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Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Department of Pharmaceutical Biosciences, Bioactivation and Toxicity, Uppsala University, Uppsala, Sweden.
2011 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 6, 633-641 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and the community. Despite this, limited information is reported in the literature on the drug interaction categories responsible for causing ADRs. In the study reported here, we investigated the drug combinations most frequently co-reported as interacting in the WHO Global Individual Case Safety Report (ICSR) database, VigiBase, and categorised these according to the drug interaction mechanism. METHODS: Reports in which drug combinations were co-reported as interacting in at least 20 reports in VigiBase during the past 20 years were included in the study. Each drug combination was reviewed in the literature to identify the mechanism of interaction and subsequently classified as pharmacodynamic and/or pharmacokinetic reaction. Report characteristics were also analysed. RESULTS: A total of 3766 case reports of drug interactions from 47 countries were identified. Of the 123 different drug combinations reported, 113 were described in the literature to interact. The mechanism of the drug interaction was categorised as pharmacodynamic (46 combinations; 41%), pharmacokinetic (28; 25%), a combination of both types (18; 16%) and unidentified (21; 19%). Pharmacodynamic drug interactions primarily concerned pharmacological additive effects, whereas enzyme inhibition was the most frequent pharmacokinetic interaction. The combinations reviewed primarily implicated drugs such as warfarin, heparin, carbamazepine and digoxin. CONCLUSIONS: Drug interactions reported in globally collected ADR reports cover both pharmacodynamic, specifically additive pharmacological effects, and pharmacokinetic mechanisms primarily accredited to the inhibition of hepatic cytochrome P450 enzymes. These ADR reports often concern serious threats to patients' safety and are particularly related to the use of high risk drugs such as warfarin and heparin.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2011. Vol. 67, no 6, 633-641 p.
Keyword [en]
Pharmacovigilance, VigiBase, Enzyme, inhibition, Additive effects
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-66507DOI: 10.1007/s00228-010-0979-yISI: 000291607500010PubMedID: 21253716OAI: diva2:404755
Available from: 2011-03-18 Created: 2011-03-18 Last updated: 2014-01-13Bibliographically approved
In thesis
1. Drug interaction surveillance using individual case safety reports
Open this publication in new window or tab >>Drug interaction surveillance using individual case safety reports
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and society in general. Post-marketing pharmacovigilance reporting databases with compiled individual case safety reports (ICSRs) have been shown to be particularly useful in the detection of novel drug - ADR combinations, though these reports have not been fully used to detect adverse drug interactions.

Aim: To explore the potential to identify drug interactions using ICSRs and to develop a method to facilitate the detection of adverse drug interaction signals in the WHO Global ICSR Database, VigiBase.

Methods: All six studies included in this thesis are based on ICSRs available in VigiBase. Two studies aimed to characterise drug interactions reported in VigiBase. In the first study we examined if contraindicated drug combinations (given in a reference source of drug interactions) were reported on the individual reports in the database, and in the second study we examined the scientific literature for interaction mechanisms for drug combinations most frequently co-reported as interacting in VigiBase. Two studies were case series analyses where the individual reports were manually reviewed. The two remaining studies aimed to develop a method to facilitate detection of novel adverse drug interactions in VigiBase. One examined what information (referred to as indicators) was reported on ICSRs in VigiBase before the interactions became listed in the literature. In the second methodological study, logistic regression was used to set the relative weights of the indicators to form triage algorithms. Three algorithms (one completely data driven, one semi-automated and one based on clinical knowledge) based on pharmacological and reported clinical information and the relative reporting rate of an ADR with a drug combination were developed. The algorithms were then evaluated against a set of 100 randomly selected case series with potential adverse drug interactions. The algorithm’s performances were then evaluated among DDAs with high coefficients.

Results: Drug interactions classified as contraindicated are reported on the individual reports in VigiBase, although they are not necessarily recognised as interactions when reported. The majority (113/123) of drug combinations suspected for being responsible for an ADR were established drug interactions in the literature. Of the 113 drug interactions 46 (41%) were identified as purely pharmacodynamic; 28 (25%) as pharmacokinetic; 18 (16%) were a mix of both types and for 21 (19%) the mechanism have not yet been identified. Suspicions of a drug interaction explicitly noted by the reporter are much more common for known adverse drug interactions than for drugs not known to interact. The clinical evaluation of the triage algorithms showed that 20 were already known in the literature, 30 were classified as signals and 50 as not signals. The performance of the semi-automated and the clinical algorithm were comparable. In the end the clinical algorithm was chosen. At a relevant level, 38% were of the adverse drug interactions were already known in the literature and of the remaining 80% were classified as signals for this algorithm.

Conclusions: This thesis demonstrated that drug interactions can be identified in large post-marketing pharmacovigilance reporting databases. As both pharmacokinetic and pharmacodynamic interactions were reported on ICSRs the surveillance system should aim to detect both. The proposed triage algorithm had a high performance in comparison to the disproportionality measure alone.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 45 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1252
Adverse drug reactions, adverse drug interaction surveillance, drug interactions, individual case safety reports, postmarketing pharmacovigilance, signal detection
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-70424 (URN)978-91-7393-106-9 (ISBN)
Public defence
2011-10-06, Nils Holger, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2011-09-07 Created: 2011-09-07 Last updated: 2011-09-20Bibliographically approved

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