title: Multiple comparison procedure and modeling: a versatile tool for evaluating dose-response relationships in veterinary pharmacology - a case study with furosemide.
abstract: Congestive heart failure (CHF) is a leading cause of mortality with an increasing prevalence in human and canine populations. While furosemide is a loop diuretic prescribed for the majority of CHF patients to reduce fluid retention, it also activates the renin-angiotensin aldosterone system (RAAS) which further contributes to the accelerated progression of heart failure. Our objective was to quantify the effect of furosemide on diuresis, renin activity (RA), and aldosterone (AL) in dogs, using a combined multiple comparisons and model-based approach (MCP-Mod). Twenty-four healthy beagle dogs were allocated to four treatment groups (saline vs. furosemide 1, 2, and 4 mg/kg i.m., q12 h for 5 days). Data from RA and AL values at furosemide trough concentrations, as well as 24-h Diuresis, were analyzed using the MCP-Mod procedure. A combination of Emaxmodels adequately described the dose-response relationships of furosemide for the various endpoints. The dose-response curves of RA and AL were found to be well in agreement, with an apparent shallower slope compared with 24-h Diuresis. The research presented herein constitutes the first application of MCP-Mod in Veterinary Medicine. Our data show that furosemide produces a submaximal effect on diuresis at doses lower than those identified to activate the circulating RAAS.
authors.affiliation: Department of Pharmacometrics, Biostatistical Sciences & Pharmacometrics, Novartis Pharma AG, Basel, Switzerland. bruno.bieth@novartis.com.
authors.forename: B
authors.initials: B
authors.lastname: Bieth
authors.affiliation: Statistical Methodology, Biostatistical Sciences & Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Bornkamp
authors.affiliation: Companion Animal Development, Novartis Animal Health, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Toutain
authors.affiliation: New Product Development, Novartis Animal Health US, Inc., Greensboro, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Garcia
authors.affiliation: Department of Pharmacometrics, Biostatistical Sciences & Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.|Department of Pharmacology, Leiden-Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Mochel
mesh_terms: D000818:Animals; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005665:Furosemide / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological
chemical_list: D004232:Diuretics; D005665:Furosemide