Harri Kanerva

Site dependent bioavailability and metabolism of levosimendan in dogs

Site specific bioavailability and metabolism of levosimendan was studied in ten dogs by placing intestinal access port catheters in different parts of the gastrointestinal tract. 14C-labelled levosimendan (0.1 mg/kg) was administered intravenously, by gastric tube and directly through catheters that were placed in the duodenum, jejunum and ileum. Plasma samples were collected and radioactivity in the different organs and tissues was measured. The results of the present study showed that bioavailability of levosimendan was high varying from 71 to 86% after extravascular administration. Metabolite OR-1855 concentrations in the plasma were about 3-4 times higher after administration to the ileum compared to the other administration routes. It can be concluded that the bioavailability of levosimendan is not affected by site specific administration. The bacteria or enzymes responsible for the metabolism of levosimendan are located in the lower parts of the gastrointestinal tract.

The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers.

The pharmacokinetics and tolerability of a new putative non‐benzodiazepine type anxiolytic compound deramciclane was studied in two consecutive studies. An open dose‐escalation design was used to study doses from 0.2 to 50 mg in 18 healthy male volunteers. In the second study doses from 50 to 150 mg were investigated in 14 healthy males in a double‐blind, placebo‐controlled, dose escalation study. Deramciclane was rapidly absorbed from the GI‐tract and Tmax was 2–4 h. The elimination half‐life increased from about 20 h to about 32 h with the increasing dose. Nevertheless, the AUC0–∞ values increased linearly within the studies over the dose ranges of 3–50 and 50–150 mg. However, the increase was more than the ratio of the dose over the total dose range of 3–150 mg. Therefore, non‐linear pharmacokinetics of deramciclane at high doses cannot be excluded. N‐desmethyl deramciclane, which is the active metabolite of deramciclane, was determined in plasma. Cmax was reached at about 6 h. The AUC0–48 h for the N‐desmethyl metabolite was about one third of the AUC0–∞ of the parent compound and the ratio remained constant at each dose level. Deramciclane was safe, and was well tolerated at each dose level. Copyright

Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration – a positron emission tomography study

Rationale: Deramciclane fumarate is a new 5-HT2A and 5-HT2C receptor antagonist with putative anxiolytic effects. In the present study the binding of deramciclane to serotonin 5-HT2A receptors in frontal cortex of healthy male volunteers was studied using [11C]-N-methyl spiperone ([11C]-NMSP) and positron emission tomography. Methods: The receptor occupancy percentage was assessed by the means of inhibition of [11C]-NMSP from the 5-HT2A receptors in the frontal cortex. Single oral doses of 20, 50 and 150 mg deramciclane were given to three subjects at each dose level (total n = 9). The receptor occupancy was measured before deramciclane and at 3 and 6 h post-dosing except at the 20 mg dose level where only the 3-h measurement was done. The occupancy percentage was calculated with the ratio method using cerebellum as a reference area. Results: Deramciclane inhibited [11C]-NMSP binding dose and concentration dependently. However, deramasciclane inhibited maximally only 52% of the [11C]-NMSP binding in the frontal cortex, indicating a non-5-HT2A receptor binding component of this radioligand in frontal cortex. On average, specific [11C]-NMSP binding cerebellum ratios below 0.355 were not possible to achieve in this population. The 52% inhibition was regarded to represent near 100% 5-HT2A receptor occupancy. The 50 and 90% receptor occupancies were reached at deramciclane plasma concentrations of 21 ng/ml and 70 ng/ml, respectively. Conclusions: Deramciclane penetrates the blood-brain barrier in humans. Deramciclane binds to the 5-HT2A receptors in the frontal cortex in a saturable manner in vivo. Consequently, the increase in deramciclane concentration in plasma above 70 ng/ml will not result in major increase in the 5-HT2A receptor occupancy in the brain.

Different absorption profiles of deramciclane in man and in dog.

We have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid‐labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in‐vitro stability of deramciclane was determined over the pH range 1.2–6.0.

Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing

The pharmacokinetics of a new serotonin 5‐HT2 antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg−1 and intravenous doses of 1, 3 and 6 mg kg−1 were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg−1 doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first‐pass metabolism the absolute bioavailability was only 45–61%. Deramciclane had a large volume of distribution (32–37 L kg−1) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h−1) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC0–∞ increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N‐desmethyl deramciclane, was also nonlinear (p =0.0002). At steady state deramciclane accumulated less than 2‐fold during repeated administration. Copyright

Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers

OBJECTIVE To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks. METHODS Sixteen healthy male subjects, age range of 20-29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings. RESULTS The mean (SD) AUC(0-infinity) of deramciclane was 1,251 (385) ng x h/ml after the first dose. The AUC(tau) calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC(0-infinity) after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration. CONCLUSIONS Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree.