The primary objective of this single‐centre, open‐label crossover study (NCT01072578) was to assess the effect of dapagliflozin on the amount of glucose in the blood and urine in healthy volunteers when dapagliflozin was administered once a day (10 mg) versus twice a day (5 mg every 12 h) after 5 days of dosing. At steady state, the AUCss (0‐24) (area under the dapagliflozin curve (0‐24 hours) at steady state), Css, av (average concentration at steady state) between dapagliflozin 5 mg twice daily and 10 mg once daily were similar AUCss(0‐24) [5 mg bid, (458.0 (28.7)) and 10 mg qd, (470.0 (28.5))] and Css, av [5 mg bid 18.8 (28.9)) and 10 mg qd, (19.6(28.5))], but minimum and maximum plasma levels of dapagliflozin differed significantly. Percent inhibition of renal glucose reabsorption (%IRGRA) and total urinary glucose excretion over 24 h were similar for both doses. The relationship between the mean dapagliflozin concentration and %IRGRA and the total urinary glucose excreted was well described by a maximum effect model. The results indicate that dapagliflozin may be used for either once daily or twice daily administration.

The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four-way crossover design, The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect, Subjects performed three practice tests before dosing to account for any effects caused by familiarization (''learning curve'') with the testing procedure, Pharmacokinetic and pharmacodynamic data were simultaneously fined to a semiparametric model, In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect, The plasma-effect site equilibrium half-life was approximately 2 1/2 times longer for midazolam than for diazepam, which is in good agreement with previously published data, Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam, This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity, The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.

Summary To investigate the electrophysiological effects of propranolol in vivo over a wide range of plasma concentrations and to distinguish effects due to β-blockade from those due to a direct membrane action, His bundle electrograms were recorded, and ventricular effective refractory periods (VERP) and monophasic action potential duration (MAP) were measured in anesthetized control dogs and in dogs given three graded infusions of d- or dl- propranolol. Dogs were excluded if the plasma concentrations attained did not fall in predefined ranges of 25–125, 125–700, and 700–3,000 ng/ml. Isoproterenol sensitivity tests were performed to determine the relative β-blocking potency of the isomers at the three concentration ranges. The highest concentration of β-propranolol had approximately the same β-blocking potency as the lowest concentration of dl-propranolol. Mean AH and HV intervals in the His bundle electrogram increased with the concentration of dl-propranolol, and the increase was greater than with β-propranolol (p < 0.03) at the first and second concentration steps but not significantly different at the highest concentrations of d- and dl-propranolol. VERP and MAP increased directly with concentration of d- and dl-propranolol. Although the mean increases of VERP and MAP tended to be greater in the dl-propranolol group, the differences between d- and dl-propranolol were not statistically significant at any concentration. We conclude that prolongations of atrioventricular and His-Purkinje conduction are stereospecific responses and are due to β-blockade. The specific mechanism for the prolongation of ventricular repolarization and refractoriness are effects of propranolol that could not be definitively classified in this study.

The antiarrhythmic efficacy of propranolol was evaluated in 32 patients with chronic high frequency ventricular arrhythmias in a placebo-controlled protocol. After a placebo control period, propranolol was begun and the dosage increased sequentially until arrhythmia suppression was achieved, side effects appeared, or a maximum dosage of 960 mg/day was reached. Computerized analysis of ambulatory recordings was used to quantify the arrhythmias. Twenty-four patients had 70--100% arrhythmia suppression at plasma levels ranging from 12--1100 ng/ml (end of dosing interval). Eight patients in this group had frequent episodes of ventricular tachycardia that were totally suppressed at or below the dosage that produced greater than or equal to 70% suppression of ventricular ectopic depolarizations (VEDs). A biphasic dose-response curve was seen in five patients who responded with a decrease in arrhythmia frequency in the lower ranges of dosages but had increased frequency of ectopic rhythms as the dosage was increased above the optimal level. Only one-third of patients responded at doses less than or equal to 160 mg/day. However, with dosages of 200--640 mg/day, an additional 40% responded. Propranolol appears to control ventricular arrhythmias safely and effectively in many patients. The finding that the antiarrhythmic effect in many patients required plasma concentrations greater than those that produce substantial beta-adrenergic blockage raises a question whether blockade of cardiac beta receptors can directly account for all of the antiarrhythmic actions of propranolol.