Beyond Recommendations and Guidelines: A Need for Closer Collaborations Between Clinician and Clinical Pharmacologist to Better Prevent Drug-Drug Interactions

Adverse drug reactions are suspected to be the main reason for urgent hospital admission, particularly in the elderly. About 3% of the emergency admission of patients older than 65 years are associated with possible adverse drug reactions, while in about half the time, these adverse events are a direct consequence of a drug-drug interaction.¹ Aiming to determine and anticipate the risk of drug-drug interactions for treatments frequently used in elderly or used in chronic diseases where patients are exposed to polypharmacy is then crucial. Statins are among the most frequently prescribed medications worldwide and correspond to such a situation. Due to an important amount of research, including large clinical trials and additional information from healthcare databases, both basic and clinical pharmacology of statins are well described. Statin therapy undoubtedly and strongly reduces the risk of major vascular events while the main serious adverse events are muscle toxicity, new-onset diabetes mellitus and probably hemorrhagic strokes.² More precisely, the treatment of 10,000 patients for 5 years would cause about 5 cases of myopathy, 50-100 new cases of diabetes, and 5-10 hemorrhagic strokes.2 Nevertheless, the benefit-risk ratio largely remains at the advantage of statin therapy in many individuals with known atherosclerotic cardiovascular disease.

Despite large clinical evidence of both efficacy and safety of these drugs,² combination therapy with statin and other cardiovascular medications potentially expose patients to significant drug-drug interactions.^3,4 From a pharmacological point of view, a drug-drug interaction can result from a pharmacodynamic interaction when a medication modifies the effect of another one by interacting on pharmacological targets with possible additive, synergistic or antagonistic effect. On the other hand, pharmacokinetic interactions can also modify the drug response through interactions at the different step of the pharmacokinetic process such as absorption, distribution, metabolism or elimination of the drug. Knowledge about specific pharmacology of drugs may help to anticipate drug-drug interactions. It should particularly be kept in mind that numerous factors may interfere in such a process, including drug-specific and patients’ related factors.

Among drug-specific factors that may be involved in drug-drug interactions, bioavailability, protein binding, lipophilicity, half-life, metabolism and elimination are perfectly known for each available statin.^3,4 In this context, the 2 most common pharmacokinetic drug-drug interactions involving statins are those involving metabolism through the cytochrome P-450 (CYP450) enzyme system and the permeability glycoprotein (P-gp), while pharmacodynamic drug-drug interactions mainly result in altered low-density lipoprotein cholesterol reductions or an enhanced risk of muscle-related toxicity.^3,4 From a theoretical point of view, an extremely large number of possible drug-drug interactions on metabolism might exist since at least 3 statins (atorvastatin, lovastatin, simvastatin) are metabolized through CYP450 3A4, which has a large variability and is involved in the metabolism of numerous drugs. Furthermore, fluvastatin, pitavastatin and rosuvastatin are metabolized through the CYP450 2C9, whose activity is under a genetic polymorphism. To this, it should be added that P-gp also has a large number of inducers, inhibitors or substrates that are sometimes shared with CYP450 3A4.^3,4 All taken together, it leads to a very complex situation for the clinician. As clearly illustrated by the present recommendations, not all these possibilities are clinically significant. The present exhaustive paper will be a very useful tool to anticipate clinically significant drug-drug interactions of cardiovascular drugs with statins. The case of the deleterious association between fibrates and statins that leads to a significant increase in muscle toxicity and of rhabdomyolisis with gemfibrozil has been largely documented.³ Because the increase in risk with the association of fibrates and statins is greater than the predicted sum of monotherapy risks, it may be that this drug-drug interaction is one example of both pharmacokinetic and pharmacodynamic causal mechanisms. An algorithm for treating patients with statin-fibrate combination therapy is particularly of great interest for the clinician.³

Another approach to anticipate the risk about drug-drug interactions is to look at patient-specific factors, including age, sex, lifestyle factors, gene polymorphisms, associated pathologies (namely hepatic and renal failure) or predisposition to treatment complication, in patients with a history of muscle diseases. If the weight of gene polymorphism remains difficult to evaluate in the context of statin therapy,⁴ both age and associated pathologies may be of greatest importance. Because the elderly are commonly prescribed multiple medications and are also at increased risk of drug-drug interactions according to concomitant pathologies, this population should be more closely followed-up and individual situations should be examined with caution to determine the benefit-risk ratio to add or to maintain a treatment. A recent systematic review has evaluated the prevalence of statin-drug interactions in older people, but due to substantial variations (1.5 to 4% in people over 65 years of age), conclusions remain problematic and further studies are needed.⁵ Besides age and beyond hepatic and renal failure, some other specific situations should particularly be taken into account. Patients receiving immunosuppressive agents are especially at risk. Indeed, when a patient is treated with cyclosporine, everolimus, serolimus, or tacrolimus, the use of lovastatin, simvastatin, and pitavastatin is potentially harmful and therefore should be avoided. Every time the risk of drug-drug interaction with statin is supported by metabolic interactions through CYP450, the use of pravastatin (the only statin without any CYP450 metabolism) should then be considered.³

Among strategies to reduce the risk of drug-drug interactions, both basic and clinical pharmacology remain important steps. The FDA and the International Conference on Harmonization provide recommendations for industry regarding the in vitro, in vivo and clinical trial evaluation of drug metabolism and drug transporter interactions.⁶ These recommendations include the conduct of pharmacokinetic studies in older adults and in patients with polypharmacy. Another emerging approach consists of systematically analyzing some genetic polymorphisms to predict patients’ metabolism in order to determine the choice of therapy. Nevertheless, little guidance on how to interpret and manage drug-drug-gene interactions in the clinic is actually available. Moreover, limited access to pharmacogenetic tests and insufficient knowledge of healthcare professionals related to pharmacogenomics are other important limitations.^4,6 In this context, post-market monitoring of drugs and their unwanted effects is of great importance. Both practitioners and patients should report adverse events and, when possible, should be assisted by a clinical pharmacologist to establish the existence (or not) of a drug-drug interaction, to identify its mechanism, and then to determine the best solution to manage therapy. This kind of approach, coupled with the development of large databases, may help in the future to better understand and prevent drug-drug interactions. The work done here is an important step that would be replicated for many other situations or drugs. It should also develop closer collaborations between clinicians and clinical pharmacologists to improve the diagnosis and the prevention of drug-drug interactions in difficult cases.⁷