The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects.

The pharmacokinetics of escitalopram (S-citalopram) and its principal metabolite, S-demethylcitalopram (S-DCT), were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion of escitalopram, the mean systemic clearance and volume of distribution were 31 L/h and 1,100 L, respectively. After oral administration of single or multiple doses, the absorption was relatively fast, with the maximum observed plasma or serum concentration (C(max)) attained after 3 to 4 hours. The mean half-lives were 27 and 33 hours, respectively; steady state was attained within 10 days. The area under the plasma or serum concentration time curve from time zero to 24 hours and C(max) was both linear and proportional to the dose. The apparent volume of distribution was around 20 L/kg. Comparison of the systemic and oral clearance implied a high absolute bioavailability. There was no evidence of interconversion from S-citalopram to R-citalopram either in plasma or in urine. Concurrent intake of food had no effect on the pharmacokinetics of escitalopram or its metabolite. All treatments were well tolerated.

The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects.

AIMS: To investigate the effects of co-administration of cimetidine or omeprazole on the pharmacokinetics of escitalopram. METHODS: Two randomized placebo-controlled crossover studies were carried out. Sixteen healthy subjects were administered placebo, or cimetidine (400 mg twice daily) for 5 days (study 1) or omeprazole (30 mg once daily) for 6 days (study 2). On day 4 (study 1) or day 5 (study 2), a single dose of escitalopram (20 mg) was administered. Blood samples were taken at predetermined times for the measurement of serum concentrations of escitalopram and its demethylated metabolite (S-DCT). Treatment-emergent adverse events were also monitored. RESULTS: Co-administration with cimetidine caused a moderate increase in the systemic exposure [AUC0, infinity] to escitalopram (geometric mean ratio = 1.72, [95% CI 1.34, 2.21]) and a small increase in t(1/2) from 23.7 to 29.0 h (5.24 h [3.75, 6.70]). Co-administration with omeprazole also resulted in a moderate increase in the escitalopram AUC(0, infinity) (1.51 [1.39, 1.64]) and a small increase in t(1/2) from 26.5 to 34.8 h (8.3 h [6.44, 10.2]). There was no significant change in S-DCT AUC0, infinity after co-administration of either cimetidine or omeprazole. Co-administration of cimetidine or omeprazole had no effect on the incidence of treatment-emergent adverse events. CONCLUSIONS: In view of the good tolerability of escitalopram, the pharmacokinetic changes observed on co-administration with cimetidine or omeprazole are unlikely to be of clinical concern.

The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects.

The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency.

Recognition of environmental and genetic effects on barley phenolic fingerprints by neural networks.

Through computational analysis of high-performance liquid chromatography (HPLC) traces we find correlations between secondary metabolites and growth conditions of six varieties of barley. Using artificial neural networks, it was possible to classify chromatograms for which the varieties were fertilized by nitrogen and treated by fungicide. For each variety of barley we could also differentiate it from the others. Surprisingly, all these classification tasks could be solved successfully by a simple network with no hidden units. When adding to the methodology pruning of the network weights, we were able to reduce the set of peaks in the chromatograms and obtain a necessary subset from which the growth conditions and differentiation may be decided. In some instances, more complex networks with hidden units could lead to a further reduction of the number of peaks used. In most cases, far more than half of the peaks are redundant. We find that it requires fewer information-rich peaks to perform the variety differentiation tasks than to recognize any of the growth conditions. Analysis of the network weights reveals correlations between weighted combinations of peaks.

Pharmacokinetic and pharmacodynamic modeling of NN703, a growth hormone secretagogue, after a single po dose to human volunteers.

The objective of this study was to describe the pharmacokinetics and pharmacodynamics of NN703, a growth hormone (GH)-releasing secretagogue, after po administration to healthy human male subjects. The study was designed as a randomized, placebo-controlled, double-blind, dose-escalating, single-dose trial of NN703 covering eight dose levels. Each of the dose levels had 6 subjects on active treatment and 2 subjects on placebo. NN703 was administered po as a solution. Blood samples for serum concentrations of NN703 and GH were collected before dosing and up to 24 hours after dosing. Serum concentrations of NN703 were determined using a validated analytical method, based on solid-phase extraction and LC/MS/MS detection. A two-compartmental model with zero-order input was used to describe the pharmacokinetics of NN703. The parameters of the elimination phase were fitted simultaneously, whereas the parameters describing the absorption phase were allowed to vary between the dose levels. The pharmacodynamics of NN703 was described by use of an indirect-response model containing both a threshold value and a modulator for the development of tolerance. It was concluded that the absorption of NN703 after po administration was nonlinear; the bioavailability increased with the dose. The serum concentration of NN703 required for half-maximal stimulation of GH was determined to be 485 ng/ml. The proposed indirect-response model requiring a threshold concentration and development of tolerance provided a useful mean of quantifying the effects of NN703. Furthermore, the development of tolerance shown based on pharmacokinetic/pharmacodynamic modeling of single-dose data presented here has been confirmed following multiple dosing in healthy male subjects.

The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers.

The aim of the present study was to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of a single dose of NN703 (tabimorelin), a growth hormone secretagogue in healthy male subjects. The study design was double blind, randomized and placebo-controlled, with eight escalating dose levels (0.05-12 mg/kg bodyweight (BW)). NN703 was well tolerated by the subjects. The GH area under the curve (AUC) (0-24 h) was significantly higher when compared to placebo for the three highest dose levels (3.0 mg/kg: P = 0.027, 6.0 mg/kg: P = 0.0023, 12 mg/kg: P< 0.0001), and for GH maximal concentration C(max)the four highest dose levels were also significantly higher when compared to placebo (1.5 mg/kg: P = 0.04, 3.0 mg/kg: P = 0.0143, 6.0 mg/kg: P = 0.0053, 12 mg/kg: P = 0.0007). Furthermore, there was a significant increase in IGF-1 levels when compared to placebo for the 6.0 and 12.0 mg/kg BW dose levels (P< 0. 0001). Statistical analysis comparing the AUC (0-24 h) of the NN703 (four highest dose levels) and placebo-treated groups showed no significant increases following NN703 for ACTH, LH, FSH, TSH, prolactin, and cortisol, however, subtle individual changes were noted in ACTH, cortisol and prolactin at doses above 3.0 mg/kg. In conclusion, NN703 is a promising potential candidate for treatment of GH deficiency/insufficiency.

Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart.

OBJECTIVE: With the aim to obtain a premixed rapid-acting insulin with a serum insulin profile more closely resembling the endogenous meal-stimulated serum insulin profiles, a 30/70 (rapid/intermediate-acting) premixed suspension of the rapid-acting insulin analogue insulin aspart (BIAsp30) was compared with a similar premixed suspension of biphasic human insulin 30/70 (BHI30) after a single subcutaneous injection. METHODS: The study had a randomised, double-blind, two-period crossover design. Twenty-four healthy male subjects received a single subcutaneous dose of either 0.2 U x kg(-1) bodyweight of BIAsp30 or BHI30 on two study days. RESULTS: BIAsp30 was absorbed faster than BHI30, as reflected in the area under the insulin concentration-time curve from 0 to 90 min after dosing [AUC(0-90 min)]. This was significantly larger for BIAsp30 than for BHI30 (1403 +/- 372 versus 752 +/- 191 mU x l(-1) x min(-1) [mean +/- SD]; P < 0.0001). Furthermore, the time to maximum serum insulin concentration (tmax) of BIAsp30 was approximately half the tmax of BHI30 (60 [45-70] versus 110 [90-180] min [median, interquartile range]; P=0.0001) and the maximum insulin concentration (Cmax) was significantly higher for BIAsp30 than for BHI30 (23.4 +/- 5.3 versus 15.5 +/- 3.7 mU x l(-1) [mean +/- SD]; P < 0.0001). The serum glucose profiles showed a significantly earlier onset of the glucose-lowering effect following BIAsp30 than following BHI30. CONCLUSIONS: The improved absorption properties of soluble insulin aspart in its premixed formulation provide a basis for a more efficient meal-related glucose control and immediate pre-meal delivery when compared with a similar human premixed insulin in the treatment of diabetes mellitus.

Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue NN304 in comparison to NPH insulin in humans.

NN304 is a long-acting insulin analogue that is acylated with a 14-C-fatty acid chain. Protraction of action of this novel insulin analogue is due not to slow absorption after subcutaneous administration but to reversible binding to albumin. We investigated the pharmacokinetic and pharmacodynamic properties of insulin analogue NN304 (0.3 and 0.6 U/kg) in comparison to NPH insulin (0.3 and 0.6 IU/kg) in 10 healthy volunteers performing a randomised, double-blind, cross-over, placebo-controlled glucose clamp study. During the observation period of 24 hours the areas under the insulin curve for NPH[0.3 IU/kg] vs. NPH[0.6 IU/kg] were 60 vs. 102 nmol min l(-1) (p<0.01) and for insulin analogue NN304[0.3 U/kg] vs. NN304[0.6 U/kg] 490 vs. 932 nmol min l(-1) (p <0.001), suggesting a clear dose-response relationship for both NPH insulin and NN304. The amount of disposed glucose (area under the curve of glucose infusion) differed with statistical significance between the five treatments and was highest with NPH[0.6 IU/kg] (2671 mg/kg) and lowest with placebo (265 mg/kg). However, area under the curve of glucose infusion after treatment with NN304 was only 36% (dose of 0.3 U/kg) and 24% (dose of 0.6 U/kg) of that observed with corresponding doses of NPH insulin. Moreover, increasing dosages of NN304 failed to demonstrate a significant dose-response with regard to the area under the curve of glucose infusion. This study demonstrates that the principle of protracted insulin action of NN304 by reversible binding to albumin is effective in humans albeit at a much lower rate of glucose utilisation when compared to NPH insulin. Thus, in contrast to animal studies NN304 and NPH insulin can not be considered equipotent in humans.