Dapagliflozin twice daily or once daily: effect on pharmacokinetics and urinary glucose excretion in healthy subjects.

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 AUC(ss)0₋24 (area under the dapagliflozin curve (0-24 hours) at steady state), C(ss,av) (average concentration at steady state) between dapagliflozin 5 mg twice daily and 10 mg once daily were similar AUC(ss)0₋24 [5 mg bid, (458.0 (28.7)) and 10 mg qd, (470.0 (28.5))] and C(ss,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.

Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects.

Dapagliflozin is a potent and selective inhibitor of sodium-glucose co-transporter type 2 that is being developed for the treatment of type 2 diabetes mellitus. This open-label, randomized, two-period, two-treatment (single doses of 10-mg dapagliflozin fasted or fed), crossover study was conducted to evaluate the effect of a high-fat meal on the pharmacokinetics of dapagliflozin in 14 healthy subjects. Compared to the fasted state, a high-fat meal decreased mean dapagliflozin maximum plasma concentrations (C(max) ) by 31%, increased the time to C(max) (T(max) ) by 1 h, but did not affect overall dapagliflozin systemic exposure [area under the plasma concentration-time curve (AUC)]. As the cumulative (daily) amount of glucose excreted in the urine induced by dapagliflozin is dependent upon dapagliflozin AUC, the effect of food on dapagliflozin C(max) is unlikely to have a clinically meaningful effect on dapagliflozin's efficacy. On the basis of these findings, dapagliflozin can be administered without regard to meals.

Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model.

A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of the actual trial until after the simulations were submitted to the holder of the trial results. Data from two clinical investigations of quetiapine in patients with schizophrenia were analyzed by use of nonlinear mixed effects modeling to derive a population pharmacokinetic- and pharmacodynamic-based simulation model. The time course of quetiapine concentrations was described by use of a one-compartment open linear pharmacokinetic model with first-order absorption and elimination. The combination of an inhibitory maximum effect pharmacodynamic model for the active treatment effect and a linear function of time for the placebo effect characterized the observed time course of change in the Brief Psychiatric Rating Scale. Simulation results were compared with those in the actual trial to evaluate how well the simulations predicted the outcome. The actual trial results for all doses except the placebo group fell within the predicted Brief Psychiatric Rating Scale scores +/- 1 SE. Unlike the phase 2 trial, from which the pharmacokinetic/pharmacodynamic model was developed, the placebo group in the actual phase 3 trial showed deterioration of Brief Psychiatric Rating Scale scores with time. We conclude that variable placebo responses observed in short-term studies of schizophrenia provide an inadequate basis for the modeling and simulation of placebo subjects in clinical trials. Knowledge of the range of placebo response observed in other studies may have provided an improved basis for the placebo effect model. The model for active drug produced adequate predictions of the actual trial outcomes.

Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

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 fitted 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.

Reassessment of dapsone as a marker of acetylator phenotypes.

The ratio of metabolite to parent dapsone concentrations at 3 hours after dosing has been used as a marker of acetylator phenotypes. The absorption of dapsone is somewhat erratic with peak concentrations often found after the 3-hour determination. The present study done in 30 healthy, male volunteers compared ratios of metabolite to parent dapsone concentrations 3 hours after dosing with AUC values calculated during a 24-hour period as well as extrapolated to infinity. A single oral dose of 100 mg of dapsone was given to fasting subjects and serial blood samples were obtained over a 24-hour period and assayed by high-performance liquid chromatography for parent and acetylated metabolite. Dapsone pharmacokinetic parameters of AUC (23.4 +/- 8.6 micrograms.h/ml), half-life (24.8 +/- 11.5 hours) and apparent clearance values (81 +/- 30 ml/min) were consistent with those reported previously. Using established criteria for acetylation phenotyping, 20 percent of the subjects (6 of 30) demonstrated rapid acetylation. Bimodality in the ratios, independent of the experimental indices used to differentiate genetic metabolism, was not readily apparent. The data suggest that large variability in the pharmacokinetics of dapsone may sufficiently obscure the evidence of polymorphic metabolism. The use of dapsone as a marker of acetylator phenotyping should be limited to patient populations.

Evaluation of methods of administering tyramine to raise systolic blood pressure.

To compare the relative merits of two different administration regimens, tyramine was administered intravenously in ascending doses to 12 healthy subjects to raise systolic blood pressure slightly more than 30 mm Hg. Six subjects received tyramine by bolus injection and six other subjects received tyramine by infusion. The bolus dose of tyramine needed was 4.34 +/- 1.51 mg (X +/- SD) and the infusion rate needed was 1.11 +/- 0.33 mg/min. Four blood pressure response patterns to continuous tyramine infusion were observed. Because different units were measured for the quantity of tyramine administered, the between-subject variance estimate to within-subject variance estimate ratios were calculated. The two techniques had equivalent consistency. With the bolus method, in contrast to the infusion procedure, the dose-response relationship was obvious in most subjects. Therefore the bolus method was judged to be more useful than the infusion method.

The effect of trimoprostil (trimethyldesoxy prostaglandin E2) on the intrauterine pressure in women.

Prostaglandin E2 is uterotonic. Trimoprostil, a prostaglandin E2 analog, is a gastric antisecretory and cytoprotective agent. The effects of single doses of 0, 0.125, 0.75, and 3.0 mg trimoprostil on intrauterine pressure were measured in a double-blind, crossover study in eight surgically sterile women. The 3 mg dose was not tolerated because of abdominal cramps. The other doses caused a dose-related increase in resting uterine tone and peak pressure with peak effect occurring between 30 and 60 minutes after administration with a duration of about 120 minutes. No effects on the frequency of uterine contractions occurred. Peak mean tone increased from 11.0 to 71.2 mm Hg (p less than 0.01) and peak pressure from 24.6 to 125.1 mm Hg (p less than 0.01) after placebo compared with the 1.5 mg dose. Adverse reactions included abdominal pain that correlated with an increase in intrauterine pressure and tone.

Phase I study of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP), an oral interferon inducer, in cancer patients.

2-Amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) was given to 59 patients in a Phase I study. The agent was selected because it is an interferon inducer and an immunotherapeutic agent in animal tumor models. The study was conducted in two phases. In the first phase, the drug was administered as a single oral dose of 25-2,000 mg/m2. In the second part, the highest tolerated dose reached during part one was used as the initial dose in a multiple-dose scheme of treatment. Patients were treated weekly. The dose was escalated each week, starting with a dose of 2 g/m2 and escalating to 3, 4, and 5 g/m2. No cardiac, hematologic, hepatic, or renal toxicity was observed. The most common toxicity was nausea and vomiting, which occurred in 18% of the patients; others were headache (8%), abdominal pain (8%), and diarrhea (6%). No consistent induction of interferon and no major modification of host defense parameters occurred. One patient with malignant melanoma showed evidence of tumor regression. Pharmacologic studies demonstrated a significant decrease in the bioavailability of the drug as it was administered in this study. Further studies of ABPP with a preparation that has good availability are indicated to determine the potential antitumor activity of this agent or this class of agents in humans.

Sorbitol induced diarrheal illness model.

Twenty-five normal volunteers participated in this study to develop a model of diarrheal illness. The ideal model would induce diarrhea with consistent onset of 18 to 24 hours duration of watery stools, and have few associated symptoms. Groups of five to six each were studied. Volunteers who received castor oil experienced watery stools of short duration associated with abdominal cramps, making it an unacceptable model of disease. Sauerkraut and prune juices inconsistently caused watery stool. Seventy percent sorbitol induced watery diarrhea with few associated symptoms, and of five to six hours duration. The administration of 45 ml of 70% sorbitol six hours apart induced watery stools that met our objective and should be a suitable model for future drug testing of anti-diarrheal medications.

Gastric antisecretory activity of arbaprostil as affected by gastric pH.

Arbaprostil [15(R),15-methyl prostaglandin E2] is inactive. In the presence of acid it is converted to the active 15(S) configuration. The degree of acidity needed for the conversion is not known. We inferred the degree of conversion in vivo in man at different gastric pHs by administering arbaprostil to normal volunteers whose gastric pH was maintained constant at various levels by intragastric titration. A pH-dependent inhibition of gastric acid secretion after stimulation with a peptone meal was observed, with 100 micrograms inhibiting 98% of acid production at pH 2, but only 15% at pH 6. Significant gastric acid inhibition occurred with the gastric pH at, or less than, 5.

Lack of effect of arbaprostil on the human non-pregnant uterus.

Arbaprostil ((15R)-15-methyl Prostaglandin E2) is being studied for the treatment of gastrointestinal illness. To determine its effect on the human uterus, eight sterilized pre-menopausal women were studied during the proliferative phase of their menstrual cycle. Using a microtransducer catheter, intra-uterine pressures were recorded for at least 30 minutes prior to and 2 hours after arbaprostil administration. Each subject was studied four times, at 48-hour intervals, receiving in a double-blind manner; 0, 10, 25, and 50 micrograms. Arbaprostil at does up to 50 micrograms was found not to have any clinically significant effects on the non-pregnant human uterus.

Oral antisecretory activity of prostaglandin E2 in man.

We studied the oral gastric antisecretory activity of prostaglandin E2 in three groups of six normal volunteers. Each volunteer was studied twice, once after receiving prostaglandin E2 (0.5, 1.0, or 2.0 mg) and the other time after receiving placebo administered in a double-blind, randomized fashion. Gastric acid secretion was stimulated with a liquid protein meal from 1/2 to 1 1/2 hr after drug administration. Acid secretion was quantitated using the technique of intragastric titration. Acid secretion after 0.5 mg of prostaglandin E2 was no different than after placebo administration, but 1.0 mg and 2.0 mg of prostaglandin E2 inhibited 58% (6.68 +/- 7.64 meq vs 14.67 +/- 6.75 meq, P less than 0.02) and 76% (2.38 +/- 2.38 meq vs 11.50 +/- 3.51, P less than 0.01) respectively, of gastric acid production compared to placebo therapy. After oral administration, prostaglandin E2 in man is antisecretory with an ED50 of 1.1 mg.

Electrophysiological effects of high-dose propranolol in dogs: evidence in vivo for effects not mediated by the beta adrenoceptor.

Closed-chest dogs anesthetized with morphine and chloralose were studied to determine if direct or nonspecific cardiac electro-physiological effects of propranolol occur at clinically relevant plasma concentrations and to differentiate the nonspecific effects from those due to beta adrenoceptor blockade. In 19 dogs, ventricular monophasic action potential durations (MAP), ventricular effective refractory periods (VERP) and His bundle electrograms (A-H and H-V intervals) were measured at base line and during sequential infusions of isoproterenol, dl-propranolol and dl-propranolol plus an isoproterenol infusion designed to overcome beta blockade. A mean plasma propranolol level of 979 +/- 344 ng/ml produced a significant (P less than .05) prolongation of A-H (95 +/- 20-115 +/- 13 msec), MAP (179 +/- 26-194 +/- 14 msec) and VERP (159 +/- 12-177 +/- 13 msec). Infusion of the beta agonist, isoproterenol, returned A-H and MAP to values not significantly different from base line, whereas VERP remained prolonged at 174 +/- 11 msec (P less than .05). No significant changes occurred in a control group of 14 dogs infused with saline. In eight additional dogs, infusions of d- and dl-propranolol, given on separate days, were used to produce equal beta blockade determined by individual isoproterenol sensitivity tests. A-H, H-V, MAP and ventricular strength-interval curves (VRP) and diastolic thresholds (DT) were measured and treatment vs. base-line changes (delta) with d- and dl-propranolol were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin-induced damage in the dog Heidenhain pouch and cytoprotection with 16,16-dimethyl PGE2.

The gastric mucosa of animals and man can be damaged by noxious agents and protected by prostaglandins. We developed a Heidenhain pouch dog model which allows the study of multiple doses of the protective or noxious agent. Mucosal damage in the pouch caused by instillation of 160 mM aspirin suspended in 150 mM HCl for two 15-min periods was determined by measuring hemoglobin concentration in isotonic mannitol washes. Hemoglobin levels 24 h after the administration of the acid-aspirin suspension were significantly higher than basal levels. Pretreatment with oral doses of 0.3-3 micrograms/kg 16,16-dimethyl PGE2 at 24 and 18 h and 30 min before the acid-aspirin suspension decreased hemoglobin concentrations in the washes (p less than 0.001).

The effects of continuous infusions of prostacyclin-Na (epoprostenol-sodium) on platelet counts, ADP-induced aggregation, and cyclic AMP levels in normal volunteers.

Six male volunteers received either 0 (buffer), 2.5 or 5.0 ng/kg/min PGI2 X Na for 72 hrs. Various platelet parameters were monitored for an additional 72 hrs. Each morning, for seven consecutive days, and +1 and +6 hrs after the termination of the infusion, blood was drawn and platelet rich plasma (PRP) was prepared. The PRP was immediately exposed to 100 ng/ml PGI2 X Na, and the subsequent increase in platelet cyclic AMP was measured by radioimmunoassay. Aggregation in response to 2 or 4 microM ADP was measured simultaneously. Three volunteers returned for a second 72 hr infusion of 5.0 ng/kg/min PGI2 X Na. After 72 hrs, the infusion rate was gradually "tapered off" over a 12 hr period at which time the infusion was terminated. The sensitivity of the PRP to ADP-induced aggregation was recorded before, during, and after the "tapering off" regimen. Platelet counts were not altered by any of the infusions. The responsiveness of the platelet adenylate cyclase to exogenous PGI2 X Na was inversely related to the concentration of PGI2 X Na infused. Desensitization occurred and was more severe after 72 hrs of infusion than after either 24 or 48 hrs. For example, after 72 hrs at 5.0 ng/kg, platelets lost approximately 50% of their responsiveness to PGI2. ADP-induced aggregation was not significantly inhibited ex vivo by the infusion of 2.5 ng/kg/min PGI2. During the infusion of 5.0 ng/kg/min PGI2, ADP-induced aggregation was inhibited at 24 and 48 hrs, but by 72 hrs, the platelets began to respond to ADP more like control cells even though the PGI2 X Na infusion was continuing. When the infusion was abruptly terminated a hyperaggregable response (rebound) to exogenous ADP was observed. In subjects where the 5.0 ng/kg/min infusion was gradually "tapered off" over a 12 hr period, there was no evidence of platelet hyperaggregability at the time points studied.

Absence of cardiac arrhythmias during a very-low-calorie diet with high biological quality protein.

Fourteen women who were at least 50 lb (22.7 kg) overweight entered the 15 week study which included 4 weeks of 1200 cal (5028 J) balanced diet followed by 7 weeks on a very-low-calorie diet (VLCD) and 4 weeks of refeeding. During the VLCD high biological quality protein (poultry, fish) and recommended supplements of vitamins, minerals and water were used. With the exception of week 5 and 14, 25-h Holter monitorings were done weekly. During the initial 4 weeks, 2 patients showed disturbances of cardiac rhythm and were discharged from the study. Twelve patients completed the trial without any clinically significant changes in cardiac rhythm. The 12 lead ECGs remained normal in all patients throughout the study. The average weight loss was 46 lb (20.9 kg) and the whole program was well tolerated. It is concluded that seven weeks of VLCD with high biological quality protein and recommended supplements appears to be a safe method for weight reduction for severely obese patients.

Gastrointestinal propulsion measurement with radiopaque capsules during 16,16-dimethyl PGE2 infusion.

A method to quantitate gastric emptying (GE) and small intestinal transit (SIT) by obtaining serial abdominal x-rays after administration of radiopaque capsules was developed. The technique was verified by studying gastric emptying and small intestinal transit in healthy volunteers treated with subcutaneous injections of 0.4 or 0.8 mgs of atropine, 2.5 mg bethanechol, or saline placebo. Atropine decreased gastric emptying and small intestinal transit, and bethanechol only increased gastric emptying. The suitability of this technique for measuring gastrointestinal propulsion in post-operative patients was demonstrated in females undergoing hysterectomy. The small intestine recovered propulsive ability at least six hours sooner than the stomach. This technique was also used while performing a single dose, intravenous tolerance study of 16,16-dimethyl prostaglandin E2 (DmPGE2) in normal volunteers. DmPGE2 was administered over five minutes at a dose of 7 to 140 ng/kg. DmPGE2 was well tolerated producing only minor side effects that were not dose related. In doses up to 70 ng/kg, DmPGE2 increased gastric emptying and inhibited small intestinal transit. The delayed small intestinal transit may make DmPGE2 an inappropriate choice for treatment of post-operative or paralytic ileus.