9/28/2018 Disclosure • I, Lauren Steffen, declare to not have any real or apparent conflicts of interest or financial interests with any Competitive Inhibition and LQTS: pharmaceutical manufacturers, medical device company, or in any product or service, including grants, employment, gifts, Managing Accumulative, stock holdings, and honoraria related to the content of this Multi-Drug Interactions presentation. • Each of the planning committee members have listed no Lauren Steffen, PharmD, BCGP financial interest/arrangement or affiliation that would be Director, Education and Training considered a conflict of interest. CareKinesis Clinical Advisory Panel September 20, 2018 2 Objectives • Explain basic principles as it pertains to bioavailability, drug metabolism and competitive inhibition. • Evaluate therapeutic effects related to enzyme substrates, inhibitors and inducers. • Calculate dose changes required under conditions of competitive Competitive Inhibition inhibition. • Apply basic electrophysiological concepts to the understanding of Principles of Drug Interactions underlying mechanisms of QT prolongation and Torsade de Pointes. • Conduct a review of the predisposing factors to drug-induced Long QT Syndrome and apply these concepts to management of individual cases. 3 4 Confidential and Proprietary Copyright © Tabula Rasa HealthCare 2018 All rights reserved. May not be used without permission. 1 9/28/2018 Predictive Concepts Enzyme Principle • Most drug-drug interactions (DDIs) – upwards of 80% – involve • A drug is a substrate of a CYP450 enzyme if that particular enzyme Phase I metabolism conducted by the CYP450 system can transform the drug into a metabolite – Mechanism can be understood & DDIs can be predicted • A drug is an inducer of a CYP450 enzyme if it is able to increase the enzyme’s activity • Four major predictive concepts • Induction takes days to weeks (i.e., produce more enzyme) • An inhibitor decreases a CYP450 enzyme’s activity when it binds to Enzyme concept Affinity concept it • Inhibition occurs immediately (i.e., transform confirmation of enzyme) Bioavailability Multiple pathway All substrates are potential inhibitors concept concept BUT Tannenbaum C, et al. Expert Rev Clin Pharmacol. 2014;7:533-44.5 All inhibitors are not necessarily substrates 6 Zhou SF. Curr Drug Metab. 2008;9:310-22. Courtesy: National Human Genome ResearchTurgeon Institute. J. InterMED Available-Rx. Available at: https://www.genome.gov/12514471/ at http://ws-ddi.intermed-rx.ca/ Enzyme Principle (cont.) Affinity Principle • Each active ingredient in a drug formulation is mapped and classified • Substrates show various degrees of affinity for CYP450 enzymes (i.e., substrates, inhibitors, and inducers) – See next slide for examples – Substrates – Phase I metabolism vs. NonP450 metabolism • Included in this mapping is the % metabolized by CYP450 enzyme(s) • Substrates with greater affinities will cause competitive inhibition – Metabolic Pathway Capacity (MPC) – usually set at >30% (i.e., bioequivalence) of the metabolism of other substrates with lower affinities (same enzyme) when administered at or around the same time of day • Active drugs can result in toxicity • Non-active drugs (pro-drugs) can result in ineffectiveness © 2018 TRHC, Inc. All Rights Reserved www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances 7 8 https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf Confidential and Proprietary Copyright © Tabula Rasa HealthCare 2018 All rights reserved. May not be used without permission. 2 9/28/2018 Affinity Principle (cont.) Affinity Principle (cont.) Degrees of Affinity Degrees of Affinity • Drug with the highest affinity wins over drug(s) with lower affinity – Higher affinity substrate: causes the interaction (i.e., “perpetrator”) – Lower affinity substrate: suffers from the interaction (i.e., “victim”) • The magnitude of the interaction will be greater the more difference there is between substrate affinities • For drugs with the same affinity, the drug administered at the highest dose wins over the other substrate © 2018 TRHC, Inc. All Rights Reserved Strong Moderate Weak 9 10 © 2018 TRHC, Inc. All Rights Reserved Enzyme + Affinity Principles Affinity Principle (revisit.) Closer Look Timing of Administration • One way to mitigate this type of DDI is to administer the substrates Weak at different times of day Moderate – Chronopharmacology Strong • Administer the substrate with the lower affinity > 2-4 hours prior to the substrate with the higher affinity Competitive Inhibition – Substrate with the lower affinity can bind to the enzyme unoccupied by Can be modulated or reversed the higher affinity substrate & be metabolized – By the time peak plasma concentrations of the lower affinity substrate are Non-competitive Inhibition achieved, a significant amount of the drug has been absorbed Typically irreversible – Thus, the magnitude of the interaction will be significantly reduced 11 12 www.biogenediary.wordpress.com/2014/03/page/3/ Confidential and Proprietary Copyright © Tabula Rasa HealthCare 2018 All rights reserved. May not be used without permission. 3 9/28/2018 Affinity Principle (revisit.) Bioavailability Principle Timing of Administration Overview • Especially important for drugs with low bioavailability • Oral bioavailability (F) of a drug is defined as: – The proportion of drug (active ingredient) that reaches the systemic circulation • See next concept unchanged following its oral administration • This approach is also very favorable for pro-drugs • Low F • Clopidogrel – A lot of the drug is lost (extracted) • Some opioids – CYP2D6 opioids (e.g., codeine, tramadol) – Low F = High E (extraction ratio) • High first-pass metabolism • High F – Most of the drug is available – High F = Low E 13 • Intrinsic clearance is very small 14 https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf Bioavailability Principle (cont.) Bioavailability Principle (cont.) Overview Overview • Low F • High F – Inhibition of drug metabolism will lead to a rapid & extensive – Inhibition of drug metabolism will lead to a slow, insidious increase in steady-state (or average) concentrations increase in peak plasma concentrations (i.e., Cmax) – The extent of increase will depend on the relative contribution of the – The magnitude of increase can be estimated by the reciprocal of pathway being inhibited to the total clearance of the drug & can be the bioavailability (1/F) estimated as 100/(100-MPC) • MPC is Metabolic Pathway Capacity – Examples – Examples F = 5% (1/0.05) = 20-fold increase in Cmax F = 70% F = 30% (1/0.30) = 3-fold increase in Cmax Pathway = 30% (100/100-30) = 1.43-fold increase in Css or Cavg F = 85% Pathway = 80% (100/100-80) = 5-fold increase in Css or Cavg 15 16 https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf Confidential and Proprietary Copyright © Tabula Rasa HealthCare 2018 All rights reserved. May not be used without permission. 4 9/28/2018 For ORAL drugs For ORAL drugs Bioavailability Principle (cont.) Bioavailability Principle (cont.) • F = ER • F = ER What happens when a drug has a bioavailability • High F = > 70% • High F = > 70% that is ‘in between’ low F and high F? • Cavg = 100/(100-MPC) • Cavg = 100/(100-MPC) Use both equations to estimate the magnitude • F = ER • F = ER of increase in concentrations • Low F = < 30% • Low F = < 30% • Cmax = 1/F • Cmax = 1/F May result in a range (e.g., 1.5- to 2-fold increase) • Drug interactions https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf 17 18 www.cyprotex.com • Genetic variants Multiple Pathway Principle Multiple Pathway Principle 20 Confidential and Proprietary Copyright © Tabula Rasa HealthCare 2018 All rights reserved. May not be used without permission. 5 9/28/2018 Multiple Pathway Principle • Drugs metabolized by a single enzyme – Likelihood of DDIs is decreased, but – Extent, when it occurs, can be much greater Competitive Inhibition • Drugs metabolized by multiple enzymes – Likelihood of DDIs is increased, but Examples – Clinical significance may be lower Rule of thumb: If the metabolic pathway contributes <30% to the overall clearance of a drug, blocking of this pathway will cause only minor increases in plasma levels of the drug substrate 21 22 https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf Clopidogrel Competitive Inhibition Clopidogrel Metabolism Clopidogrel + PPI Medication F% CYP2C19 CYP3A4 Clopidogrel 1 10%* 5%* 15% 2C19 Omeprazole 35 65% 35% Clopidogrel Omeprazole (inactive) 1A2 2B6 Inactive * = Pro-drug or drug that is converted to a more active metabolite 3A4 Metabolite 2-oxo-clopidogrel CES1 (inactive) Hepatocyte 2C9 3A5 2C19 Clopidogrel 2B6 2C19 (inactive) Inactive metabolite 2-oxo-clopidogrel Active metabolite 85% (inactive) 2C19 Elimination P2RY12 Platelet inhibition Active metabolite Increased Clots 23 24 Whirl-Carillo M. Clin Pharmacol Ther 2012;92:414-17. Confidential and Proprietary Copyright © Tabula Rasa HealthCare 2018 All rights reserved. May not be used without permission. 6 9/28/2018 Citalopram Metabolism However, genotype-based dosing Citalopram Dosing guidelines are only available for Label Information CYP2C19 S-Citalopram CYP2C19 S-desmethylcitalopram CYP3A4 R-desmethylcitalopram Highlights information about usage of drugs CYP2D6 R-Citalopram that inhibit CYP2D6 CYP2D6 Hepatocyte Maximum dose of 20 mg/day in those who are CYP2C19 PM R/S- Citalopram- R/S-didesmethylcitalopram Medication CYP1A2