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Ozanimod Pharmacodynamics

 
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Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

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Ozanimod Pharmacodynamics in IBD

Primary Disease-Specific Mechanisms

Intestinal Immune Cell Regulation

  1. Lymphocyte Sequestration

    • Reduces infiltration of autoreactive lymphocytes into intestinal tissue

    • Decreases T cell populations in gut-associated lymphoid tissue (GALT)

    • Lowers circulating memory T cells that target intestinal antigens

  2. Local Inflammatory Response

    • Decreases mucosal T cell populations

    • Reduces pro-inflammatory cytokine production:

      • TNF-α, IL-1β, IL-6, IL-23

Barrier Function Enhancement

  1. Epithelial Integrity

    • Strengthens tight junctions between intestinal epithelial cells

    • Reduces barrier permeability

    • Enhances mucosal healing

  2. Vascular Effects

    • Decreases endothelial activation

    • Reduces leukocyte adhesion and trafficking

    • Improves intestinal microcirculation

Disease-Specific Biomarkers

Inflammatory Markers

  1. Systemic Markers

    • Fecal calprotectin reduction

    • C-reactive protein (CRP) normalization

    • Serum cytokine profile improvement

  2. Tissue-Specific Changes

    • Decreased mucosal inflammatory infiltrates

    • Reduced tissue expression of adhesion molecules

    • Lower levels of matrix metalloproteinases

Clinical Response Parameters

  1. Early Response Indicators

    • Reduction in stool frequency

    • Decreased rectal bleeding

    • Improvement in abdominal pain

  2. Long-term Effects

    • Mucosal healing

    • Histological improvement

    • Reduced fibrosis development

    • IBD-Specific Pharmacodynamic Timeline

    • Initial Response Phase (0-8 weeks)

    • Lymphocyte count reduction begins within days

    • Symptomatic improvement typically by week 2-4

    • Initial mucosal changes observable by week 8

Maintenance Phase

  • Sustained reduction in inflammatory markers

  • Progressive improvement in mucosal healing

  • Stabilization of clinical parameters

Special Considerations in IBD

Disease Phenotype Effects

  1. Ulcerative Colitis

    • More rapid response in moderate disease

    • Higher efficacy in left-sided colitis

    • Variable response in pancreatic involvement

  2. Crohn's Disease

    • Better response in inflammatory phenotype

    • Variable efficacy in stricturing disease

    • Limited effect on fistulizing disease

Concomitant Therapy Interactions

  1. Combination with Standard IBD Treatments

    • Safe with aminosalicylates

    • Potential synergy with corticosteroids

    • Caution with other immunomodulators

  2. Impact on IBD-related Procedures

    • Endoscopy timing considerations

    • Surgery planning implications

    • Vaccination scheduling

Ozanimod Pharmacokinetics

 
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Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Absorption Parameters

Oral Bioavailability

  • Absolute bioavailability: ~84%

  • Time to peak concentration (Tmax): 6-8 hours

  • Food effect: Minimal (~14% decrease with high-fat meals)

  • Site of absorption: Throughout GI tract

IBD-Specific Considerations

  1. Disease Location Impact

    • Small bowel involvement: Minimal effect on absorption

    • Colonic disease: No significant impact

    • Absorption remains consistent regardless of disease activity

  2. Local Factors

    • pH changes: Limited impact due to pH-independent absorption

    • Transit time variations: Minimal effect on bioavailability

    • Mucosal inflammation: No significant impact on absorption

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Distribution

Volume of Distribution

  • Vd: Approximately 48L

  • Protein binding: ~98.2%

  • Tissue distribution: Extensive

IBD-Related Distribution Factors

  1. Inflammatory State Effects

    • Alpha-1 acid glycoprotein changes: Minimal impact

    • Albumin variations: Limited effect on free drug

    • Distribution to inflamed tissue: Enhanced

  2. Tissue Concentrations

    • Intestinal tissue levels: 2-3x plasma concentration

    • Lymphoid tissue: High accumulation

    • Inflamed mucosa: Increased local concentrations

Metabolism

Primary Metabolic Pathways

  1. Phase I Metabolism

    • CYP3A4: Major pathway

    • Formation of active metabolites:

      • CC112273 (major active metabolite)

      • CC1084037 (minor active metabolite)

  1. Metabolite Properties

    • CC112273:

      • Similar potency to parent

      • Longer half-life (11 days)

CC1084037:

  • Active at S1P receptors

  • Contributes to overall effect

IBD Impact on Metabolism

  1. Disease State Effects

    • Inflammatory cytokine impact on CYP3A4: Minimal

    • Hepatic function in IBD: Generally preserved

    • No dose adjustment needed based on disease activity

  2. Drug-Drug Interactions

    • Common IBD medications:

      • Aminosalicylates: No interaction

      • Corticosteroids: No significant effect

      • Antibiotics: Monitor for CYP3A4 interactions

Elimination

Elimination Parameters

  • Terminal half-life: ~21 hours (parent compound)

  • Active metabolite half-life: ~11 days

  • Primary route: Hepatic metabolism and biliary excretion

  • Renal excretion: <1% unchanged

Time to Steady State

  • Parent compound: ~7 days

  • Active metabolite: ~3 weeks

  • Accumulation ratio: ~2

Ozanimod Pivotal Studies

Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Ulcerative Colitis

  1. TRUE NORTH Trial (2021)

    • Phase 3, randomized, double-blind, placebo-controlled trial

    • Published by Sandborn et al. in the New England Journal of Medicine

    • Included 645 patients in the induction phase and 457 in the maintenance phase

    • Key results:

      • Clinical remission at week 10: 18.4% (ozanimod) vs. 6.0% (placebo), p<0.001

      • Clinical remission at week 52: 37.0% (ozanimod) vs. 18.5% (placebo), p<0.001

      • Endoscopic improvement at week 10: 39.5% vs. 13.8%, p<0.001

      • Established ozanimod's efficacy for FDA and EMA approval in UC

  2. TOUCHSTONE Trial (2016)

    • Phase 2, randomized, double-blind, placebo-controlled trial

    • Published by Sandborn et al. in the New England Journal of Medicine

    • Included 197 patients with moderate-to-severe UC

    • Evaluated two doses (0.5 mg and 1 mg) against placebo

    • Key results:

      • Clinical remission at week 8: 16% (1 mg) vs. 6% (placebo), p=0.048

      • Clinical remission at week 32: 21% (1 mg) vs. 6% (placebo), p=0.01

      • First proof-of-concept study showing efficacy of S1P receptor modulation in UC

Ulcerative Colitis​

  1. TOUCHSTONE Open-Label Extension (2022)

    • Long-term extension of the phase 2 TOUCHSTONE trial

    • Published by Danese et al. in Alimentary Pharmacology & Therapeutics

    • 3-year follow-up data on safety and efficacy

    • Key findings:

      • Sustained efficacy with long-term treatment

      • No new safety signals identified

      • Demonstrated durability of response

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Crohn's Disease

  1. STEPSTONE Trial (2022)

    • Phase 2, open-label, multicenter trial

    • Published by Feagan et al. in Journal of Crohn's and Colitis

    • Included 69 patients with moderate-to-severe Crohn's disease

    • Primary endpoint: change in Simple Endoscopic Score for CD (SES-CD)

    • Key results:

      • 50% reduction in SES-CD at week 12: 23.2%

      • Clinical remission at week 12: 56.5%

      • Established proof-of-concept for efficacy in CD

      • Supported progression to phase 3 trials

  2. Ongoing Phase 3 Trials in Crohn's Disease

    • YELLOWSTONE Program:

      • YELLOWSTONE 1 and 2: Identical phase 3, randomized, double-blind, placebo-controlled trials

      • Currently ongoing, results expected 2024-2025

      • Primary endpoints: CR-100 response at week 12, clinical remission at week 52

      • Will form the basis for potential regulatory approval in CD

Ozanimod Adverse effects and Monitoring

 
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Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

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Most Common (>5%):

  • Upper respiratory infections (10-13%)

  • Hepatic transaminase elevation (8-10%)

  • Orthostatic hypotension (7%)

  • Headache (5-7%)

  • Urinary tract infections (4-6%)

Cardiovascular:

  • Initial heart rate reduction (first dose)

  • Mild bradycardia

  • AV conduction delays (rare)

  • BP changes (usually mild)

  • First-dose monitoring only needed for high-risk patients

Hepatic:

  • ALT/AST elevations (typically mild)

  • Usually reversible

  • Monitoring recommended

  • Discontinue if severe elevation

Infections:

  • Herpes viral infections

  • Upper respiratory tract infections

  • Risk of opportunistic infections

  • PML risk (theoretical, no cases reported)

  • VZV reactivation risk

Laboratory Abnormalities:

  • Lymphocyte reduction (40-50% decrease)

  • Recovers 4-8 weeks after discontinuation

  • Neutropenia (rare)

  • Liver enzyme elevations

Ophthalmologic:

  • Macular edema risk (especially in diabetes)

  • Baseline eye exam recommended

  • Monitor symptoms

Respiratory:

  • Mild decline in FEV1/FVC

  • Usually not clinically significant

  • Monitor in respiratory disease

Contraindications:

  • Recent MI or stroke

  • Severe untreated sleep apnea

  • Class III/IV heart failure

  • High-grade heart block

  • Active serious infections

Required Monitoring:

Baseline:

  • ECG

  • LFTs

  • CBC with lymphocytes

  • Ophthalmic exam

  • VZV status

Ongoing:

  • LFTs

  • FBC

  • Blood pressure

  • New neurological symptoms

  • Infection signs

Population-specific considerations:

  • Pregnancy: Contraindicated

  • Elderly: No dose adjustment

  • Liver disease: Caution in severe impairment

  • Diabetes: Enhanced macular edema monitoring

Ozanimod Drug Interactions

 
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Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Key Drug Interactions:

Strong CYP3A4/BCRP Inhibitors:

  • Ketoconazole, itraconazole

  • Clarithromycin

  • HIV protease inhibitors

  • Effect: ↑ ozanimod exposure

  • Management: Avoid combination

Strong CYP3A4 Inducers:

  • Rifampin

  • Carbamazepine

  • St. John's Wort

  • Effect: ↓ ozanimod exposure

  • Management: Avoid combination

Common IBD Medications:

  • Corticosteroids: Safe combination

  • Aminosalicylates: No interaction

  • Thiopurines: Monitor lymphocytes

  • Anti-TNFs: Generally safe but monitor

  • Methotrexate: No significant interaction

MAO Inhibitors:

  • Contraindicated within 14 days

  • Risk of hypertensive crisis

  • Includes both MAO-A and MAO-B inhibitors

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Tyramine-containing Foods:

  • No dietary restrictions needed

  • Unlike older MAO inhibitors

Cardiac Active Drugs:

  • Beta blockers: Monitor HR

  • CCBs: Monitor HR/conduction

  • Class 1a/III antiarrhythmics: Avoid

  • QT-prolonging drugs: Use with caution

Vaccines:

  • Live vaccines: Avoid during treatment

  • Inactivated vaccines: May have reduced response

  • Plan vaccinations before initiation

Special Considerations:

Timing-Related:

  • Stop for 7 days before starting interacting drugs

  • Restart with dose titration after discontinuation

Ozanimod Use in Pregnancy

Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Key Points About Ozanimod in Pregnancy:

Pregnancy Category

  • Not formally categorized (post-FDA pregnancy categories)

  • Contraindicated during pregnancy

  • Requires contraception during use

Current Recommendations:

  • Avoid pregnancy during treatment

  • Contraception required during therapy

  • Continue contraception 3 months after last dose

  • Pregnancy test before initiation

  • Regular pregnancy testing during treatment

Risks:

  • Developmental toxicity in animal studies

  • Increased risk of fetal malformations

  • Potential for:

    • Cardiovascular defects

    • Skeletal abnormalities

    • Embryolethality (animal data)

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Management Guidelines:

  • Discontinue if pregnancy occurs

  • Notify healthcare provider immediately

  • Consider pregnancy registry enrollment

  • Document exposure details

  • Enhanced fetal monitoring if exposed

Preconception Planning:

  • Stop 3 months before planned pregnancy

  • Consider alternative IBD treatments

  • Monitor disease activity closely

  • Plan for pregnancy during remission

IBD-Specific Considerations:

  • Balance maternal disease control

  • Risk of IBD flare upon discontinuation

  • Alternative treatment options:

    • Biologics with better pregnancy data

    • Established safety profiles

    • Disease activity monitoring

Breastfeeding:

  • Not recommended during treatment

  • Unknown excretion in breast milk

  • Potential risks to infant

  • Consider alternative treatments

Ozanimod General References

 
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Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

PRIMARY PUBLICATIONS

TRUE NORTH Trial:

  • Sandborn WJ, Feagan BG, D'Haens G, et al. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2021;385(14):1280-1291. doi:10.1056/NEJMoa2033617

TOUCHSTONE Trial:

  • Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med. 2016;374(18):1754-1762. doi:10.1056/NEJMoa1513248

REVIEWS/META-ANALYSES

Mechanism/Pathway:

  • Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759-777. doi:10.1002/ana.22426

  • Pérez-Jeldres T, Tyler CJ, Boyer JD, et al. Cell Trafficking and Adhesion Molecules as Therapeutic Targets in Inflammatory Bowel Disease. J Crohns Colitis. 2019;13(11):1359-1373. doi:10.1093/ecco-jcc/jjz056

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Safety Reviews:

  • Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778-1792. doi:10.1111/bph.13476

Clinical Placement:

  • Feagan BG, Sandborn WJ, Danese S, et al. Ozanimod treatment for ulcerative colitis. Expert Opin Pharmacother. 2020;21(14):1681-1690. doi:10.1080/14656566.2020.1785429

  • D'Amico F, Fiorino G, Furfaro F, et al. Positioning Ozanimod in Moderate-to-Severe Ulcerative Colitis. Expert Rev Clin Immunol. 2022;18(1):1-12. doi:10.1080/1744666X.2022.2028476

CONFERENCE ABSTRACTS/SUPPLEMENTS

DDW 2022:

  • Feagan BG, et al. Long-term Efficacy and Safety of Ozanimod in Moderate to Severe Ulcerative Colitis: Results from the Open-Label Extension of the True North Study. Gastroenterology. 2022;162(7):S-591

ECCO 2023:

  • Danese S, et al. Clinical and Endoscopic Outcomes with Ozanimod in Bio-naïve versus Bio-experienced Patients with Moderately to Severely Active Ulcerative Colitis. J Crohns Colitis. 2023;17(Supplement_1):i054-i055

EMERGING CROHN'S DATA

YELLOWSTONE Program:

  • Protocol published on clinicaltrials.gov (NCT03440385)

  • Preliminary results presented at DDW 2023 (abstracts pending full publication)

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