Safety,pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban,a factor Xa inhibitor,in healthy subjects

Aim

Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.

Method

This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).

Results

Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile.

Conclusion

Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.     

Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic,in a first-in-human study

Aims

The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).

Methods

T2DM subjects (glycosylated haemoglobin: 7.0–10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5–200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride – an early marker of drug activity.

Results

No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5–7.7 h and 66.5– 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.

Conclusions

Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.     

Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

AIMS

To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC).

METHODS

The data set included 78 escitalopram overdose events (median dose, 140 mg [10–560 mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes.

RESULTS

A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC_i/dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α = 0.35). The heart rate corrected QT interval (QT_c) was linearly dependent on predicted escitalopram concentration [slope = 87 ms/(mg l^–1)], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200 mg.

CONCLUSIONS

There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.     

Apixaban,an oral,direct factor Xa inhibitor: single dose safety,pharmacokinetics, pharmacodynamics and food effect in healthy subjects

Aims

To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics.

Methods

A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT).

Results

In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median t_max occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban C_max and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration.

Conclusions

Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food.     

Effect of experimental hyperlipidaemia on the electrocardiographic effects of repeated doses of halofantrine in rats

BACKGROUND AND PURPOSE

Halofantrine can cause a prolongation of the cardiac QT interval, leading to serious ventricular arrhythmias. Hyperlipidaemia elevates plasma concentration of halofantrine and may influence its tissue uptake. The present study examined the effect of experimental hyperlipidaemia on QT interval prolongation induced by halofantrine in rats.

EXPERIMENTAL APPROACH

Normolipidaemic and hyperlipidaemic rats (induced with poloxamer 407) were given 4 doses of halofantrine (i.v., 4–40 mg·kg⁻¹·d⁻¹) or vehicle every 12 h. Under brief anaesthesia, ECGs were recorded before administration of the vehicle or drug and 12 h after the first and last doses. Blood samples were taken at the same time after the first and last dose of halofantrine. Hearts were also collected 12 h after the last dose. Plasma and heart samples were assayed for drug and desbutylhalofantrine using a stereospecific method.

KEY RESULTS

In the vehicle group, hyperlipidaemia by itself did not affect the ECG. Compared to baseline, QT intervals were significantly higher in both normolipidaemic and hyperlipidaemic rats after halofantrine. In hyperlipidaemic rats, plasma but not heart concentrations of the halofantrine enantiomers were significantly higher compared to those in normolipidaemic rats. Despite the lack of difference in the concentrations of halofantrine in heart, QT intervals were significantly higher in hyperlipidaemic compared to those in normolipidaemic rats.

CONCLUSIONS AND IMPLICATIONS

The unbound fraction of halofantrine appeared to be the controlling factor for drug uptake by the heart. Our data suggested a greater vulnerability to halofantrine-induced QT interval prolongation in the hyperlipidaemic state.     

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study

AIMS

To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.

METHODS

A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers ({"type":"clinical-trial","attrs":{"text":"NCT00903747","term_id":"NCT00903747"}}NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.

RESULTS

Estimated mean difference in study specific corrected QT interval (QT_cSS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT_cSS were all <10 ms. There were no outlying QT_cSS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT_cSS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min^–1), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.

CONCLUSION

Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.     

Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects

AIMS

To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine.

METHODS

In this open-label, randomized, two-way crossover study, 28 healthy subjects (18–55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration–time curve from 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), time to C_max (t_max), and half-life (t_1/2), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine.

RESULTS

Concomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and C_max of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t_max or t_½. Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters.

CONCLUSION

Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters.     

Clinical experience with argatroban for heparin-induced thrombocytopenia in a large teaching hospital

Background:

Argatroban is a direct thrombin inhibitor approved for the prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). The product monograph does not guide clinicians beyond specifying the initial dose of 2 μg/kg per minute (or 0.5 μg/kg per minute for patients with hepatic impairment). Some authors have suggested that in the intensive care unit (ICU) and for patients with acute cardiac disease and those with renal or hepatic dysfunction, this dose may result in a supratherapeutic activated partial thromboplastin time (aPTT).

Objectives:

To evaluate the efficacy and safety of argatroban in adult patients with suspected HIT in a large teaching hospital, and to review dosing for patients in the ICU, patients with acute cardiac disease, and patients with renal or hepatic dysfunction.

Methods:

Charts of patients with suspected HIT who had received argatroban for at least 24 h between October 1, 2005, and October 1, 2007, at the Foothills Medical Centre, Calgary, Alberta, were examined retrospectively.

Results:

Thirty patients met the inclusion criteria, with charts available for review. Of these, 21 (70%) patients had an initial argatroban dose of 2 μg/kg per minute and 4 (13%) had an initial dose of 0.5 μg/kg per minute. The median duration of therapy was 6 days, and the mean dose was 2.14 μg/kg per minute. There were 122 dosage adjustments, the most common change being 0.5 μg/kg per minute, followed by adjustments of 1 and 0.1 μg/kg per minute. Six patients had supratherapeutic aPTT values (above 100 s), and none experienced major bleeding.

Conclusions:

The results of this study suggest that an initial argatroban dose of 2 μg/kg per minute is appropriate for patients with no hepatic dysfunction. Patients with acute cardiac disease and critically ill patients may require lower doses of argatroban; however no dosage adjustments are required for patients with renal dysfunction.     

High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

Aims

To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings.

Methods

This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist''s discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QT_cF (Fridericia''s HR correction) was calculated and >500 ms was defined as abnormal.

Results

Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QT_cF >500 ms but only in one taking methadone was the timing of QT_cF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias.

Conclusion

QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.     

Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers

AIMS

To assess the efficacy, pharmacodynamics, safety and tolerability of a range of doses of cetilistat, a novel inhibitor of gastrointestinal lipases, in healthy volunteers.

METHODS

Three Phase I, randomized, placebo-controlled, parallel-group studies were conducted. Enrolled subjects in the three studies (n = 99) received a controlled calorie diet (total intake 2160 calories daily, 30% from fat). Twenty-four subjects were randomized to placebo and 66 were randomized to the following cetilistat doses: 50 mg three times daily [t.i.d. (n = 7)], 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9). Nine subjects received the approved orlistat dose (120 mg t.i.d.). Treatment was for 5 days, with a 2-day run-in period and 1-day post-treatment follow-up. The primary outcome measure was daily faecal fat excretion. Secondary outcomes included plasma lipid levels, tolerability [gastrointestinal adverse events (AEs)] and safety.

RESULTS

Cetilistat increased faecal fat excretion relative to baseline at all doses. Cetilistat was well tolerated, with gastrointestinal AEs the most common (51%). Steatorrhoea (oily stool) was more frequent in the orlistat group (4.11 events per subject) than in any cetilistat dose group (0.14–1.81 events per subject). Most AEs (98%) were mild or moderate in intensity.

CONCLUSIONS

Cetilistat increased dietary fat excretion in healthy volunteers receiving a controlled calorie diet. Cetilistat was well tolerated at all doses examined and tolerability appeared to be improved relative to orlistat. Faecal fat excretion in the cetilistat groups was at least comparable to the orlistat 120 mg t.i.d. group.     

Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects

AIMS

To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects.

METHODS

Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed.

RESULTS

PF-04457845 was rapidly absorbed (median t_max 0.5–1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5- to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated.

CONCLUSIONS

PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.     

Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

Background and Purpose

Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential.

Experimental Approach

We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC₅₀ value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.

Key Results

Introducing a 50% hERG-channel current block results in 8% prolongation of the APD₉₀ and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD₉₀ is not affected.

Conclusions and Implications

Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.     

Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting

AIMS

Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV.

METHODS

Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response.

RESULTS

Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups.

CONCLUSION

Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.     

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

AIMS

To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies.

METHODS

Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations.

RESULTS

Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin.

CONCLUSIONS

Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.     

Efficacy of a Non-Hormonal Treatment,BRN-01, on Menopausal Hot Flashes: A Multicenter,Randomized, Double-Blind,Placebo-Controlled Trial

Background

Homeopathic medicines have a place among the non-hormonal therapies for the treatment of hot flashes during the menopause.

Objective

The objective of this study was to evaluate the efficacy of the non-hormonal treatment BRN-01 in reducing hot flashes in menopausal women.

Study Design

This was a multicenter, randomized, double-blind, placebo-controlled study carried out between June 2010 and July 2011.

Setting

The study was conducted in 35 active centers in France (gynecologists in private practice).

Patients

One hundred and eight menopausal women, ≥50 years of age, were enrolled in the study. The eligibility criteria included menopause for <24 months and ≥5 hot flashes per day with a significant negative effect on the women’s professional and/or personal life.

Intervention

Treatment was either BRN-01 tablets, a registered homeopathic medicine containing Actaea racemosa (4 centesimal dilutions [4CH]), Arnica montana (4CH), Glonoinum (4CH), Lachesis mutus (5CH), and Sanguinaria canadensis (4CH), or identical placebo tablets, prepared by Laboratoires Boiron according to European Pharmacopoeia standards. Oral treatment (2 to 4 tablets per day) was started on day 3 after study enrollment and was continued for 12 weeks.

Main Outcome Measure

The main outcome measure was the hot flash score (HFS) compared before, during, and after treatment. Secondary outcome criteria were the quality of life (QoL) [measured using the Hot Flash Related Daily Interference Scale (HFRDIS)], severity of symptoms (measured using the Menopause Rating Scale), evolution of the mean dosage, and compliance. All adverse events (AEs) were recorded.

Results

One hundred and one women were included in the final analysis (intent-to-treat population: BRN-01, n = 50; placebo, n = 51). The global HFS over the 12 weeks, assessed as the area under the curve (AUC) adjusted for baseline values, was significantly lower in the BRN-01 group than in the placebo group (mean ± SD 88.2 ± 6.5 versus 107.2 ± 6.4; p = 0.0411). BRN-01 was well tolerated; the frequency of AEs was similar in the two treatment groups, and no serious AEs were attributable to BRN-01.

Conclusion

BRN-01 seemed to have a significant effect on the HFS, compared with placebo. According to the results of this clinical trial, BRN-01 may be considered a new therapeutic option with a safe profile for hot flashes in menopausal women who do not want or are not able to take hormone replacement therapy or other recognized treatments for this indication.Trial registration number (EudraCT): 2009-016959–21.     

AQW051, a novel,potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation

Background and Purpose

Activation of the α7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7-nACh receptor agonist AQW051 as a promising drug candidate for this indication.

Experimental Approach

AQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects.

Key Results

In vitro, AQW051 bound with high affinity to α7-nACh receptors and stimulated calcium influx in cells recombinantly expressing the human α7-nACh receptor. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200 mg and multiple daily doses up to 75 mg. Once-daily oral administration of AQW051 resulted in continuous exposure and a two- to threefold accumulation compared with steady state was achieved by 1 week.

Conclusions and Implications

These data support further development of AQW051 as a cognitive-enhancing agent, as a therapeutic, for example, in Alzheimer''s disease or schizophrenia.     

Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia

Aim

The use of corticosteroids as adjunctive therapy might be effective in patients with community-acquired pneumonia (CAP). Oral administration of dexamethasone is a practical and safer alternative to the intravenous route. Since patients hospitalized with pneumonia might have delayed gastric emptying, this study explored systemic exposure in terms of area under the concentration–time curve (AUC) of oral dexamethasone in patients hospitalized with CAP.

Methods

In this randomized, open label study, 30 patients admitted with CAP were randomized to receive either 4 mg intravenous or 6 mg oral dexamethasone for 4 consecutive days. Serial blood samples were obtained before and after drug administration.

Results

Median AUC to infinity was 626 μg l⁻¹ h (IQR 401–1161) for the intravenous group and 774 μg l⁻¹ h (IQR 618–1146) for the oral group. The AUC ratio of 6 mg oral and 4 mg intravenous dexamethasone was 1.22 (95% confidence interval (CI) 0.81, 1.82)_, which represents a bioavailability of 81% (95% CI 54, 121) after correction for differences in dexamethasone dose.

Conclusions

Bioavailability of oral dexamethasone in patients hospitalized with pneumonia is sufficient. This makes oral dexamethasone an appropriate alternative for intravenous administration in these patients.     

Observational study on safety and tolerability of duloxetine in the treatment of female stress urinary incontinence in German routine practice

Aims

To evaluate the safety and tolerability of duloxetine during routine clinical care in women with stress urinary incontinence (SUI) in Germany, and in particular, to identify previously unrecognized safety issues as uncommon adverse reactions, and the influence of confounding factors present in clinical practice on the safety profile of duloxetine.

Methods

Office-based urologists, gynaecologists and primary care physicians were asked to document women newly started on treatment for moderate to severe symptoms of SUI. Six thousand eight hundred and fifty-four patients from urologist/gynaecologist practices and 5879 primary care patients were assessed. In a two-armed, observational study with parallel 12 week (urologists and gynaecologists) or 24 week (primary care physicians) design, patients were treated with duloxetine or other conservative treatment. The main outcome measure was the occurrence of adverse events (AEs).

Results

Baseline characteristics differed slightly between patient groups and studies. Duloxetine doses in most patients were lower than recommended. Overall, AE frequency with duloxetine was lower than in controlled studies (15.9% (95% CI 14.9, 16.9) and 9.1% (95% CI 8.2, 10.0) in the 12 and 24 week treatment groups, respectively), but exhibited a similar qualitative spectrum. In the logistic regression models, the following factors were associated with greater AE risk: investigator specialization (gynaecologist vs. urologist and primary care physician), initial duloxetine dose (80 vs. 20 mg day⁻¹) and use of any concomitant medication. Within the 24 week study, a positive screen for depressive disorder was surprisingly common, but no case of attempted suicide was reported in either study.

Conclusions

Our results from German clinical practice show that women with SUI were often treated with duloxetine doses lower than recommended. This was associated with a low incidence of AEs. Suicide attempts were not reported.     

Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects (pages

AIMS

There is no consensus as to what extent the results of thorough QT interval/corrected QT interval (QT/QTc) studies need to be bridged.

METHODS

The results of two studies using levofloxacin in Japanese and Caucasian subjects were compared in a post hoc analysis to investigate the similarity of dose–effect responses.

RESULTS

Concentration–response analysis based on the change of QT interval corrected using Fridericia''s formula (QTcF) from time-matched placebo was planned and performed in the combined data sets. At the geometric maximum mean concentration for the two doses in the Caucasian study, a predicted effect on QTcF comparable to the effects observed was found. For the Japanese study, the predicted effect was lower, but the difference was not statistically significant.

CONCLUSIONS

No statistically significant differences in QTc-prolonging effect between Japanese and Caucasian subjects were observed following levofloxacin dosing. However, a trend suggests that Caucasian subjects may be more sensitive. Age and sex did not have an impact.     

Electrocardiogram changes and arrhythmias in venlafaxine overdose

AIMS

To investigate serial electrocardiogram (ECG) parameters, haemodynamic changes and arrhythmias following venlafaxine overdose.

METHODS

The study included 369 venlafaxine overdoses in 273 patients presenting to a toxicology unit where an ECG was available. Demographic information, details of ingestion, haemodynamic effects [heart rate and blood pressure (BP)] and complications (arrhythmias and conduction defects) were obtained. ECG parameters (QT, QRS) were measured manually and analysed by visual inspection, including plotting QT–HR pairs on a QT nomogram.

RESULTS

The median ingested dose was 1500 mg [interquartile range (IQR) 600–3000 mg; range 75–13 500 mg). Tachycardia occurred in 54% and mild hypertension (systolic BP >140 mmHg) in 40%. Severe hypertension (systolic BP >180 mmHg) and hypotension (systolic BP <90 mmHg) occurred in 3% and 5%, respectively. No arrhythmias occurred based on continuous telemetry, and conduction defects were found in only seven of 369 admissions; five of these conduction defects were pre-existing abnormalities. In 22 admissions [6%, 95% confidence interval (CI) 4–10] there was an abnormal QT–HR pair, with larger doses being more likely to be associated with an abnormal QT. The median maximum QRS width was 85 ms (IQR 80–90 ms; range 70–145 ms) and the QRS was greater than 120 ms in only 24 admissions (7%, 95% CI 4–10).

CONCLUSIONS

Venlafaxine overdose causes only minor abnormalities in the QT and QRS intervals, unlikely to be associated with major arrhythmias, except possibly with large doses.