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• 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.
• 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.
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.
• 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.
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.
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.
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.
• 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.
• 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.
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.