An Integrated Approach to Assessing Drug-Drug Interactions: A Regulatory Perspective

Abstract Purpose To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different “SS reporting zones” were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). Discussion Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

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Effective Law from a Regulatory and Administrative Law Perspective

European Journal of Risk Regulation ◽

10.1017/err.2018.52 ◽

2018 ◽

Vol 9 (3) ◽

pp. 391-415 ◽

Cited By ~ 1

Author(s):

Maria DE BENEDETTO

Keyword(s):

Decision Making ◽

Public Interest ◽

Law And Economics ◽

Integrated Approach ◽

Administrative Law ◽

Sociology Of Law ◽

The Public ◽

Regulatory Perspective ◽

Administrative Procedures ◽

Behavioural Sciences

The question of effective law has been studied in many fields of research, such as philosophy and sociology of law, law and economics, public policy and behavioural sciences. This article aims to treat it as a genuine administrative law issue which is currently having a significant impact on administrative procedures, especially affecting the way in which rules are adopted and implemented. Furthermore, the article attempts to reconcile conflicting views in existing literature on the meaning of effective law and on which factors lead to effectiveness by proposing an integrated approach: starting from a regulatory perspective it considers both traditional determinants of effectiveness, ie compliance and enforcement, as well as the emerging aspect of outcomes, focused on the idea that a rule can be defined as effective when its desired effects have been achieved and the public interest which justifies the rule has been safeguarded without producing unwanted or disfunctional consequences.Far from being simply a decisional problem for institutions (arising in legislative, regulatory and administrative procedures), effectiveness calls for a “steering administration” and represents a criterion for decision-making, since expected effectiveness can be used in the logic of “whether” and “how” institutions should arrive at decisions.

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Toxicogenomics: regulatory perspective on current position

Human & Experimental Toxicology ◽

10.1191/0960327105ht495oa ◽

2005 ◽

Vol 24 (1) ◽

pp. 35-40 ◽

Cited By ~ 16

Author(s):

Jon M Battershill

Keyword(s):

Decision Making ◽

Dose Response ◽

A Priori ◽

Integrated Approach ◽

Decision Making Process ◽

Current Position ◽

Mutagenicity Testing ◽

Mechanisms Of Toxicity ◽

Regulatory Perspective ◽

Screening Approaches

Published studies on the utility of toxicogenomic approaches (transcriptomics, proteomics and metabonomics) in screening for toxicological mechanisms and evaluation of dose response effects have been reviewed. The information supports the use of transcriptomics to screen for specific toxicological mechanisms for which there is an a priori hypothesis, although in some areas such as mutagenicity testing, toxicogenomics appear to have limited value for identifying mutagens. Data from such screening approaches cannot be used to exclude the possibility of toxicity. Targeted transcriptomics might be valuable for screening for specific mechanisms of toxicity considered to be irrelevant for assessing risk to humans, which would help to reduce the need for detailed testing of some chemicals. An integrated approach is suggested where data from more than one toxicogenomic approach could be used as an adjunct to conventional toxicology to assess dose-response in toxicological tests. An outline preliminary proposal for use by regulators is suggested although it is noted that more data are required before this could be formally used in a decision-making process.

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