Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes.

BACKGROUND: Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. OBJECTIVE: To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS). METHODS: This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat. RESULTS: In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns. CONCLUSIONS: As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03504982.

Vericiguat is approved for treating worsening heart failure with reduced ejection fraction. As part of the safety evaluation of vericiguat, this study assessed its effect on the QT interval of the electrocardiogram. An electrocardiogram measures electrical activity of the heart. The QT interval is the time from the start of the Q wave to the end of the T wave. A longer than normal QT interval indicates an increased chance for abnormal heart rhythms. Usually, a QT study is conducted at high doses in healthy volunteers. Previous studies indicated that high doses of vericiguat may cause increased changes in blood pressure in healthy volunteers. Therefore, this study was performed in patients at a normal therapeutic dose. Patients with chronic coronary syndromes were enrolled rather than patients with heart failure with reduced ejection fraction, because they have fewer electrocardiogram abnormalities. The starting dose of vericiguat was 2.5 mg once daily, and the dose was increased to 5 mg and then to 10 mg at 14-day intervals. Placebo was tested for comparison and moxifloxacin (400 mg), a drug known to increase the QT interval, was tested to confirm that the study could detect a change in the QT interval. An increase in the QT interval of more than 10 ms was considered clinically relevant. Of 74 patients included, 72 completed the study. At each timepoint (up to 7 h after dosing), the difference between the QT change for vericiguat and placebo was less than 10 ms; therefore, vericiguat does not prolong the QT interval to a clinically relevant extent.

Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized, phase Ib, VISOR study.

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long-acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co-administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double-blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co-administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty-five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline- and placebo-adjusted vital signs showed reductions of 1.4-5.1 mmHg (systolic blood pressure) and 0.4-2.9 mmHg (diastolic blood pressure) and increases of 0.0-1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose-dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well-tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Vericiguat in Combination with Short-Acting Nitroglycerin in Patients With Chronic Coronary Syndromes: The Randomized, Phase Ib, VENICE Study.

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in adults with symptomatic chronic HF and ejection fraction less than 45%. Guidelines recommend short-acting nitrates, such as sublingual nitroglycerin, for the treatment of acute angina pectoris in patients with chronic coronary syndromes (CCSs), common comorbidities in HF. We evaluated safety, tolerability, and the pharmacodynamic interaction between vericiguat and nitroglycerin, coadministered in patients with CCSs. In this phase Ib, double-blind, randomized, multicenter study, 36 patients with CCSs received either vericiguat 2.5 mg (up-titrated every 2 weeks to 5 mg and 10 mg) or placebo. Patients also received nitroglycerin (0.4 mg sublingual). In total, 31 patients completed the study (vericiguat + nitroglycerin, n = 21; placebo + nitroglycerin, n = 10). There was no increase in treatment-emergent adverse events (TEAEs) with vericiguat + nitroglycerin vs. placebo + nitroglycerin; three patients discontinued due to TEAEs (vericiguat + nitroglycerin, n = 1; placebo + nitroglycerin, n = 2). Decreases in mean blood pressure (BP; 6-10 mmHg systolic BP (SBP); 4-6 mmHg diastolic BP (DBP)) were independent of vericiguat exposure and occurred to a similar extent at trough and peak concentrations with all vericiguat doses and placebo. Coadministration of vericiguat with nitroglycerin in patients with CCSs was well tolerated, and the combination is unlikely to cause significant adverse effects beyond those known for nitroglycerin.

Intravaginal Tolterodine Formulation Intended for Overactive Bladder Treatment-Results of a Pharmacokinetic Phase I Pilot Study in Healthy, Postmenopausal Women.

The aim was to assess the pharmacokinetics of tolterodine released from vaginal rings and of its active metabolite 5-hydroxymethyl tolterodine (5-HMT) compared to the respective pharmacokinetics resulting from oral administration of extended-release tolterodine in healthy, postmenopausal women. In this single-center, open-label trial, subjects received 4 treatments in a fixed sequence: fasted oral extended-release tolterodine 2.74 mg/d (reference, 5 days), single vaginal rings; tolterodine releasing rates: 0.95 mg/d (test 1, 13 days), 1.40 mg/d (test 2, 28 days), 1.90 mg/d (test 3, 28 days). Systemic exposure of tolterodine, 5-HMT, and the molar sum of unbound tolterodine/5-HMT (active moiety [AM]) in steady state was determined. Sixteen of 18 included women completed the study. For the oral formulation, peak-trough fluctuations of tolterodine, 5-HMT, and AM plasma concentrations (AM: mean maximum/minimum concentration, 2580/574 pmol/L = 4.5) were large. Intravaginal application led to steadier plasma concentrations (AM, test 3: mean maximum/minimum concentration, 1880/814 pmol/L = 2.3; fluctuation due to initial peak), which is the result of constant releasing rates after ring insertion over the 28-day application period. The vaginal rings demonstrated a favorable local tolerability. The most common adverse events with oral and vaginal tolterodine were headache (n = 11) and dry mouth (n = 8). Vaginal rings releasing tolterodine represent a promising new formulation for overactive bladder treatment with little fluctuation of drug plasma levels. This is expected to lead to a more predictable and continuous therapeutic effect and a reduced frequency of side effects compared to oral tolterodine.

Development of a furosemide-containing expandable system for gastric retention.

More than 50 years ago, the first gastroretentive dosage forms came up. Since then, no practical and at the same time reliable gastroretentive system is available on market. A major obstacle in the development of novel gastroretentive systems is the lack of proper predictive test methods. In the present work, we aimed at developing and fully characterizing an expandable gastroretentive system containing furosemide as model drug. On the one hand, we used well-established in vitro tests for drug dissolution and gastroretentive properties (paddle apparatus, swelling characteristics). On the other hand, we used two novel models (dissolution stress test device, mechanical antrum model) to assess these properties under biorelevant conditions. Moreover, we performed an in vivo study under fed and fasted conditions that combined blood sampling and a high-resolution imaging technique (magnetic marker monitoring) to determine gastrointestinal location with the assessment of a pharmacodynamic endpoint (urinary sodium excretion). In vitro dissolution tests confirmed prolonged drug release over more than 8 h independent from pH and with slight pressure sensitivity. Swelling studies indicated good swelling behavior within 4 h along with medium gastroretentive properties as determined with the mechanical antrum model. In vivo imaging showed prolonged gastric residence time after fed compared to fasted administration (481 min vs 38 min). Comparison of geometric means of AUCo-tlast of the model drug confirmed this observation with 10 times higher value after fed administration. Urinary excretion of sodium well reflected the increased sodium-reuptake inhibition due to higher furosemide exposure under fed conditions. However, the poor performance after fasted intake of the system is in line with data from several other gastroretentive formulations. The present study highlighted the value of novel test methods during the development of gastroretentive formulations. Yet, a system with reproducible gastroretentive properties especially under fasted conditions has to be designed.

Pharmacokinetics of oral pridinol: Results of a randomized, crossover bioequivalence trial in healthy subjects.

OBJECTIVES: To establish the relative bioavailability and to assess bioequivalence of oral, immediate-release tablets containing pridinol and to determine the pharmacokinetic properties of the compound. METHODS AND MATERIALS: In this single-center, open-label, randomized, crossover trial, healthy male and female adult subjects received single doses of the test and reference product containing 4 mg pridinol mesylate (equivalent to 3 mg pridinol) each under fasting conditions. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours post dose. Pridinol in plasma was quantified by validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Adverse events (AEs) were analyzed descriptively. RESULTS: Of 34 randomized subjects, 33 completed all treatments. The determined pharmacokinetic parameters were quite similar for both products, with geometric means for maximum exposure (Cmax) of 29.27 ng/mL (test) and 27.44 ng/mL (reference), reached after 1.00 and 0.90 hours (mean tmax), respectively. The extents of bioavailability (geometric mean AUC0-tlast) were 187.93 h×ng/mL (test) and 183.51 h×ng/mL (reference). Elimination half-lives (T1/2) ranged from 8.97 to 34.85 hours with comparable mean T1/2 of 19.14 hours (test) and 18.85 hours (reference). The point estimates of the test/reference-adjusted geometric mean ratios of AUC0-tlast, Cmax (primary), and AUC0-∞ (secondary) were 102.54% (90% confidence interval: 96.19 - 109.32%), 106.79% (99.00 - 115.20%), and 102.60% (96.20 - 109.43%), respectively. Overall, 23 subjects experienced 50 AEs; headache and dizziness (15 cases each) were most frequently reported. CONCLUSION: Bioequivalence of both pridinol products was demonstrated in terms of rate and extent of absorption. Safety and tolerability were in accordance with the known AE profile of the drug substance.

How to Interpret an Investigator's Brochure for Meaningful Risk Assessment: Results of an AGAH Discussion Forum.

PURPOSE: A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator's Brochure (IB) for meaningful risk assessment of early clinical trials. MATERIALS AND METHODS: Four topics were specifically discussed: deficiencies/uncertainties in IBs, guidance for the investigator, reference safety information, and potential risks for human subjects associated with inadequate non-clinical safety assessment in the IB. In each case, 43 participants took part in a real-time online survey with pre-defined questions to capture the audience's opinion. RESULTS: The 'Summary of Data and Guidance for the Investigator' was considered as the section of the IB with the highest need for improvement with emphasis on readability, comprehensibility, timeliness of data, and appropriateness for risk assessment. It was suggested that the IB should at least be signed by the sponsor's scientist responsible for the content on pharmacology and toxicology. It was agreed that sponsors should consider thoroughly whether changes to an IB constitute a substantial amendment, and that the IB should include a section on the change history. Non-clinical pharmacology studies with negative outcomes should be reported in the IB in order to avoid assessment bias. The reference safety information for expectedness assessment of suspected serious adverse reactions should be provided as a stand-alone section of the IB. CONCLUSION: The overall consensus was that an optimised presentation of data will ensure the best possible understanding of a compound's characteristics and an optimal benefit-risk assessment which will safeguard the participants in clinical trials.

Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin.

OBJECTIVES: To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. MATERIALS AND METHODS: 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. RESULTS: Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. CONCLUSION: To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

A novel rizatriptan oral gel formulation: Bioavailability and bioequivalence.

OBJECTIVES: To establish the relative bioavailability between a newly developed oral gel and a marketed oral lyophilisate-containing rizatriptan benzoate. MATERIALS AND METHODS: A total of 47 out of 48 healthy subjects, aged 34 ± 10 (SD) years and body mass index 24.7 ± 3.3 (SD) kg/m2 completed this single-center, open-label, randomized, 2-period cross-over trial with single-dose fasted administrations. Intake of both investigational products was separated by a washout period of at least 6 days. For pharmacokinetic evaluation, blood samples were withdrawn until 24 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for the determination of rizatriptan in plasma. The lower limit of quantitation (LLOQ) was 0.100 ng/mL. Adverse events (AEs) were descriptively analyzed in the study population. Palatability of the new product was investigated based on a questionnaire. RESULTS: The geometric means of the parameters related with the extent of total exposure, i.e., AUC0-tlast and AUC0-∞, were 60.285 ng × h/mL and 60.865 ng × h/mL for test and 62.729 ng × h/mL and 63.312 ng × h/mL for reference, respectively. The geometric means of the peak exposure, i.e., Cmax, were 21.262 ng/mL for test and 21.447 ng/mL for reference. The point estimates (PEs) of the test/reference (T/R) adjusted geometric mean ratios of AUC0-tlast, Cmax, and AUC0-∞ (secondary parameter) were 96.11%, 99.12%, and 96.15%, respectively, and all of them showed 90% confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 13 subjects experienced 20 AEs during the trial; the most frequently reported AEs were headache (5 cases) and dizziness (3 cases). No AEs of severe intensity were reported. Palatability assessment of the new product provided sufficient data to discuss its acceptability. CONCLUSION: Bioequivalence was demonstrated in terms of rate and extent of absorption after administration of test and reference products. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined. Based on ratings by the subjects no relevant problem concerning acceptability of the new formulation in particular regarding taste and smell is to be expected.

Efficacy of 8 mg lidocaine and 2 mg cetylpyridinium chloride (CPC) fixed-combination lozenges on sore throat pain intensity compared with 1 mg lidocaine and 2 mg CPC fixed-combination lozenges in subjects with sore throat due to upper respiratory tract infection: a randomized double-blind parallel-group single-dose study.

BACKGROUND: Lozenges containing lidocaine and cetylpyridinium chloride (CPC) are commonly used for the treatment of sore throat. The lidocaine acts locally to provide pain relief and the CPC has an antiseptic effect. Mebucaine CL, a well-established fixed-combination sore throat lozenge, contains 1 mg lidocaine and 2 mg CPC. Single-agent lozenges containing 8 mg lidocaine have also been demonstrated to be significantly superior to placebo in confirmatory pain intensity assessments. This study compared a new lozenge formulation, containing 8 mg lidocaine and 2 mg CPC, with the currently marketed lozenge for the treatment and relief of sore throat symptoms in subjects diagnosed with a sore throat due to an upper respiratory tract infection (URTI). METHODS: In this double-blind parallel-group study, 250 adults with a sore throat due to an URTI were randomized to receive a single lozenge containing either 8 mg lidocaine + 2 mg CPC (n = 125) or 1 mg lidocaine + 2 mg CPC (n = 125). The primary efficacy endpoint of the study was the change in sore throat pain intensity (STPI) between baseline (immediately pre-treatment) and the 2-h post-dose assessment, measured on a 100 mm visual analog scale. STPI was measured at baseline and regular intervals up to 240 min after the lozenge was administered (evaluated in clinic). Any difficulty in swallowing and time to onset and duration of the analgesic effect were also assessed. RESULTS: No increase in efficacy was demonstrated with the higher dose of lidocaine. The difference in the 2-h post-dose change in STPI was not statistically significant between the treatments. There was only one statistically significant difference between the treatments in all of the efficacy outcomes assessed: pain relief scores at 4 h post-dose were higher with 1 mg lidocaine + 2 mg CPC than with 8 mg lidocaine + 2 mg CPC (P = 0.0461). The most commonly reported adverse event (AE) was a headache; the only other AE experienced by more than one subject was throat irritation. No severe adverse events were reported during the assessment period. CONCLUSIONS: The modest difference in the pattern of effectiveness between the two treatments observed in this study does not support use of the 8 mg lidocaine + 2 mg CPC lozenge. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01265446 . Registered on 20 December 2010.

A randomized, open-label, crossover study evaluating bioequivalence of two N-acetylcysteine 2% oral solution formulations in healthy subjects
.

OBJECTIVE: N-acetylcysteine is a mucolytic agent used to treat bronchopulmonary diseases associated with airway mucus hypersecretion. The bioequivalence of a new oral N-acetylcysteine 2% formulation was evaluated relative to an appropriate reference product. MATERIALS AND METHODS: This open-label, randomized, crossover study assessed the bioequivalence of a new N-acetylcysteine 2% oral solution compared to an approved reference N-acetylcysteine 2% oral solution in healthy subjects in terms of pharmacokinetics, including area under the plasma concentration vs. time curve of N-acetylcysteine plasma concentrations from time 0 to the last measurable sampling time point and the maximum postdose concentration. Bioequivalence was concluded if the 90% confidence intervals for the ratio of the geometric means of the two pharmacokinetic parameters with baseline correction were entirely within the range of 80 - 125%. RESULTS: 46 participants were randomized. The ratios of the geometric means for the test vs. reference treatment, with baseline correction, were 1.0961 (90% confidence interval: 1.0228, 1.1746) for area under the plasma concentration curve of test N-acetylcysteine plasma concentrations and 1.0938 (90% confidence interval: 1.0142, 1.1796) for maximum postdose concentration; both were within the predefined range to demonstrate bioequivalence. Most treatment-emergent adverse events were mild or moderate and not considered study drug related. CONCLUSION: The new N-acetylcysteine 2% oral solution was found to be bioequivalent to the marketed reference formulation. Treatments were generally safe and well tolerated.
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Evaluation of the warming sensation, acceptability, and local tolerability of an acetylcysteine oral solution containing the flavoring agent IFF flavor 316282 in the treatment of productive cough
.

OBJECTIVE: This open-label study sought to evaluate the warming sensation produced by IFF flavor 316282 in an acetylcysteine oral solution in subjects with productive cough. MATERIALS: 2% ace-tylcysteine oral solution (200 mg per 10 mL) containing IFF flavor 316282. METHODS: Subjects (N = 57; mean age 38.7 years; 58% female) with a productive cough lasting < 7 days and rated as mild to moderate in severity received 10 mL of study product. Warming sensation intensity was assessed using a 100-mm visual analog scale, its onset and duration using stopwatches, its acceptability using a 9-point scale (from "dislike extremely" to "like extremely") and the taste, texture, and overall acceptability of the solution using 5-point scales (from "unacceptable" to "excellent"). RESULTS: 53 (93.0%) subjects perceived a warming sensation within 10 minutes of swallowing the solution; median onset was ~ 14 seconds, and median duration was ~ 2.8 minutes. Warming sensation intensity increased from baseline by a mean of 29.2 mm when evaluated 60 seconds after ingestion. 30 subjects (52.6%) thought the warming sensation was "just about right"; 25 (43.9%) considered it "too weak" or "much too weak." Most subjects had positive overall ratings ("fair," "good," or "excellent") of the taste (79.0%), texture (96.5%), and solution (91.2%). No treatment-emergent adverse events were reported, and no evidence of oral mucosal irritation was found. CONCLUSION: The addition of IFF flavor 316282 to a 2% acetylcysteine oral solution produced a warming sensation with rapid onset and relatively short duration, which the majority of subjects found acceptable.
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Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

AIM: Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. METHODS: This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml-1 , 25 µl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. RESULTS: Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day-1 , the dose approved in cancer indications. CONCLUSION: These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml-1 tid for use in clinical studies.

Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.

INTRODUCTION/METHODS: A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority. RESULTS: Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity. CONSEQUENCES: The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.

Randomized trial of the efficacy and safety of a new oral spray for drug-induced xerostomia.

The aim of this study was to evaluate the efficacy, safety, and tolerability of three formulations of DC161 oral spray, a saliva substitute, and a comparator in relieving drug-induced xerostomia. This was an open-label, randomized, 4-period, cross-over study in adult subjects with drug-induced xerostomia and documented hyposalivation. During each of the four 1-day periods, one product (one of three DC161 formulations or the comparator) was applied at T0 and then at T4h (before a meal). Mouth dryness and related symptoms were evaluated by the subject on a 100-mm visual analog scale. The primary efficacy criterion was the area under the curve of the dry mouth evaluation (baseline to T4h) after the first application. The oral mucosa was examined by a dental specialist; tolerability and product acceptability were assessed by the subject. Twenty-four subjects were randomized and completed the study. Despite large variability in data among the products, the selected aqueous formulation - DC161-DP0292 - reduced the intensity of dryness of mouth at least as well as the comparator; DC161-DP0292 provided a fast relief and a long-lasting effect on mouth dryness. Both products improved other symptoms such as swallowing and speaking, even when applied just prior to a meal. DC161-DP0292 was well tolerated and rated by subjects as providing a slightly higher acceptability of taste/aftertaste, texture, and lubricating effect than the comparator. No clinically relevant signs were reported for any product following the oral examination. DC161-DP0292 provides fast and long-acting symptomatic relief and is a relevant new treatment for drug-induced xerostomia.

Relative bioavailability of a newly developed 5-mg levomethadone hydrochloride IR tablet (L-Polamidon® 5 mg tablets) in comparison with the 5-mg levomethadone hydrochloride oral solution (L-Polamidon® solution for substitution) as reference product.

OBJECTIVES: To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon® 5 mg tablets (test) vs. L-Polamidon® solution for substitution (reference). To assess the safety and tolerability of both formulations. SUBJECT AND METHODS: A total of 33 healthy male subjects, aged 29 ± 6 years (BMI: 23.9 ± 2.5 kg/m2) completed this single center, open-label, randomized, 2-period cross-over study with single dose administrations under fasting conditions and coadministration with naltrexone for safety reasons. Administrations of both investigational products were separated by a washout period of at least 2 weeks, i.e., 13 treatmentfree days. The total dose for each subject was 2 x 5 mg resulting in 10 mg levomethadone hydrochloride. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose. A validated non-stereoselective liquid chromatography-tandem mass spectroscopy method (LC-MS/MS) was applied for the determination of levomethadone in plasma. The lower limit of quantitation was 0.100 ng/mL. Adverse events were descriptively analyzed in the study population. RESULTS: The geometric means of the parameters related with the extent of total exposure of levomethadone, i.e., AUC(0-tlast) and AUC(0-∞), were 244.422 ng x h/mL and 332.999 ng x h/mL for test and 246.837 ng x h/mL and 329.467 ng×h/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., Cmax, were 8.923 ng/mL for test and 8.635 ng/mL for reference. The point estimates (PEs) of the Test/Reference (T/R) adjusted geometric mean ratios of AUC(0-last), AUC(0-∞), and C(max) were 99.20%, 101.42%, and 104.11%, respectively, and all of them showed 90%-confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment In total, 21 subjects experienced 55 AEs during the study, the most frequently reported AE, i.e., headache, accounted for 13 out of the total 55 AEs (23.6%) and no AEs of severe intensity were reported. CONCLUSIONS: Bioequivalence could be demonstrated in terms of rate and extent of absorption after administration of test and reference products under naltrexone protection. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined.

Bioavailability and pharmacodynamics of two 10-mg estradiol valerate depot formulations following IM single dose administration in healthy postmenopausal volunteers.

OBJECTIVE: To establish the bioequivalence (BE) between two i.m. estradiol valerate (E2V) depot formulations, i.e., Estradiol-Depot 10 mg® (test) and Progynon Depot-10® (reference). To compare the effect of both treatments on the vaginal maturation index and on the increase of the endometrial thickness after administration of both formulations. METHODS: A total of 24 postmenopausal females aged 54.7 ± 5.35 year (BMI 25.84 ± 1.98 kg/m2) completed this BE assessment. The investigation was planned and designed as a single center, openlabel, single dose, cross-over study including 2 periods with 2 treatments and 2 sequences. Baseline levels were obtained for all subjects. Single doses of 10-mg E2V of each product were administered and pharmacokinetics and pharmacodynamics were assessed over 2 weeks with a washout period of 4 weeks. A gas chromatographic-mass spectrometric method with negative chemical ionization and selected ion monitoring was applied, after validation, for the determination of estradiol (E2), estrone (E1) and internal standard estradiol-D4 derivatives. The cytology of the vaginal smear (parabasal, intermediate and superficial cells from lateral wall opposite tip of cervix) was assessed by investigation of ~ 200 cells. The vaginal maturation index (VMI) was calculated by the equation: VMI (%) = (superficial cells × 1) (%) + (intermediate cells × 0.5) (%). Endometrial thickness was measured by transvaginal ultrasonic scans and recorded in mm. RESULTS: The geometric means (Gmeans) of the measured values of Cmax and AUC0-t for E2 were 543.5 pg/ ml and 84,734 pg × h/ml for test and 505.7 pg/ml and 82,660 pg × h/ml for reference, whereas those for E1 were 219.0 pg/ml and 38,950 pg × h/ml for test and 204.9 pg/ml and 37,159 pg × h/ml for reference, respectively. The point estimates (PEs) of the Test/ Reference (T/R) mean ratios of the variables Cmax and AUC0-t for E2 (measured values) were 107.3% and 102.5%, respectively. The PEs of the T/R mean ratios of the variables Cmax and AUC0-t for E1 (measured values) were 106.9% and 105.0%, respectively. Median endometrial thickness increased in Period I from baseline levels of ~ 3 mm (Day -2) to ~ 7 mm (Day 21) after administration of both products without returning completely to baseline prior to the next administration. In Period II, median values of 7 mm were also reached (Day 21) after administration of both products. Median vaginal maturation indices increased in Period I from baseline levels of ranging from 45 - 60% (Day -2) to 86 - 94.5% (Day 21). In Period II maturation indices of ≥ 90% were calculated as baselines (Day -2) and these levels remained constant until the end of the assessment (Day 21) independently from the products. After 21 days of treatment, test and reference presented practically no differences in terms of their effects on endometrial thickness and vaginal maturation index. CONCLUSIONS: The 95% CIs for the T/R mean ratios of AUC0-t and Cmax for E2 and E1 fell within the acceptance limits of 80 - 125% and therefore bioequivalence could be demonstrated for both formulations. The changes in endometrial thickness and the vaginal maturation index indicated that the pharmacodynamic effect is pronounced already after the first administration and that the effect continued notably for longer time compared to the presence of E2 and E1 in plasma. A 4-week washout phase was insufficient to avoid residual pharmacological effects after the administration of both preparations.

Biomarkers and coagulation tests for assessing the biosimilarity of a generic low-molecular-weight heparin: results of a study in healthy subjects with enoxaparin.

Low-molecular-weight heparins (LMWHs) differ considerably in their influence on clotting tests and release of tissue factor pathway inhibitor (TFPI). Biosimilarity therefore becomes an issue when generic forms of LMWHs are developed. So far, no bioequivalence study with a generic LMWH has been reported. A generic enoxaparin (test) was compared with the originator (reference) in 20 volunteers after single-dose subcutaneous administration (40 mg enoxaparin sodium, 4000 IU/mL anti-factor Xa (anti-FXa; activity). Target variables were anti-FXa and anti-FIIa activity, activated partial thromboplastin time (aPTT), prothrombinase-induced clotting time (PiCT), and TFPI over 24 hours. The statistical evaluation of the anti-FXa activity profile demonstrated bioequivalence of test and reference with confidence intervals of area under the plasma concentration-time curve (AUC0-tlast) (93%-99%) and Amax (88%-95%). Confidence intervals of AUC(0-tlast) (89%-102%) and Amax (90%-103%) of anti-FIIa activity also fulfill bioequivalence criteria. The 90% confidence interval for the maximum concentration of TFPI ranged from 90% to 113%. The claim of similarity was also supported by aPTT and PiCT profiles. Bioequivalence with the originator enoxaparin could be demonstrated by ex vivo inhibition of FXa and FIIa activity, by coagulation tests (aPTT and PiCT), and by in vivo release of TFPI. Whether such data also prove biosimilarity of the generic enoxaparin needs to be determined.

Electrophysiological profile of propiverine--relationship to cardiac risk.

Drugs that prolong the QT interval by blocking human ether-a-go-go (HERG) channels may enhance the risk of ventricular arrhythmia. The spasmolytic drug propiverine is widely used for the therapy of overactive bladder (OAB). Here, we have investigated the effects of propiverine on cardiac ion channels and action potentials as well as on contractile properties of cardiac tissue, in order to estimate its cardiac safety profile, because other drugs used in this indication had to be withdrawn due to safety reasons. Whole-cell patch clamp technique was used to record the following cardiac ion currents: rapidly and slowly activating delayed rectifier K+ current (I(Kr), I(Ks)), ultra rapidly activating delayed rectifier K+ current (I(Kur)), inwardly rectifying K+ current I(K1), transient outward K+ current (I(to)), and L-type Ca2+ current (I(Ca,L)). Action potentials in cardiac tissue biopsies were recorded with conventional microelectrodes. The torsade de pointes screening assay (TDPScreen) was used for drug scoring. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native I(Kr) current in ventricular myocytes of guinea pig (IC50 values: 10 microM and 1.8 microM respectively). At high concentrations (100 microM), propiverine suppressed I(Ks). I(K1) and the transient outward current I(to) and I(Kur) were not affected. In guinea-pig ventricular and human atrial myocytes, propiverine also blocked I(Ca,L) (IC50 values: 34.7 microM and 41.7 microM, respectively) and reduced force of contraction. Despite block of I(Kr), action potential duration was not prolonged in guinea-pig and human ventricular tissue, but decreased progressively until excitation failed altogether. Similar effects were observed in dog Purkinje fibers. Propiverine obtained a low score in the TDPScreen. In conclusion, in vitro and in vivo studies of propiverine do not provide evidence for an enhanced cardiovascular safety risk. We propose that lack of torsadogenic risk of propiverine is related to enhancement of repolarization reserve by block of I(Ca,L).

Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment.

An acute pharyngitis is characterised by mild to severe sore throat mostly accompanied by inflammation, throat pain, pain on swallowing, and burning. This randomised, double-blind, placebo-controlled phase III study was conducted for comparison of the efficacy and safety of a newly developed lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, CAS 137-58-6) 8 mg lozenge formulation (Trachisan Halsschmerztabletten) for the treatment of acute sore throat not necessarily to be treated with antibiotics. 240 patients of both genders were enrolled. The study was performed in a single centre setting and consisted of two parts. A 2-h stationary phase (single dose treatment) was directly followed by a 46-h ambulatory phase, where patients were allowed to take up to a maximum of 11 further lozenges (multiple dose treatment). Pain intensity was assessed via Visual Analogue Scale during the course of the study. Moreover, the global efficacy and tolerability of the treatments were assessed. Lidocaine 8 mg sore throat lozenges were found to be superior to placebo for all efficacy parameters investigated. For the primary efficacy parameter, area under the curve of pain intensity from baseline over 2 h (AUC(0-2h)), i.e. after single-dose treatment, a significant treatment difference with a p-value of p < 0.001 in favour of the verum treatment could be demonstrated. Significant superiority could also be demonstrated for the descriptive AUC(0-48h) values, reflecting the treatment effect during the ambulatory multiple dose phase. Pain relief, minimum pain intensity, meaningful pain relief and the time of onset of meaningful pain relief as well as the assessments of global efficacy underlined the superiority of the treatment with lidocaine 8 mg sore throat lozenges. Global tolerability of the verum treatment was rated as "good" or "very good" in the majority of cases, the number of study drug related adverse events was low and evenly distributed to both treatment groups. Therefore, the results of the trial emphasise lidocaine 8 mg sore throat lozenges to be a favourable option in the treatment of pain symptoms of an acute sore throat.