Pharmacology Journal

There has been an increasing interest in pharmacokinetic-pharmacodynamic modelling to describe the time course of drug effects in relation to the concentration vs time profile in the body. Preferably, these models should consider the mechanisms involved in the pharmacological action of the drug, because it may increase the understanding of how drug effects are affected by other covariates such as disease, gender, age and concomitant drugs. Distinguishing between different pharmacokinetic-pharmacodynamic models and selecting the most appropriate model for a certain drug may be further complicated by time-dependent events such as tolerance development. The loop diuretic frusemide mainly acts from the luminal surface of the renal tubule and its pharmacological effects are adequately described as a function of the urinary excretion rate of the drug. It is common to observe a delay in the onset of diuretic response after an intravenous dose of frusemide in relation to its plasma concentration or even urinary excretion rate. Both effect-compartment (‘direct-response’) models and indirect-response models have been applied to relate the pharmacokinetics of a drug to its pharmacodynamics, when the time course of the pharmacological effect does not apparently reflect the plasma concentrations. The effect-compartment approach assumes that this delay is due to distributional events, governed by a first-order distribution to and from an effect site. Indirect-response models are used to describe the pharmacodynamics of drugs that are assumed to act indirectly, by inhibiting or stimulating the production or loss of endogenous substances or mediators, that are related to the measured drug response. Effect-compartment models and indirect-response models differ in their structural assumptions. Both models may account for a delay in the appearance of drug effect in relation to the concentration at the measurement site. However, they differ fundamentally in the prediction of the time of maximum response of a drug. If an effect-compartment approach is used to describe the effects of a drug, the same time of maximum response will be obtained, independent of the dose. For the indirect-response model, the time of maximum response is predicted to increase with increasing doses. The need for experimental designs and methods to distinguish between different types of apparent direct-response, indirect-response or more general models, has recently been emphasized. The aim of the present study was to use the time of maximum response as a discriminator for pharmacokinetic-pharmacodynamic modelling. The appropriateness of using an indirect-response model vs an effect-compartment model for describing the pharmacokinetic-pharmacodynamic relationship of frusemide was investigated by studying the time of maximum response after administration of three different intravenous doses.

The study had a randomized cross-over design and three frusemide doses of 10, 25 and 40  mg were administered on separate study days with intervals of at least 1 week. To standardize experimental circumstances, no medications were allowed within 1 week before each study day. The subjects were asked to refrain from alcohol and extreme physical activity for 3 days before the start of each experiment. Standardized meals were provided the day before and during each study day with a total content of 159  mmol sodium and 81  mmol potassium  day⁻¹ and caffeinated drinks such as coffee or tea were not allowed during this time. Urine was collected for 24  h on the day before each study day to assess adherence to the diet and to have an estimation of basal diuresis. The subjects fasted overnight and the study started in the morning at the closure of the 24  h urine collection. A cannula was inserted into an antecubital vein of each arm and blood samples were taken to measure basal levels of plasma sodium, potassium and chloride. Then, each subject emptied his bladder after which the administration of frusemide was started (at 0  h). A rapid infusion of 10, 25 or 40  mg of frusemide (Furix^®, Nycomed Pharma, Oslo, Norway), diluted with saline solution to a total volume of 10  ml, was given intravenously over 5  min. The subjects provided urine samples by voiding at 5  min intervals for the first hour and at 15  min intervals for another 4  h after dosing. Urine losses of each period were replaced volume for volume using an intravenous isotonic rehydration fluid to prevent depletion of volume and electrolytes. This solution was prepared by the hospital pharmacy and contained 0.45% NaCl and 2.5% glucose. The fluid was administered using two to four infusion pumps, depending on the urinary volume produced during the preceding interval (IMED 960 volumetric infusion pump with a 9200 accuset, Imed Corporation, San Diego, USA). The subjects remained fasting throughout the 5  h study period. Blood samples were taken to measure plasma sodium, potassium and chloride at 2.5  h and 5  h after dosing. Plasma samples were stored at −20°  C. The urine volumes were weighed and aliquots were carefully protected from light and stored in plastic tubes at −70°  C, until analyzed for frusemide and sodium.

Filed under: Clinical Pharmacology