We evaluated a transparent decision model that reproducibly rates drug interactions and identifies systematic rating discrepancies. Altman
 suggests that kappa is the appropriate means of judging agreement or reproducibility between classification categories obtained by two different rating methods and is supported by the higher weighted Kappa values, which strengthened the approach in the present study. No systematic differences showed up on the Bland–Altman plot of DM versus MMX, following removal of the systematic differences. Divergence in decision making remains an issue and review of certain cases is unavoidable. The review time, however, decreases as a result of the standardization. When comparing two ratings, our visualization of the decision path enables rapid comprehension of one side of the differences
, thus clarifying (at least partially) the rating discrepancies. Such transparency improves the clinical value of the interpretation of the rating
[29, 30]. To our knowledge, we publish the first visualized decision model that is comparable with other ratings. Previously published ratings, though based on expert group decisions, are not guided by specified rules of an algorithm. The output of the decision model, corrected for systematic differences between rating systems, closely resembles that of other ratings. To illustrate the systematic nature of these differences, we summarize the most important ones (highlighted in the cross tables) below.
If more than simple precautionary measures are required in first line therapy, or if complex monitoring of a likely side-effect is required, we assume that a suitable drug alternative precludes co-administration, because the latter disproportionately raises patient risk or health care costs. This explains why DM rated 30 cases of higher severity than the clinical pharmacologist (Table
1) and 25 cases of higher severity than MMX (Table
Interactions requiring complex monitoring were rated of higher severity by DM than either the clinical pharmacologist (DM rated 18 of 30 cases more severely) or MMX (DM rated 21 of 25 cases more severely). (i) The clinical pharmacologist assigned a rating of C (“moderate”) to the combination of citalopram and tramadol, whereas both DM and MMX recommended avoiding this combination (ratings: DM: D and “major”, respectively), since co-administration increases the risk of serotonin toxicity. Monitoring for SAEs such as hyperreflexia, CNS symptoms, myoclonus, sweating and hyperthermia is imperative and is complex in an outpatient setting. (ii) Risk of amiodarone and phenytoin co-administration was rated C (“moderate”) by MMX and C (“precautionary measures”) by the clinical pharmacologist. The DM assigned a rating of D (“avoid”), since amiodarone concentrations in plasma may be reduced to as low as 30% in the presence of phenytoin. This effect can occur several weeks into phenytoin therapy, therefore amiodarone concentrations must be monitored for several weeks to enable dose adjustment. Furthermore, phenytoin toxicity can occur and surveillance requires considerable effort. (iii) Co-administration of duloxetine and amitriptyline increases the risk of anticholinergic or serotonin syndrome and may lead to elevated amitriptyline plasma concentrations. Because of the complex clinical surveillance required, this interaction was rated D by the DM, whereas MMX assigned a C rating.
The inclusion of suitable treatment alternatives in the decision process caused DM to rate an interaction more severely than the clinical pharmacologist in 12 of 30 cases, and more severely than MMX in 4 of 25 cases. (i) Co-administration of digoxin and alprazolam was rated C by the clinical pharmacologist, since alprazolam interferes with digoxin levels and therefore requires drug concentration monitoring at the initiation and discontinuation of alprazolam therapy. The DM rated this interaction as D, because a suitable alternative (lorazepam) exists. (ii) MMX rated the combination of midazolam and phenytoin as “moderate”. Although the co-presence of phenytoin depresses midazolam levels, alternative benzodiazepines are available which carry a lower potential for interaction.
In one case, a rating discrepancy of two categories was found (the drug combination was rated B by MMX and D by DM). The drugs in question were fluconazole and fluvastatin, for which co-administration increases the risk of severe myopathy while an alternative to fluvastatin exists.
This study focused solely on the decision making process, and the positive contribution of the rating output to medical therapy was not evaluated. Although every attempt has been made to ensure that the categories are objective (i.e. they represent a consensus between four clinical specialists in three different fields), they are nonetheless subject to user interpretation and should not be regarded as a “gold standard”, but as an approach to standardize ratings with defined rules. We hope that publication of this decision model will stimulate other groups to test the models’ reproducibility. The feasibility of the decision model to illustrate system differences has been tested with a single database, MMX. In future, the DM may elucidate systematic differences between other rating discrepancies reported in the literature
[11, 13, 14]. Concordance between the DM and expert assessment has been validated by only one pharmacist from our group.
The agreement between DM and MMX was evaluated as “fair”, which can be explained partly by systematic differences in 25 cases, but which must also consider the missing information from MMX in 62 cases. The omission of information in MMX regarding a specific drug combination cannot be considered as the absence of a DDI. Therefore our database distinguishes between missing information and a safe combination (DM: A). No information was yielded by MMX for the following complications of drug co-administration. (i) The combination of phenobarbital and acetaminophen increases the risk of hepatotoxicity. (ii) The concurrent use of phenobarbital and mirtazepine may inhibit mirtazepine efficacy and therefore requires clinical monitoring. (iii) Duloxetine increases the area under the plasma concentration time curve (AUC) of metoprolol 1.8-fold. As a result, blood pressure and heart rate monitoring are required, particularly at the start and cessation of duloxetine therapy. Drugs that are used in Europe but not in the U.S. explain a portion of the missing data.