Use of 24 h ambulatory ECG recordings in the assessment of new chemical entities in healthy volunteers.

Stinson, J.; Pears, John; Williams, A.; Campbell, R. W. F.

doi:10.1111/j.1365-2125.1995.tb05724.x

Cited by 24 publications

(22 citation statements)

References 22 publications

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“…Thus there is no evidence of a significant attenuation or enhancement of during 24 h dosing, its adverse effects and effects on blood pressure might decrease. On the other hand, increased peak cardiovascular effects on repeat dosing, even taking into account the accumulation of zolmitriptan, although it must concentrations after the last dose compared to the first might be recognised that there is little evidence of any significant tachycardia on Holter tapes in apparently healthy young adults is 1-2% [17][18][19]. In this study, the episode which impact of zolmitriptan on blood pressure in this study.…”

Section: Pharmacokinetic Parametersmentioning

confidence: 86%

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

Dixon¹,

Gillotin²,

Gibbens³

et al. 1997

Brit J Clinical Pharma

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Aims Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT 1D -receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan. Methods Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study. Results Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CL R . After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml −1 h compared with 86.5 ng ml −1 h after the single 10 mg dose (95% CI for ratio 0.76-1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CL R . There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg ) was significantly lower than that after placebo (147 mmHg, 95% CI for difference −18, −2) and that after the last 5 mg dose (148 mmHg, 95% CI −19, −3). Conclusions Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.

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Section: Pharmacokinetic Parametersmentioning

confidence: 86%

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

Dixon¹,

Gillotin²,

Gibbens³

et al. 1997

Brit J Clinical Pharma

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“…However, a 2% incidence is not greater than the expected ('background') rate of 1-3% in healthy subjects. [17][18][19] These episodes of NSVT were isolated and short (3-7 beats) with only one patient having two episodes (3 and 4 beats). No clinically relevant decreases in potassium or increases in non-fasting glucose were observed.…”

Section: Discussionmentioning

confidence: 99%

Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β₂agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomised trial

Busse

O'Byrne

Bleecker

et al. 2013

Thorax

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BackgroundThe inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2 agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease.ObjectiveTo assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma.MethodsPatients (aged ≥12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening, or fluticasone propionate (FP) 500 µg twice daily. Safety evaluations included adverse events (AEs), non-fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate.ResultsOn-treatment AEs were similar across groups (FF/VI 66–69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6–7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p≤0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 µg and 1.09 [0.87 to 1.38] for FF/VI 200/25 µg). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia's formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [Tmax], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 µg]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 µg]). Mean heart rate (24-h Holter monitoring) decreased from screening values in all groups (0.2–1.1 bpm FF/VI vs 5 bpm FP; Week 52).ConclusionsFF/VI (100/25 µg or 200/25 µg) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern.ClinicalTrials.govNCT01018186

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“…In one striking example from a case report, an idiosyncratic ventricular rhythm was found under placebo medication during a double-blind phase I study [15] . …”

Section: Discussionmentioning

confidence: 99%

Who is a ‘healthy subject’?—consensus results on pivotal eligibility criteria for clinical trials

Breithaupt-Groegler¹,

Coch

Coenen

et al. 2017

Eur J Clin Pharmacol

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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.

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Use of 24 h ambulatory ECG recordings in the assessment of new chemical entities in healthy volunteers.

Cited by 24 publications

References 22 publications

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β₂agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomised trial

Who is a ‘healthy subject’?—consensus results on pivotal eligibility criteria for clinical trials

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Use of 24 h ambulatory ECG recordings in the assessment of new chemical entities in healthy volunteers.

Cited by 24 publications

References 22 publications

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomised trial

Who is a ‘healthy subject’?—consensus results on pivotal eligibility criteria for clinical trials

Contact Info

Product

Resources

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Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β₂agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomised trial