competitive inhibition and pgx - tabula rasa healthcare

Medication Risk Identification and Mitigation 12019 (NASDAQ: TRHC)Proprietary and Confidential -- © 2019 Tabula Rasa HealthCare, Inc.

Competitive Inhibition and PGx:Managing Accumulative, Multi-Drug Interactions

Veronique Michaud, BPharm, PhDCOO, TRHC Precision Pharmacotherapy R&D Institute

Associate Professor, Université de Montréal

Jacques Turgeon, BPharm, PhD,Chief Scientific Officer, TRHC

Professor Emeritus, Université de MontréalFellow, Canadian Academy of Health Sciences

Fellow, Académie nationale de médecine, France2019 (NASDAQ: TRHC)Proprietary and Confidential -- © 2019 Tabula Rasa HealthCare, Inc.


We were co-founders of InterMed-Rx which was licensed to Tabula Rasa HealthCare in 2013.

InterMed-Rx was acquired by Tabula Rasa HealthCare in September 2016. We hold shares in TRHC.

InterMed-Rx was incorporated into the TRHC’s MedWise software enhancing the basic Pharmacodynamics (ACB/Sedative) of the TRHC model.

Disclosure


• Recount milestones in competitive inhibition research.

• 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 inhibition.

• Describe how genetic variants may affect drug pharmacokinetics and pharmacodynamics for a series of drugs.

Session Objectives


• Recount milestones in competitive inhibition research.

• 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 inhibition.

• Describe how genetic variants may affect drug pharmacokinetics and pharmacodynamics for a series of drugs.

• Discuss drug-induced and disease-induced phenoconversion.

• Introduce the concept of repressor and reverse-repressor as it pertains to new biologics.

And also …


• Over the last 2-3 decades, transformative changes have been seen in the science and clinical practice of DDIs.

The approach to DDIs has changed since the 1990s.

• Big Pharmas do no longer routinely conduct box-checking clinical DDI studies with narrow therapeutic drugs or with drugs expected to be frequently coadministered.

Leaving all potential DDIs to postmarking reports and hoping them to be not serious.

• DDI assessment is now embedded into a multidimensional optimization approach

Molecular determinants of drug clearance (enzymatic systems, transporters)

Foundational mathematical frameworks for in vitro-in vivo extrapolation and PKPD modeling.

Transformative Changes in the Landscape of DDIs



• DDI studies are designed not to answer questions related to specific drug pairs that can be concomitantly administered. Instead, they are performed with well characterized probe substrates, inhibitors or inducers of specific enzymes or transporters.

• Innovations in mechanistic assessment of ADME, PGx, PBPK modeling, understanding DME-mediated DDIs and enzyme-transporters interplay have enabled the emphasis from a descriptive to a predictive science of DDIs:

Health agencies (e.g. FDA, EMA, Japan) adopted a mechanism-informed quantitative translational approach to DDI risk assessment

Moved away from traditional/irrational DDI studies towards informed DDI studies based on in vitro studies combined with translational modeling and simulation.


Clinical Pharmacology & Therapeutics, Volume: 105, Issue: 6, Pages: 1345-1361, First published: 27 March 2019, DOI: (10.1002/cpt.1435)

Evaluation of DDIs



FDA Approves XENLETA (Lefamulin) Injection and Tablets for the Treatment of Adults with Community-Acquired Bacterial Pneumonia (CABP)

Drug Interactions

• Strong and Moderate CYP3A Inducers or P-gp Inducers: Avoid concomitant use of XENLETA Injection and XENLETA Tablets with strong and moderate CYP3A4 inducers or P-gp inducers unless the benefit outweighs the risks. Concomitant use of XENLETA Injection or XENLETA Tablets with strong CYP3A4 inducers or P-gp inducers decreases lefamulin AUC and Cmax, which may reduce the efficacy of XENLETA.

• Strong and Moderate CYP3A Inhibitors or P-gp Inhibitors: Avoid concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gpinhibitors. Monitor for adverse effects of XENLETA Tablets when administered concomitantly with moderate CYP3A inhibitors or P-gpinhibitors. Concomitant use of XENLETA Tablets with strong CYP3A inhibitors or P-gp inhibitors increases lefamulin AUC, which may increase the risk of adverse reactions with XENLETA Tablets.

• CYP3A4 Substrates: Concomitant use with CYP3A substrates known to prolong the QT interval is contraindicated. Concomitant use of sensitive CYP3A substrates with XENLETA Tablets requires close monitoring for adverse effects of these drugs. Concomitant use of XENLETA Tablets with sensitive CYP3A4 substrates increases the AUC and Cmax of CYP3A4 substrates, which may increase the risk of toxicities associated with cardiac conduction. Concomitant use of XENLETA Injection with CYP3A4 substrates does not affect the exposure of CYP3A4 substrates.

• Drugs that Prolong QT: Avoid concomitant use of XENLETA Injection and XENLETA Tablets with other drugs that effect cardiac conduction (for example, Class IA and III antiarrhythmics, antipsychotics, erythromycin, moxifloxacin, tricyclic antidepressants). XENLETA has the potential to prolong the QT interval of the electrocardiogram (ECG) in some patients. The PD interaction potential to prolong the QT interval between XENLETA and other drugs that effect cardiac conduction is unknown.

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• With an increasing prevalence of multi-morbidities and polypharmacy in elderly people, it is anticipated that DDIs would occur at an higher frequency:

Clinicians need to understand mechanisms underlying DDIs when facing with complex multi-drug regimens to perform a proper risk assessment of drug-related adverse events.

• Transporter-mediated DDIs represent major challenges.

• Complex and large molecules (e.g. biologics):

Underlying mechanisms of DDIs with biologics are not straightforward (linked to their mechanism of action or modulation of the disease pathophysiology).

Can produce complex effects on the immune system leading to cytokine modulation/or release.

• Many harmful DDIs are based on alterations of plasma concentrations of a victim drug due to another drug causing inhibition, competitive inhibition and/or induction of the metabolism or transporter-mediated disposition of the victim drug.

Knowledge Gaps and Barriers


Basic Concepts in Enzymatic Processes: Definition

SUBSTRATE : molecule that demonstrates affinity for a protein. This protein iscapable of transforming this molecule by a chemical reaction. Inlay terms, a drug is the substrate of an enzyme if that particularenzyme is able to convert it into a metabolite.



INHIBITOR : compound that binds to CYPP450 isoforms but that bindingresults in a decreased activity of the enzyme. Inhibitors maybind at the enzymatic site and thus prevent the binding andtransformation of a substrate (competitive inhibition).



INHIBITOR : However, inhibitors can also bind to sites other than theenzymatic site, and lead to a change in conformation (structure)of the protein; this is called inhibition at an allosteric site. Thisinhibition is non-competitive since the substrate could haveaccess to its enzymatic site but the protein is not functionalsince distorted.



INDUCER : molecule that is capable of increasing the activity of the enzyme.Generally, the inducer increases the synthesis (i.e. the amount) ofenzymes present thereby increasing the total activity.


Basic Concepts in Enzymatic Processes

CLint = Vmax / Km

Substrate concentration

Velo

city

of m

eta

bolit

efo

rmation

Metabolite(s)



CLint = Vmax / Km


The CYP450 system:To understand, manage and predict drug interactions

Substrate

Metabolite

Several DDIs are due to Impaired Drug Disposition


17 publications on the characterization of mexiletine

metabolismCYP1A2

CYP2D6

CYP450 Superfamily: in 1987, 7 Isoforms. J Turgeon PhD Thesis


CYP2D6 Involvement in the Metabolism of Na+ Channel Blockers


Clin Pharmacol Ther 2000;67:44-57

How to take advantage of

phenoconversion.

CYP2D6 and CYP1A2: Mexiletine and Propafenone


For 3A4 inhibitionCave = 100 / (100 – 50)Cave = 2

For CYP2C9 inhibitionCave = 100 / (100 – 5)Cave = 1.053

The CYP450 Superfamily: Metabolic Pathways (1995-20…)

5%

10%50%

35%


F = 80%

Time

Log P

lasm

a C

oncentr

ation

0.1

0.01

1

10A small increase in the Cmax is to be expected on first dose.

Clinical Decision Support System: The Matrix


• The strategy is to avoid having two substrates of the same isoenzyme being present at high concentrations in the liver/intestine at the same time.

• Give the substrate with the lowest affinity first.

• Determine the Tmax of the substrate with the lowest affinity.

• Give the substrate with the highest affinity with a delay equal or greater than the Tmax of the low affinity substrate.

Clinical Decision Support System: Time of Dosing


AM J Geriatrics PharmacotherVol 9(6), 2011:461-470

Clinical Decision Support System: Clinical Application


Clinical Decision Support Systems


•The Innovative CDSS opened the door for translational researches in Pharmacogenomics.

•Possibility to analyze:

Drug-Drug Interactions,

Multi-Drug Interactions,

Drug-Gene Interactions,

Drug-Drug-Gene Interactions (Phenoconversion)

•Machine learning

Complex algorithms

Behavioral analyses

The Value of Innovative Clinical Decision Support System


Drug-induced Phenoconversion

The use of an advanced clinical decision support systems supported by complex algorithms (artificial intelligence) is mandatory to help clinicians make the appropriate decision.

Some strategies could be developed to prevent phenoconversion, when associated with competitive inhibition.

Pharmacogenomics and Disease state are another conditions to consider.


Intersubject Variability in Drug Response: PGx as a Causal Factor

Figure adapted from R. BR. Leon-Cachon 2015 & Simonosky 2019

drugs disease

food Etc…

Drug effectiveness


Pharmacogenetics: Translating a Genotype to a Phenotype

Genotype Phenotype Activity

2 increased function alleles Duplication of functional alleles (*N)

Ultra-Rapid Metabolizer (gUM)

Increased

1 normal + 1 increased function allele2 normal (wild-type) function alleles

1 increased + 1 decreased allele

Normal Metabolizer (gNM)Extensive Metabolizer

(gEM)

Normal(reference)

1 normal + 1 decreased function allele1 normal function allele + 1 null allele

Intermediate Metabolizer (gIM)

Decreased

2 decreased function alleles 2 null alleles

Gene deletionPoor Metabolizer (gPM)

Little to none

*This classification varies based to the gene


CYP450GCCGCCTC

GCCTCCTC CYP450

Wild-type (ref. as normal expression/activity)

Genetic polymorphism(e.g. altered expression/activity)

Wild-type genotype

Poor metabolizer genotype

X

Pharmacogenetics: Translating a Genotype to Concentrations


Wild-type genotype

Wild-type genotype

Wild-type genotype

Adapted from DelRe et al. 2017

Intragenotype Variation due to Phenoconversion


Wild-type genotype

Wild-type genotype

Wild-type genotype

Predicting a patient’s phenotype from his/her genotype is highly complex and not always reliable

Adapted from DelRe et al. 2017

Intragenotype Variation due to Phenoconversion


Addressing Phenoconversion

• Mismatch genotype-phenotype

Intragenotype differences observed in clinical responses/outcomes

• Phenoconversion usually results from nongenetic extrinsic factors:

Comedications

o As genetically inherited variant traits give rise to DMEs of altered activity, administration of certain drugs can inhibit a DME, mimicking the genetic defect and producing a PM phenocopy or induce the DME converting to an EM or UM phenocopy.

Disease states

Significant impact on the analysis and interpretation of genotype-focused clinical outcome in routine clinical practice

• There is no standardized process by which to translate a genotype into a phenotype assignment.


Intragenotype variation due Drug-Drug Interactions Leading to Phenoconversion

DelRe et al. Cancer Treatment Rev 2017


Pharmacogenomics by TRHC

Sample work flow


Disease-induced Phenoconversion

Figure adapted from R. BR. Leon-Cachon 2015 & Simonosky 2019

drugs diseasefood Etc…

Drug effectiveness


Clinical Evidence of Disease-induced Phenoconversion


Adapted from Zanger et al. Pharmacol&Ther 2013

Theoretical Correlation between Disease-mediated Alterations in Drug Metabolizing Enzymes and Drug Levels

Disease


CYP450s and Inflammatory Cytokines

• CYP450s metabolize a plethora of xenobiotics and are involved in many physiological functions.

• Evidences exist relating the modulatory role of inflammatory mediators on CYP450 activities.

• Infection and inflammation are closely related to hepatic and extrahepatic metabolism by CYP450s.

• Recent knowledge brought light to the impact of inflammatory mediators on the expression of CYP450 enzymes in animal models.


Evidence Suggestive for Inflammatory Cytokines Suppressing CYP450 Activities

Shah and Smith. DMD 2015


Pavek Front Pharmacol 2016

REPRESSOR : inflammatory conditions or drugs associated with a downregulation of CYP450 expression.This mechanism requires time.

CYP3A4

PXR activator PXR repressor

Rifampin IL-6, LPS, TNFα

Evidence Suggestive for Inflammatory Cytokines Suppressing CYP450 Activities


Can T2D Induce CYP450 Phenoconversion?Clinical Evidence: Clopidogrel

• Patients with T2D show highly variable responses to different drugs;

In addition to antidiabetic drugs, the prevention of micro- and macro-vascular complications in T2D generally requires multiple treatments.

Some patients are resistant to certain drugs while others are more sensitive to other drugs.

• Patients with T2D and treated with Clopidogrel have higher number of non-responders and less inhibition of platelet function than non-T2D patients.

Residual platelet reactivity after CLO 600mg loading dose

OPTIMUS study: 60% of T2D patients remained

poor respondersGeisler et al. Diabetes Care 2007

Angiolillo et al. Diabetes 2005Angiolillo et al. JACC 2007



Clopidogrel is a prodrug that requires CYP2C19

activity for transformation into its

active metabolite



• PD assessments revealed that patients with diabetes have ~ 40% less exposure to Clopidogrel’s active metabolite than patients without diabetes.

Poor responsiveness to Clopidogrel in diabetic

patients could be due to insufficient generation

of the active metabolite through CYP2C19.

Angiolillo et al. JACC 2014


Can T2D Induce CYP450 Phenoconversion?Clinical Study (NTC02291666)



ClinPharmacolTher2019

1.8-fold

1.9-fold

1.6-fold

*adjusted p-value for age and gender

Metabolic ratios of CYP450 probes



ClinPharmacolTher2019

Inflammatory markers, T2D and CYP450 activities


• IL-6 plays a central role in the immunopathogenesis of RA.

• Patients with active RA exhibit high levels of IL-6.

• Elevated IL-6 levels as observed in patients with RA have been shown to modulate CYP450 activities:

Studies using animal rat model of RA showed a decrease of gene expression, hepatic and intestinal activities of CYP450s during the development of induced arthritis.

PK and bioavailability of drugs may be altered in rheumatic diseases.

Rheumatoid Arthritis


• Disease modifying agents (Biologics) have considerably changed the management of RA.

Often combined with conventional drugs.

• Despite the efficacy and safety profile of biologics (e.g. monoclonal antibody of IL-6 receptor), information on biologics-drug interactions is limited.

• Up-regulation of IL-6 reduces the activity of CYP450 activities, then blocking this cytokine could reverse IL-6 induced reduction of CYP450 expression/activities.

Mallick et al. ExpOpinDrugMetabolToxicol 2017

Rheumatoid Arthritis & Biologics


Single dose of SIM 40mg to patients with RA at baseline and one week after a single SC dose of sarilumab 200mg (n=17)

Single dose of SIM 40mg to patients with RA at baseline, and one week and 5 weeks after a single SC dose of tolicizumab (injected on day 8) (n=12)

AUC reduced by 54%

AUC reduced by 57%

Bong Lee et al. Clin Pharmacokinet 2017 Schmitt et al. Clin Pharmacol Ther 2011

Could Anti-IL-6 Therapy Reverse the Downregulation of CYP450 Activity Mediated by IL-6?


• Concomitant oral dosing of 4-probe drugs was used:

CYP3A (MDZ), CYP2C19 (OME), CYP2C9 (warfarin) and CYP1A2 (caffeine).

No CYP2D6 probe was included : inhibition of the IL-6 signaling pathway did not seem to

impact CYP2D6 activity in vivo. (Xang et al. Clin Pharmacol 2009)

Zhuang et al. J Clin Pharmacol 2015


AUC x30-35%

X37-45%

X18-20%

x20-34%

Zhuang et al. J Clin Pharmacol 2015

Could Anti-IL-6 Therapy Reverse the Downregulation of CYP450 Activity Mediated by IL-6 in an Isoform-dependent Manner?


Morgan. Clin Pharmacol Ther 2009EvaluatePharma. Worldwide review 2014

• Biologics are immunomodulators including immunosupressor and immunostimulator agents: the impact of biologic treatment on drug

metabolism will be dependent on the pro- or anti-inflammatory properties of the biologics.

• Within the top 100 prescription products in 2020, biological products expected to account for more than 50% of sales.

Rheumatoid Arthritis : May Biologics Reverse Phenoconversion?


Morgan. Clin Pharmacol Ther 2009

Reverse-REPRESSOR:molecule capable to restore/reverse cytokine-mediated suppression of DMEs and transporters.The magnitude of reversion is variable and it requires time.

Rheumatoid Arthritis : May Biologics Reverse Phenoconversion?


• The use of advanced Clinical Decision Support Systems is of great value for the establishment of personalized, more precise and improved drug regimen.

• Pharmacogenetic results accurately predict phenotype in healthy subjects taking no medications. Correspondence in homozygous with variant alleles.

• Polypharmacy is clearly associated with risk of phenoconversion

Time of administration Order of administration

• Inflammatory diseases can modulate drug disposition e.g. T2D and RA Biologics may restore partially CYP450 activities. Biologic-drug-disease interactions could impact the safety and effectiveness of concomitant

drug regimen.

• Magnitude of these effects is also influenced by the PK properties of the drug.

Conclusion


Thank you

competitive inhibition and pgx - tabula rasa healthcare

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