Pharmacokinetic drug-drug interactions (PK-DDIs) are a major contributor to the failure of drug therapy, either from toxicity leading to patient harm or from sub-therapeutic concentrations resulting in loss of efficacy. Previous research has reported a DDIs prevalence of 19% in >70 years old, that is even higher among patients using cytochrome (CYP)450 enzyme system. Also, clinically significant transporter-mediated DDIs have already demonstrated for a number of commonly used medications including multiple statins, cimetidine, digoxin, metformin, anti-epileptics and anti-cancer agents, to name a few. Together with the increasing use of pharmacologic therapy along with over-the-counter medications and herbal supplements, patients may be exposed to the risk of potential DDIs when more than one drug is metabolized via CYP450 enzyme system , . In opioid-treated patients, this type of multi-drug regimen is very prevalent and nearly 20% of them take 10 or more different medications per week .
Prior studies of chronic pain conditions have found that CYP450 interactions between specific opioids (codeine, fentanyl, hydrocodone, methadone, oxycodone, and tramadol) and concomitant pain medications (anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors) that serve as substrates or inhibitors of isoenzymes 3A4 and 2D6, are very frequent. This explains reports of overdosing or underdosing after administration of standard doses of two drugs as codeine and tramadol, strongly influenced by the CYP2D6 genotype . Also, duloxetine can inhibit isoenzymes 2D6 and 1A2 and is highly bound to plasma proteins resulting in many potential DDIs with other medications (nearly 34%). Alternatively, pregabalin has minimal pharmacodynamic or PK-DDIs (2.9%) . In vivo DDI studies with morphine are few, but they suggest that inhibition or induction of uridine 5′-diphospho-glucuronsyltransferase enzymes, i.e. by ketamine, could alter morphine and its metabolite levels and could change the analgesic efficacy. Despite this information and its impact on hospitals’ economic performance, still no advice is given concerning the combination of opioids and other drugs in the current guidelines .
This lack of formal translation to clinical practice might have several explanations. For obvious ethical reasons, there are no randomized controlled trials or other well-designed controlled studies exploring DDIs. Recommendations must therefore be based upon case reports of serious adverse drug reactions and basic knowledge about drug mechanisms. Clinicians, who often do not have the time, experience, or interest to publish clinical observations, mostly observe DDIs. Thus, DDI may not be detected, or the symptoms are believed to be caused by the disease. Also, several DDIs may be considered as frequent and part of common knowledge, and therefore, not reported. Finally, many journals only occasionally publish case reports and, perhaps, mainly in national journals and, therefore, they are not identified by a search strategy excluding non-English papers .
With an increase in our understanding of genetics-associated drug responses and increased availability of cheaper genetic testing, pharmacogenomics is more often nowadays incorporated into clinical decision making. In fact, the number of drugs with labels containing DDI pharmacogenetic test information is on the rise. For instance, a noninvasive saliva test might 1 day allow clinicians to determine if a particular medication would be efficacious, have adverse effects, or have potential DDIs. That could result in an improved drug development, testing, and registration, reducing the time for introduction into the clinical practice, and therefore the overall cost. Whether and to what extent this individual genetic-based approach to medicine results in an improved economically feasible therapy remains to be seen for most drugs. The decision as to whether each set of pharmacogenomic results has the necessary evidence to support clinical validity and utility to warrant use in prescribing depends on many factors and has to overcome the aforementioned barriers. This will have considerable consequences on patient-prescriber-payer and public health services and infrastructures .
To guarantee safe use of medication, Joint Commission International requires that medication prescriptions or orders must be reviewed for suitability prior to dispensing. The United States Food and Drug Administration, Japan’s Pharmaceutical and Medical Devices Agency, the European Medicines Agency, and the International Transporters Consortium have all released guidelines highlighting the importance of studying DDI. To exploit these opportunities: (i) multidisciplinary groups DDIs guidelines would be needed to provide advice to regulatory agencies, together with the industry, exploring how to use genetic testing to prevent DDI in pre- and postmarketing studies; (ii) payers need to be convinced about the positive cost-benefit of pharmacogenomics-guided healthcare; (iii) legal and ethical questions must be clarified to harmonize research (personal data protection rules, inform consent, biobanks regulation, massive population sequencing, and similar); (iv) affordable companion diagnostics and timely molecular profiling technologies are prerequisites; (v) healthcare professionals need to be trained and reassured on the availability and utility of genomic testing; and (vi) public must be informed about the implications of genetic testing in drug therapy and disease management.
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About the article
Published Online: 2018-01-06
Published in Print: 2018-03-28
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.