Pharmacokinetic and Pharmacodynamic Parameters of Ramipril and Ramiprilat in Healthy Dogs and Dogs with Reduced Glomerular Filtration Rate

Ramipril, an angiotensin-converting enzyme (ACE) inhibitor for use in dogs, is converted in vivo to its active form, ramiprilat, which is eliminated in the bile and urine in the dog. The objective of this study was to assess the effect of renal impairment on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ramipril and ramiprilat. Ten adult Beagle dogs were used. PK/PD studies were performed before and after the induction of subclinical renal impairment. Ramiprilat was given at 0.25 mg/kg by a single IV bolus. After a 2-week washout period, ramipril was administered PO at 0.25 mg/kg once daily for 8 days. Ramipril and ramiprilat PKs were studied by using a physiologically based model. The relationship between free plasma ramiprilat concentration and ACE activity was described by using the fractional Hill model. Glomerular filtration rate was decreased by 58%. No biologically relevant changes in usual plasma variables were observed between the 1st and the 8th day of oral treatment with ramipril under either condition. After an IV bolus of ramiprilat, the only changes in renal-impaired dogs were a 14 and 49% decrease in clearance of the free fraction of ramiprilat (P <.01) and free plasma concentration required to produce 50% of the maximal effect (P <.05), respectively. After repeated PO administration of ramipril, there were no alterations in any of the PK and PD parameters in healthy or renal-impaired dogs. No adjustment of the recommended PO dosage of ramipril is needed in dogs with moderate renal impairment.