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Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.

ABSTRACT: INTRODUCTION:When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities. OBJECTIVE:We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9). METHODS:Using phenome-wide association study (PheWAS) methods, we analyzed available genotype and clinical data from 29,722 patients, leveraging the known effects of changes in PCSK9 to identify novel phenotypes in which this protein and its inhibitors may have impact. RESULTS:PheWAS revealed a significantly reduced risk of hypercholesterolemia (odds ratio [OR] 0.68, p = 7.6 × 10-4) in association with a known loss-of-function variant in PCSK9, R46L. Similarly, laboratory data indicated significantly reduced beta mean low-density lipoprotein cholesterol (- 14.47 mg/dL, p = 2.58 × 10-23) in individuals carrying the R46L variant. The R46L variant was also associated with an increased risk of spina bifida (OR 5.90, p = 2.7 × 10-4), suggesting that further investigation of potential connections between inhibition of PCSK9 and neural tube defects may be warranted. CONCLUSION:This novel methodology provides an opportunity to put in place new mechanisms to assess the safety and long-term tolerability of PCSK9 inhibitors specifically, and other new agents in general, as they move into human testing and expanded clinical use.

SUBMITTER: Jerome RN

PROVIDER: S-EPMC5828879 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.

Jerome Rebecca N RN Pulley Jill M JM Roden Dan M DM Shirey-Rice Jana K JK Bastarache Lisa A LA R Bernard Gordon G B Ekstrom Leeland L Lancaster William J WJ Denny Joshua C JC

Drug safety 20180301 3

<h4>Introduction</h4>When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities.<h4>Objective</h4>We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine pro ...[more]

PMID: 29185237

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Project description:Background and purposePredicting the risk of drug-induced adverse psychiatric effects is important but currently not possible in non-human species. We investigated whether the affective bias test (ABT) could provide a preclinical method with translational and predictive validity.Experimental approachThe ABT is a bowl-digging task, which quantifies biases associated with learning and memory. Rats encounter independent learning experiences, on separate days, under either acute manipulations (e.g. pro-depressant vs. control) or different absolute reward values (e.g. high vs. low). A bias is observed during a preference test when an animal's choices reflect their prior experience. We investigated the effects of putative pro-depressant drug treatments following acute or chronic administration on the formation of an affective bias or reward-induced positive bias respectively.Key resultsThe immunomodulators LPS (10 μg·kg-1 ), corticosterone (10 and 30 mg·kg-1 ) and IFN-α (100 U·kg-1 ) induced a negative affective bias following acute treatment. Tetrabenazine (1 mg·kg-1 ) also induced a negative bias, but no effects were observed with varenicline, carbamazepine or montelukast. Chronic treatment with IFN-α (100 U·kg-1 ) and retinoic acid (10 mg·kg-1 ) impaired the formation of a reward-induced positive bias but did not alter sucrose preference test (SPT).Conclusions and implicationsThe ABT has the potential to provide a novel approach to predict pro-depressant risk in a non-human species. Negative biases induced by acute treatment in the standard version of the task may also predict longer-term effects on reward processing as shown by the deficit in reward-induced positive bias following chronic treatment, an effect distinct from anhedonia in the SPT.Linked articlesThis article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Project description:INTRODUCTION:National competent authorities (NCAs) use Direct Healthcare Professional Communications (DHPCs) to communicate new drug safety issues to healthcare professionals (HCPs). More knowledge is needed about the effectiveness of DHPCs and the extent to which they raise awareness of new safety issues among HCPs. OBJECTIVE:The objective was to assess and compare general practitioners' (GPs'), cardiologists', and pharmacists' familiarity with DHPCs as communication tools, their awareness of specific drug safety issues, and the sources through which they had become aware of the specific issues. METHODS:GPs, cardiologists, and pharmacists from nine European countries (Croatia, Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the UK) completed a web-based survey. The survey was conducted in the context of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Respondents were asked about their familiarity with DHPCs in general and their awareness of safety issues that had recently been communicated and involved the following drugs: combined hormonal contraceptives, diclofenac, valproate, and ivabradine. Those HCPs who were aware of the specific safety issues were subsequently asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a Pearson ?2 test per country and post hoc Pearson ?2 tests in the case of statistically significant differences. RESULTS:Of the 3288 included respondents, 54% were GPs, 40% were pharmacists, and 7% were cardiologists. The number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with DHPCs, with one significant difference between the professions: pharmacists were more familiar than GPs in Italy (99 vs 90%, P = 0.004). GPs' awareness ranged from 96% for the diclofenac issue to 70% for the ivabradine issue. A similar pattern was shown for pharmacists (91% aware of the diclofenac issue to 66% of the ivabradine issue). Cardiologists' awareness ranged from 91% for the ivabradine issue to 34% for the valproate issue. Overall, DHPCs were a common source through which GPs (range: 45% of those aware of the contraceptives issue to 60% of those aware of the valproate issue), cardiologists (range: 33% for the contraceptives issue to 61% for the valproate issue), and pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the specific safety issues, followed by information on websites or in newsletters. CONCLUSIONS:GPs, cardiologists, and pharmacists were to a similar extent (highly) familiar with DHPCs, but they differed in awareness levels of specific safety issues. Cardiologists were less aware of safety issues associated with non-cardiology drugs even if these had cardiovascular safety concerns. This implies that additional strategies may be needed to reach specialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their field of specialisation. DHPCs were an important source for the different professions to become aware of specific safety issues, but other sources were also often used. NCAs should consider the use of a range of sources when communicating important safety issues to HCPs.

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Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.

Publications

Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.

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