Biomarkers for the effects of benzodiazepines in healthy volunteers

Abstract

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose-response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose ( r 2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.

A systematic literature review of the human skin microbiome as biomarker for dermatological drug development

“…This is due to the correlation between Staphylococcus abundance, microbiome diversity profile and disease severity that seems to exist in multiple trials, therewith complying with most of the criteria for a useful biomarker, Table 2 4. Objective data on the change of the microbiota may be valuable to support subjective AD efficacy scores in early phase clinical trials.…”

“…A biomarker is defined as a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention 1, 2. Clinical biomarkers are thought to reflect disease activity and pathophysiology 3, 4. A useful biomarker in any class has to comply with the following general criteria: (i) there must be a consistent response of the biomarker across studies (preferably from different research groups) and drugs from the same mechanistic class; (ii) the biomarker must respond clearly to therapeutic (not supratherapeutic) doses; (iii) there must be a clear dose‐ or concentration‐response relationship; and (iv) there must a plausible relationship between the biomarker, pharmacology of the drug class and disease pathophysiology 4.…”

“…Clinical biomarkers are thought to reflect disease activity and pathophysiology 3, 4. A useful biomarker in any class has to comply with the following general criteria: (i) there must be a consistent response of the biomarker across studies (preferably from different research groups) and drugs from the same mechanistic class; (ii) the biomarker must respond clearly to therapeutic (not supratherapeutic) doses; (iii) there must be a clear dose‐ or concentration‐response relationship; and (iv) there must a plausible relationship between the biomarker, pharmacology of the drug class and disease pathophysiology 4. Validated biomarkers are often being used to guide drug development programmes from human pharmacology studies, i.e.…”

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

“…Visually guided SPV is a biomarker of sedation mediated through the a1-GABAAR (de Haas et al, 2009;de Haas et al, 2010;de Visser et al, 2003). We were interested in obtaining this marker at baseline (time point B0) and after drug intake (time point B1, cf.…”

“…We measured increases in GABAAR-mediated inhibition by slowing of saccadic peak velocity (SPV) (de Visser et al, 2003), rather than by other available techniques such as pharmacoelectroencephalography (Valle et al, 2002) or pharmacotranscranial magnetic stimulation because changes in SPV reflect changes specifically in synaptic a1-GABAAR-rather than a2-and a3-GABAARmediated inhibition (de Haas et al, 2009;de Haas et al, 2010) and, therefore, are expected to capture the sedative effects of alprazolam and zolpidem.…”