Results Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. Conclusions and Clinical Relevance Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in ng/mL. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, needs to be determined.

Naturally-Occurring Canine Invasive Urothelial Carcinoma: A Model for Emerging Therapies

“…Signaling of the mTOR pathway can contribute to the growth and progression of several cancers including osteosarcoma, and mTOR inhibitors are being evaluated for cancer therapy [ 68 ]. The mTOR inhibitor, rapamycin, has been evaluated in dogs with osteosarcoma, and the pharmacokinetics/pharmacodynamics and anticancer effects reported [ 69–70 ]. A clinical trial conducted by the National Cancer Institute (NCI) Comparative Oncology Trials Consortium is currently ongoing to evaluate oral rapamycin treatment in pet dogs with osteosarcoma [ 71 ].…”

The dog aging project: translational geroscience in companion animals

“…Those dogs that do not present with any abnormalities or significant pre-existing health conditions are randomized into either placebo or rapamycin treatment groups for a 10 week treatment period. Initial rapamycin dosing regimens were determined, in part, based on pharmacokinetic analysis of rapamycin treatment in healthy dogs (Larson et al 2016). After 10 weeks in the study, each dog receives another full exam and blood chemistry panel as well as repeat cardiac exam.…”

A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs

“…While the pharmacokinetics and pharmacodynamics of both orally and parenterally administered rapamycin in dogs are known (Paoloni et al 2010;Larson et al 2016), no data on its use for periods exceeding 7 days in companion dogs have been previously published. Thus, the primary goal of this study was to determine whether low, non-immunosuppressive doses of rapamycin would cause significant clinical side effects in privately owned domestic dogs when given orally over a 10-week period.…”