Patients taking two concurrent medications have a 13% risk of an adverse drug event, rising to 38% for four medications, and 82% for seven or more medications prescribed simultaneously.
2 million
1.3 million
1.7 to 4.6
350,000 39%
50%20.4%
Affected Hospital Stays
Emergency Department VisitsPhysician Office Visits
Increased Days Per Affected Hospital Stay
Hospitalizations Of Seniors in U.S. on 5+ meds(Approx. 20 million people)
Of Seniors in U.K. on 5+ meds (Increase of 12% from 20 years ago)
Adverse Drug Events is estimated to be the 4th leading cause of death— ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.source: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm110632.htm
TRHC Precision Pharmacotherapy Research andDevelopment (PPR&D) Institute is committed tothe development of proprietary products and theirvalidation and recognition by the scientific andregulatory communities to optimize medicationregimen, improve patient outcomes, reduceutilization of various healthcare services, lowerhealthcare costs, and manage risk.
The PPR&D Institute vision expands with the emergingresearch initiatives that include bioinformatics,biomedical engineering systems, nanoscale science,patient-specific information, data-driven technologiesand solutions, and translational research.
Vision
Preference Population Personalized Precision Predictive
A 74-year-old man with known hypercholesterolemiaand hypertension, has presented in the recentmonths recurrent angina. A PTCA procedure wasperformed and appropriate platelet inhibitor therapyinitiated (clopidogrel) with GI bleeding protection(omeprazole). The participant also has a depressivestatus and chronic pain. He currently receives 10chronic meds plus multi-vitamins.
Assuming normal and functional CYP2C19 activity (*1/*1), our pharmacists would recommend to either administer omeprazole and clopidogrel at different times of the day or to change omeprazole for pantoprazole ( ).
1) Since this paricipant is a poor metabolizer for CYP2C19 (non-functional enzyme), the use of clopidogrel is not recommended (CPIC Guidelines) as this is a prodrug with impaired transformation into its active metabolite. Another platelet aggregation inhibitor such as ticagrelor (directly active) should be used instead.
1) Since this patient is an ultra-rapid metabolizer for CYP2C19 (hyper-functional enzyme), a lower dose of clopidogrel should be used (CPIC Guidelines) as more of the active metabolite is formed, increasing the efficacy of the drug but also the risk of bleeding.
2) The concomitant use of omeprazole may be seen as a good thing as it would decrease the risk of bleeding due to competitive inhibition and decrease formation of the active metabolite. However, omeprazole will be metabolized more rapidly and expected to be less efficacious.
Schwartz et al., J Am Board Fam Med 10.3122/jabfm.2017.06.170145 on 27 November 2017.
Phenotype distribution: all patients had at least 1 variant allele, and the majority (66.0%) had >5. Notably, among the genes tested, 36.0% of patients were identified as rapid metabolizers for the CYP2C19 isoform; 40.0% were considered intermediate or poor metabolizers for the CYP2D6 isoform.
• Patients with T2D and treated with clopidogrel have higher number of non-responders, and less platelet inhibition than non-T2D.
• In the OPTIMUS study, 60% of the diabetes patients remained poor responders even though a doubling of the maintenance dose of clopidogrel was used and associated with an increase in platelet inhibition.
Geisler et al. Diabetes Care 2007Angiolillo et al. Diabetes 2005Angiolillo et al. JACC 2007
Platelet response to clopidogrel is attenuated in diabetics.
Residual platelet reactivity after a 600mg loading dose of clopidogrel
Use of Biomarkers as a Phenotype Measurement in Patients
• Several probe drugs are used to study the impact of genes, ethnicity, environmental factors, drug-drug interactions on CYP450s.
• The usual phenotyping strategy involves the administration of an exogenous probe drug with serial blood samplings or urine collection.
• The identification of an endogenous biomarker could be of interest as less invasive measure. 6β-OH cortisol:cortisol ratio and 4β-OH cholesterol:cholesterol
• Not a single patient included in clinical trials looks like PACE participants taking 15-25 drugs/day.
• Usual software based on one-to-one drug analyses cannot predict DDIs in such patients and cannot provide an appropriate, clinically relevant recommendation.
• Computer simulations using PK-PD models allow us to define complex models of drug combinations and predict drug plasma levels and responses.
• In silico nano-technologies such as “Human-on-a-chip” also allow us to expose human tissues to various drug combinations under various conditions.
• All these approaches provide us with answers without exposing patients to potentially toxic conditions.
