J.P. Mochel (1,2), B. Bornkamp (2), and B. Bieth (2)
(1) Department of Pharmacology, Leiden-Academic Centre for Drug Research, 2300 Leiden, The Netherlands. (2) Integrated Quantitative Sciences, Novartis Pharmaceuticals, Werk Saint Johann 4056 Basel Switzerland
Objectives: Congestive heart failure (CHF) is a leading cause of morbidity and mortality which is commonly associated with fluid overload and shortness of breath in canine populations. Furosemide is a non-potassium sparing loop diuretic prescribed for the majority of patients suffering from heart diseases. Although furosemide provides an overt clinical benefit in reducing fluid retention, it also has the disadvantage of activating the renin-angiotensin aldosterone system (RAAS), which further contributes to the accelerated progression of CHF. Despite the widespread use of loop diuretics and concerns regarding activation of the RAAS in dog patients, no detailed information on the dose-response relationship of furosemide is presently available. Our objective was to quantify the effect of several increasing doses of furosemide on diuresis, renin activity (RA) and aldosterone (AL) in dogs, using a model-based approach.
Methods: 24 healthy beagle dogs were allocated to 4 treatment groups (saline control, furosemide 1, 2, and 4 mg/kg I.M., q12 hrs for 5 days). Dogs were placed in metabolism cages for collection of urine. RA was determined using a dedicated enzyme immunoassay, while AL concentrations were quantified in plasma by mass spectrometry. Data from trough RA and AL values, as well as 24-hr diuresis were analyzed at steady state using dose-response modelling based on a multiple comparison procedure and modelling (MCP-Mod) approach [1]. To cover a broad range of anticipated dose-response shapes, a set of candidate models was characterized, and a multiple contrast test was performed to assess the presence of a dose response signal (MCP part). Finally, a model averaging technique was used to derive the dose-response curve for each endpoint of interest (Mod part).
Results: Sigmoid Emax models were found to adequately describe the dose-response relationships of furosemide. The derived ED50 and ED90 values were estimated to be lower for 24-hr diuresis (0.6 and 1.3 mg/kg q12 hrs, respectively), compared with RA (1.0 and 1.9 mg/kg) and AL (1.0 and 2.1 mg/kg).
Conclusions: MCP-Mod is a powerful tool for evaluating dose-response relationships in veterinary pharmacology. Our data show that furosemide produces a sub-maximal effect on diuresis at doses lower than those identified to activate the systemic RAAS.
References:
[1] Pinheiro J, Bornkamp B, Glimm E, Bretz F. Multiple comparisons and modeling for dose-finding using general parametric models. Statistics in Medicine (2014) 33(10):1646-61.
Reference: PAGE 24 (2015) Abstr 3382 [www.page-meeting.org/?abstract=3382]
Poster: Methodology - Other topics