Clinical cross-over trials in phase I

Senn, Stephen; Ezzet, Farkad

doi:10.1177/096228029900800306

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…As a consequence, full concentration—effect curves were available for most of the subjects. A crossover design is also more powerful to detect nonlinearity in pharmacokinetics, and it allows the assessment of the intrasubject variability for pharmacokinetics and/or pharmacodynamics 30 …”

Section: Discussionmentioning

confidence: 99%

“…A crossover design is also more powerful to detect nonlinearity in pharmacokinetics, and it allows the assessment of the intrasubject variability for pharmacokinetics and/or pharmacodynamics. 30 R1663 pharmacokinetics were characterized by rapid oral absorption, relatively short elimination (3-4 hours), and dose proportionality. There was almost no renal elimination of unchanged drug, with less than 2% recovered in the urine.…”

Section: Discussionmentioning

confidence: 99%

“…This single ascending dose study was designed as a single-blind, randomized, and placebo-controlled study with a crossover (leapfrog) design in 3 cohorts of 10 volunteers each. Nine dose steps were planned (1,3,10,30,60,120,240,480, and 600 mg). Each volunteer in a given cohort was dosed on 3 occasions.…”

Section: Methodsmentioning

confidence: 99%

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Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Schmitt¹,

Pannier²,

McIntyre³

et al. 2012

The Journal of Clinical Pharma

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This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Schmitt¹,

Pannier²,

McIntyre³

et al. 2012

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Although the carry over effect can be assumed to be negligible for pharmacokinetic studies if a sufficient washout period is included (as per Senn and Ezzet, 1999), the same assumption is not necessarily valid for pharmacodynamic studies. In some circumstances pharmacodynamic effects may be prolonged and last considerably longer than drug concentrations.…”

Section: Model and Optimality Criterionmentioning

confidence: 99%

Optimal Crossover Designs for Logistic Regression Models in Pharmacodynamics

Waterhouse

Eccleston

Duffull

2006

Journal of Biopharmaceutical Statistics

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Pharmacodynamics (PD) is the study of the biochemical and physiological effects of drugs. The construction of optimal designs for dose-ranging trials with multiple periods is considered in this paper, where the outcome of the trial (the effect of the drug) is considered to be a binary response: the success or failure of a drug to bring about a particular change in the subject after a given amount of time. The carryover effect of each dose from one period to the next is assumed to be proportional to the direct effect. It is shown for a logistic regression model that the efficiency of optimal parallel (single-period) or crossover (two-period) design is substantially greater than a balanced design. The optimal designs are also shown to be robust to misspecification of the value of the parameters. Finally, the parallel and crossover designs are combined to provide the experimenter with greater flexibility.

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“…Because of this reduction in variance, and because each patient is used several times, crossover studies often have greater statistical power than parallel group designs that include 5 or 10 times the number of subjects. This is generally an important practical advantage, particularly when studies are performed in a single centre [40,49,79].…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of Motor and Somatosensory Skills in Humans

Pleger¹,

Tegenthoff²,

Dinse³

et al. 2005

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The pharmacological basis of changes in human behaviour and associated cortical reorganization remains poorly understood. Different paradigms have been introduced to alter motor and somatosensory skills in humans. The underlying changes in synaptic efficacy can be modulated by pharmacological agents acting to gate synaptic plasticity. Non-invasive imaging techniques offer the possibility to assess parallel changes in cortical processing.Cellular studies suggest that there might be only few, but very basic mechanisms that control regulation of synaptic transmission. In particular, the γ-aminobutyric acid (GABA) and the N-methyl-D-aspartic acid (NMDA) receptor, a specific subtype of the glutamatergic receptors, are thought to be crucial in synaptic plasticity. Thus, the application of benzodiazepines facilitating the binding of GABA on GABA(A) receptors, and NMDA receptor blockers, were found to prevent learning and associated cortical reorganization.While there are many approaches to block plastic processes, less is known about drugs, which enhance learning and cortical plasticity. Growing evidence from human studies support the suggestion that learning is subject to amplification by amphetamine. Amphetamine however acts non-specific by increasing centrally the levels of dopamine, serotonin, and noradrenaline. Thus, first approaches that intend to scrutinize the apparently ubiquitous role of only one of these neurotransmitter systems used more specifically acting pharmacological agents.In this review we focus on studies that aimed to investigate the pharmacology of the motor and somatosensory system. First, we introduce standards for testing potential effects of a substance. Then, we focus on biochemical mechanisms of learning, before discussing different motor and somatosensory paradigms which were introduced to elicit changes in cortical excitability or organization in animals and humans. Emphasis is placed on the role of inhibitory and excitatory pharmacological agents acting to gate synaptic plasticity in healthy subjects and patients. It is concluded that future studies that investigate the interaction between artificially modulated receptor activity and specific patterns of behaviour in various neurological disorders may help to improve our understanding of how to support recovery of motor and somatosensory function pharmacologically.

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Clinical cross-over trials in phase I

Cited by 13 publications

References 30 publications

Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Optimal Crossover Designs for Logistic Regression Models in Pharmacodynamics

Pharmacology of Motor and Somatosensory Skills in Humans

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