proposing a new indication for sporanox tm - in the treatment of cancer

Certificate in Clinical Pharmacology and SafetyAssessmentsPresented by: Carolina Hung HoResearch Director: Professor Peivand PirouziMay 05, 2016

Proposed New Indication forSporanox® in the Treatmentof Cancer

Outline Introduction

PharmacokineticsAbsorptionDistributionMetabolism Elimination

PharmacodynamicsCYP-450-dependent Inhibition

of Ergosterol SynthesisDrug and Drug InteractionsDrug and Food InteractionsAdverse Drug Reactions

Pharmacogenomics

Special Population

Proposed New Indication: Anti-Cancer Properties Proposed Mechanisms forAnti-cancer activityCyclodextrinsChallenges

Conclusions

Question Session

Introduction Itraconazole (ITZ) is used to treat many fungal

infections.

Invented in 1984.

Marketed under several brand names.

Janssen Pharmaceutica: Sporanox®

Available as a 100 mg capsule and 10 mg/mLoral suspension

Prescription only

IV form is not available in the USA or CAD.

DIN: 02047454(Canada, 1993)

DIN: 02231347(Canada, 1997)

Chemical Information Proper name: ItraconazoleA synthetic triazole derivative

Chemical name:(±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

Structural formula:

Lipophilic molecule

pKa = 3.7

Log partition coefficient inoctanol/water =8.2

Figure 1: Chemical Structure of Itraconazole (Janssen, 2015)

Approved Indications SPORANOX® capsules (100 mg):

1. Invasive and non-invasive pulmonary aspergillosis.

2. Oral and/or esophageal candidiasis.

3. Chronic pulmonary histoplasmosis.

4. Cutaneous and lymphatic sporotrichosis.

5. Paracoccidioidomycosis.

6. Chromomycosis.

7. Blastomycosis.

8. Dermatomycosis

9. Onychomycosis.

Systemic fungalinfections

Topical fungalinfections

Approved Indications(Cont’d)

Systemic fungalinfections

Topical fungalinfections

Fig. 2.1: Photomicrographof Asperlligus fumigatus

Fig. 2.2: Photomicrographof Candida albicans

Fig. 2.3: Photomicrographof Dermatocomyses

Fig. 2.4: Onychomycosisaffects the nails

Approved Indications(Cont’d) SPORANOX® oral solution (10 mg/ mL):

1. Oral and/or esophageal candidiasis

• SPORANOX® is safe for use in normal, predisposed, orimmunocompromised adult patients (e.g. HIV-positive)

• SPORANOX® oral solution and SPORANOX® capsules should not beused interchangeably

• For use in special populations, see Special Populations

Pharmacokinetics

Absorption Oral bioavailability of SPORANOX® capsules is maximal

when taken immediately after a full meal. (Addedexcipient: sugar spheres)

Oral bioavailability of SPORANOX® oral solution is maximalwhen taken without food. (Added excipient:hydroxypropyl-β-cyclodextrin)

Table 1: Pharmacokinetic data on Itraconazole froma randomized, cross-over study on 7 healthy malesubjects following administration of an oral solutionPlasma clearance rate = 381 ± 95 mL/minVolume of distribution = 796 ± 185 LOral bioavailability = 33% - 55% (variable)

Pharmacokinetics

Absorption ITZ exposure is lower with the capsule formulation

than with the oral solution when the same dose ofdrug is given.

Gastric acidity = Absorption Can be caused by medications (e.g. H2 receptor

agonists and proton pump inhibitors) Can be caused by certain diseases (e.g.

achlorhydria) Non-diet Cola can help to absorb ITZ under fasted

conditions

Fig 3 Bioavailabilityof ITZ as capsuleand oralformulationamong 60 healthyvolunteers (Baroneet al. 1998)

Pharmacokinetics (Cont’d)

Distribution The plasma protein binding of ITZ is 99.8% and that

of hydroxy-ITZ is 99.5%

ITZ is extensively distributed into tissues which areprone to fungal infection: Lung Kidney Bones Stomach Spleen Muscle Skin Cskin is 5X higher than

Cplasma

Ctissues is 2X times than Cplasma


Metabolism Extensive metabolism by the liver

Major enzyme: CYP 3A4

Main metabolite: Hydroxy-itraconazole (OH-ITZ) Same antifungal effect efficacy maintained Present 3x higher in the tissues (HPLC) Shorter T1/2 of elimination

> 30 other metabolic pathways involved.


Hydroxylation – adding –OH

By CYP 3A4-body attempt to makecompound more polar forconjugation and subsequentelimination.


Elimination The feces (18% as active drug, 54% as inactive

metabolites ) Active transport in the bile Using oral radiolabelled dose to track its fate.

The urine (< 0.03% active drug, 35% as inactivemetabolites)


Fig. 5: The fate of Itraconazole in the humanbody.

Half-Life (T1/2) Elimination:

Single dose: 16 to 28hours

Multiple doses: 34 to 42hours

Cirrhotic (single dose): 37hours

Mode of Action

ITZ Inhibits P450 lanosterol 14-demethylase Enzyme responsible for

converting lanosterolergosterol

Ergosterol is needed for cellmembrane fluidity & stability.

Without ergosterol, cellmembrane is disrupted.

Fungi are unable to grow anddivide Fig 6: Structure of P450

lanosterol 14-demythalase(Podul et al.)

Mode of Action

Fig 7: Cell membrane and cell wall structure of a fungal cell

Drug-Drug Interactions ITZ (and its metabolites) are potent CYP 3A4 inhibitors By competing with other substrates for CYP 3A4 binding

sites in liver hepatocytes

ITZ is a potent P-glycoprotein (P-gp) inhibitor By competing with other substrates for P-g binding sites in

the liver, kidney, endothelium, and brain. Pg is responsible for active transport drugs back into the

gut lumen or into the bile.

RESULT: May alter Cp of other drugs or other drugs mayalter Cp of ITZ Prolonged therapeutic effects or overdose of these drugs Therefore, many drugs are contraindicated with

SPORANOX® a long list!

e.g. ITZ mayelevate morphineplasmaconcentrations,possibly byinhibiting P-gelimination ofmorphine into gutlumen

Drug Contraindications

Refer to Product Monograph for Itraconazole fora list of contraindicated medications

• CONTRAINDICATED (Table 1)• May increase risks of serious cardiovascular events

(e.g. QT prolongation, Torsade de pointes, bleeding,etc).

• NOT RECOMMENDED (Table 2)• If co-administration cannot be avoided, consider

monitoring signs, symptoms, plasma levels of ITZ, doseadjustment, etc.

• USE WITH CAUTION (Table 3)• Interaction is not well established.• Monitoring required• Special populations

Food-Drug Interactions Grapefruit juice is also a CYP 3A4

inhibitor

The culprit: furanocomarins

It may:1. May reduce or raise Cp of ITZ2.

Therefore, grapefruit juice is NOTrecommended when takingSPORANOX®

Fig. 8 Furanocomarinin Grapefruit juice

Adverse Reactions Rare and serious: Hepatotoxivity Acute liver

failure and death

Common ADRs: GI origin (dyspepsia, nausea,vomiting, diarrhea, abdominal pain, andconstipation).

Overdosage: No experience with overdosage If suspected, treated with activated charcoal. ITZ cannot be removed through hemodialysis

Other toxicity: Mutagenicity : NO Teratogenicity: NO

Pharmacodynamics In vitro studies (cultured cells):

[ITZ] = 4 x 10-7M 50% inhibition of cholesterol biosynthesis inhuman lymphocytes.

[ITZ] = 4 x 10-5M 50% inhibition of ergosterol in Candidaalbicans cells.

Point 1: ITZ is selectively toxic to fungal cells

Phase I (healthy volunteers):

100 mg ITZ o.d. for 1 month no difference in basal serumcholesterol levels between control and treatment groups.

50 - 400 mg ITZ o.d. for max. 2 years basal serumcholesterol were not significantly affected in 3 studies.

Point 2: Short and long-term exposure to ITZ does notsignificantly affect cholesterol levels in human

Note:Your Total Blood (orSerum) Cholesterol.Your total cholesterolscore is calculatedby the followingequation: HDL + LDL+ 20% of yourtriglyceride level. Atotal cholesterolscore of less than 180mg/dL is consideredoptimal.

Pharmacodynamics Phase I (healthy volunteers):

100 mg or 200 mg daily for 1 month no significant change in hormone levels: CNS (e.g. LH, FSH, prolactin) Reproductive organs (e.g. estrogen, testosterone) Adrenal gland (e.g. cortisol)

Point 3: ITZ does not cross BBB into cerebrospinal fluid. (cannot reachyour brain)

200 mg daily for 5 weeks no significant effect on the HR, BP, ECG-intervals inhealth volunteers

Point 4: ITZ does not affect the cardiovascular system

200 mg daily for 5 weeks no negative effect on immune functions. Values forOKT4 positive lymphocyte showed a significant shift from 42 ± 3.3% to 53 ±3.3%. This increase, as well as shifts in the other immunological parameters,remained within the normal ranges.

Point 5: ITZ does not affect immune system.

Pharmacodynamics

In summary:

Safe for human; does not affect cholesterol levels Does not adversely affect the brain, the heart or the immune

system directly. Exception: Rare cases of CHF. Precautions must be taken, however, when co-administered

with other medications and grapefruit juice.

But what about the kidney and the liver? See “Warnings and Precautions” See “Drug Interactions”

Special Population Geriatrics (> 65 years of age):

Use caution

Use only when potential benefit outweighs thepotential risks

Pediatrics (< 18 years of age):

The efficacy and safety of SPORANOX® have notyet been established.

Use caution

Special Population Pregnant Women and Lactating Mothers:

Should not be used if pregnant or planningpregnancy, except for life-threatening cases wherethe potential benefit to the mother outweighs thepotential harm to the fetus.

For women of childbearing age, SPORANOX®should not be prescribed unless effectivecontraception methods are used prior to the startof therapy.

Nursing Women:

Itraconazole is excreted in human milk; therefore,the patient should be advised to discontinuenursing while taking SPORANOX®.

Special Population Impaired renal function:

Limited data available. Exercise caution.

ITZ is mainly excreted through the feces, so BA isslightly increased if kidney function is impaired.

Impaired liver function:

Limited data available. Exercise caution

Cmax was reduced by 47% and resulted in atwofold increase in half-life (capsules).

ITZ is extensively metabolized by the liver, soimpaired liver function (e.g. cirrhosis, liver failure)elevate BA of other drugs overdose + toxicity

Pharmacodynamics(Cont’d) Efficacy & Safety

Large Vdist’n

Long T1/2

Main metabolite works just aswell as the parent drug

Precaution taken with: Concomitant medications Liver or kidney failure History of CHF Special populations

Fig. 9: Plasma concentrations ofItraconazole and its metabolite,hydroxyitraconazole.

Proposed New Indication forSporanox®

FungalInfections

Anti-CancerDrug

Current Indication: Proposed Indication:

Use as prophylacticagent and/or as part of

chemotherapy

Fights off infectionscaused by many fungal

species

Why Choose Sporanox® ?

Shown to have anti-neoplastic effects in vitro and invivo pre-clinical trials 2 Proposed Mechanisms

1 Block the angiogenesis pathway2 Block the Hedgehog signaling pathway

Types of cells studied: Basal cell carcinoma Non-small lung cancer cells Prostrate cancer cells Breast cancer cells

Long and well established safety profile

An affordable and accessible generic drug

Why Choose Sporanox® ?

Phase II Trial:A Randomized Phase II Clinical Trial of Two Dose-levels ofItraconazole in Patients With Metastatic Castration-resistantProstate Cancer

Identifier: NCT00887458

Sponsor: Johns Hopkins University

Collaborator: Memorial Sloan Kettering Cancer Center

Start date: July 2009

End date: December 2013

Phase II Study

Investigational drug: Itraconazole

Condition: Prostrate Cancer

Study type: Efficacy

Duration: 24 weeks (6 months)

N= 42 patients

Treatment:

Group Treatment Total dailydose

Low dose 200 mg by mouth, once daily 200 mgHigh dose 300 mg by mouth, twice daily 600 mg

Phase II Study (Cont’d) Results

1. Efficacy

*PSA – Prostrate Specific Antigen are secreted by prostratetumour cells; serve as tumour markers

*PSA progression is defined as a 25% increase in PSA over baselineor a 2 ng/ml increase when confirmed again 4 weeks later.

Conclusion: High dose ITZ (600mg/day) significant PSA responsesand delay in tumour progression.

Group Total daily dose Subjects No PSA Progression at24 weeks (95% CI)

Low dose 200 mg 17 11%High dose 600 mg 25 48%

Phase II Study (Cont’d) Results

2. Safety – Adverse Events

Type of AE AE Low dose High dose

Serious Fatigue 6% 0%Other events (5%) Hypertension

AnorexiaFatigue

HypokalemiaRash

-11%52%

-18%

31%17%20%17%7%

Limitations:Small sample size N=42 patientsAdvanced stages of prostrate cancerAEs – no causality established yet.

Anti-cancer Properties ofItraconazole

Figure 10: Proposed Mechanisms for Anti-cancer activity.1) Blocking theSignal in the Hedgedog Pathway and 2) Blocks Angiogenesis (King, 2015)

Blocking the AngiogenesisPathway: Sporanox®

Angiogenesis describes the processwhy which new blood vessels grow.

Cancer cells need blood vessels togrow and metastasize.

Cancer cells grow their vessels byreleasing angiogenic growth factorproteins (e.g. VEGH).

ITZ has been shown to block thispathway in cancer cell lines byinducing inhibitory factors

Hope to see that it can also stopcancer cells from growing vessels inhumans

Blocking the AngiogenesisPathway: Sporanox®

Watch Video: https://www.youtube.com/watch?v=hVYdV3wKg-k

Fig 11.Angiogenesisand TumourMetastasis. Thesearch fordrugs thatinhibit thishallmark ofcancer.

Figure 12:Itraconazole andItraconazole plusCisplatin (anapprovedchemotherapeuticdrug) has shownsignificantreduction inendothelial cellproliferation,migration, andtube formation inresponse toangiogenicstimulation fromnon-small cellcancer lines(Afba, et al., 2011)

Blocking the HedgehogSignaling Pathway Sporanox®

LINK: https://www.youtube.com/watch?v=gFWO3I-oqsE

Fig. 13: Thehedgehogsignalingpathway andoverstimulation in tumourcells

Blocking the HedgehogSignaling Pathway Sporanox®

Hedgehog signaling pathway is essential forembryonic development; remains active in adulttissues

Involve proteins that control cell proliferation,differentiation, and tissue patterning.

Over-stimulation of this pathway has been linkedto cancer of the brain, GI, lung, breast, andprostrate gland.

ITZ has shown to inhibit this signaling pathway;thus slowing cancer progression.

Challenges for Sporanox®:

Challenge 1: Varied bioavailability Capsule: 6%-20% Oral Solution: 20%-60%

2-(HYDROXYPROPYL)-BETA-CYCLODEXTRIN An excipient in oral solution and IV formulation Used to improve water solubility, rate of

dissolution, and hence, its bioavailability By forming a complex with drug molecule Lipophilic cavity – holds ITZ Hydrophobic exterior


Excipient: 2-(HYDROXYPROPYL)-BETA-CYCLODEXTRIN

In the 1996, Horsky et al. From National Institute of Health (NIH)indicated that:

“HP-B-Cyclodextrin, when used in pharmaceutical formulations, haspotential to increase the absorption of carcinogens which enter theGI tract as food components or from air pollution.”

Note: The author cautions against the use of very large quantities ofthe substance, because if it can enhance BA of a therapeutic drug, itcan also provide the same service for harmful chemicals.


SafetyFor oral, high doses (> 1000 mg/kg/day) : Diarrhea Enlargement of faeces seen only in animals

For IV, high doses nephrotoxicity in animal studies seen only in animals

At present, it is not required to add information on these excipients inthe package leaflet of medicinal products (European Union , 2015)

The presence of cyclodextrins should always be stated as a precaution because of limited information and possible interaction with

active substances.


Fig 14: Chemical structure ofhydroxypropyl-beta-cyclodextrinand formation of inclusion complexwith lipophilic molecule such as ITZ(European Union, 2015)

Pharmacokinetic Properties ofHydroxypropyl-beta-cyclodextrinAbsorption PoorDistributionBioavailability

None0-3%

Metabolism NoneExcretion Oral – faeces

IV – kidney

GRAS – generally recognized as safeMaximum Daily Intake: 8000 mg/day

Estimated Dose from Sporanox:~160 mg/day

Improving its Bioavailability

Nanosizing - to reduce the particle size of the ITZ tosub-micron range, typically between 100-200nm, toenhance its oral bioavailability.

Mechanism: Maximizing surface area to improve itsdissolution rate, which in turn, enhances itsbioavailability.

Require the use of stabilizers (e.g. polymers)

Examples:

1. High Pressure Homogeneous

2. Supercritical Fluid Process

Improving its Bioavailability

Fig. 15: Scanning electronmicroscopy micrographsof coarse itraconazolepowders (top) andlyophilized intraconazolenanocrystals byhomogenized highpressure. (Sun, et al. (2011)

Nanosizing ITZ

Figure 16: By nanosizing ITZ with silica into flakes, it is going to increase the rate ofdissolution of ITZ in the stomach, thus increasing absorption rate in the intestine


Challenge 2: Potential Drug to Drug Interactionswith Anti-neoplastic Drugs

AntineoplasticDrugs

Coadministrationwith Sporanox

Clinical Comments

irinotecan CONTRAINDICATED: The potential increase in plasma concentrations of irinotecanwhen coadministered with SPORANOX® may increase the risk of potentially fatal adverseevents.

axitinibdabrafenibdasatinibibrutinibnilotinibsunitinibtrabectedin

May increase plasmalevels of these drugs

NOT RECOMMENDED: It is recommended that the use of these drugs be avoidedduring and up to 2 weeks after discontinuation of treatment with itraconazole, unless thebenefits outweigh the potentially increased risks of side effects. If coadministration cannotbe avoided, clinical monitoring for signs or symptoms of increased or prolonged effects orside effects of the interacting drug is recommended, and its dosage be reduced orinterrupted as deemed necessary. When appropriate, it is recommended that plasmaconcentrations be measured.

bortezomib busulphandocetaxelerlotinibgefitinibimatinibixabepilonelapatinibponatanib trimetrexatevinca alkaloids

May increase plasmalevels of these drugs

USE WITH CAUTION: Careful monitoring is recommended when these drugs arecoadministered with itraconazole. Upon coadministration, it is recommended that patientsbe monitored closely for signs or symptoms of increased or prolonged effects or sideeffects of the interacting drug, and its dosage be reduced as deemed necessary. Whenappropriate, it is recommended that plasma concentrations be measured. See 3 above forfurther information.


Challenge 2: Potential Drug to DrugInteractions with Anti-neoplastic Drugs

Antineoplatic Drugs Tested In-Vitro So Far:

1. Pemetrexed At 3 months, 67% of the patients on

itraconazole plus pemetrexed wereprogression-free versus 29% on thecontrol arm of pemetrexed alone (p =0.11) (Rudin, et al., 2013)

2. Cinsplastin Itraconazole and Itraconazole plus

Cisplatin has shown significantreduction in endothelial cellproliferation, migration, and tubeformation in response to angiogenicstimulation from non-small cell cancerlines (Afba, et al., 2011)

Fig 17: Survival rate of small cancercell lines exposed to permetrexed +itraconacole vs. permetrexed alone(Rudin, et al., 2013)

Conclusions ITZ should be further considered for its potential

anticancer effects Long record of safety. In-vitro and early phase clinical trials showcases

consistent anti-cancer effects. Oral capsules do not contain 2-(HYDROXYPROPYL)-BETA-

CYCLODEXTRIN, even if it is GRAS.

But must take into consideration: Limited applicability in clinical practice due to its wide

range of interactions with other drugs. Angiogenesis and Hedgehog signaling pathways are

not well understood – more research. Selecting a safe excipient or using biotechnology to

enhance its BA. How to incorporate this new drug into a chemotherapy

regime – Diarrhea is the common side effects.

References(2014). Background review for cyclodextrins used as excipients CPMP/463/00 Rev. 1 . European Medicines Agency.http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/12/WC500177936.pdf

Barone, J., Moskovitz, B., Guarnieri, B., Hassell, A., Colaizzi, J., Bierman, R., & Louis, J. (1998). Enhanced Bioavailability ofItraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers. American Society ofMicrobiology, 42 (7), 1862-1865.

Carducci, M. (2014). A Two-dose Level Clinical Trial of Itraconazole in Patients With Metastatic Prostate Cancer Who HaveHad Disease Progression While on Hormonal Therapy. National Institute of Health: Clinicaltrials.org. Identifier: NCT00887458.https://clinicaltrials.gov/ct2/show/results/NCT00887458?sect=X70156&term=sporanox&rank=27#outcome1

Diamond, R. (1999). Atlas of Fungal Infections. Introduction to Medical Mycology. Merck and Co.

Du, R., Lu, K. V., Petritsch, C., Liu, P., Ganss, R., Passegué, E., … Bergers, G. (2008). HIF1α Induces the Recruitment of BoneMarrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and Invasion. Cancer Cell, 13(3), 206–220.http://doi.org/10.1016/j.ccr.2008.01.034

Horsky, J., Pitha, J. (1996). Hydroxypropyl cyclodextrins: potential synergism with carcinogens. Journal of PharmaceuticalScience, 85(1), 96-100. http://www.ncbi.nlm.nih.gov/pubmed/8926593

McMillan, R., Matsui, W. (2012). Molecular Pathways: The Hedgehog Signaling Pathway in Cancer. American Associationfor Cancer Research, 18(18): 4883–4888. http://clincancerres.aacrjournals.org/content/18/18/4883.full.pdf+html

References (Cont’d)Nanonization of Itraconazole by High Pressure Homogenization: Stabilizer Optimization Podust LM, von Kries JP, EddineAN, Kim Y et al. "Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-ray Crystallography." Antimicrob Agents Chemother. 2007, 51(11): 3915-23.

Pantziarka, P., Sukhatme, V., Bouche, G., Meheus, L., & Sukhatme, V. P. (2015). Repurposing Drugs in Oncology (ReDO)—itraconazole as an anti-cancer agent. Ecancermedicalscience, 9, 521. http://doi.org/10.3332/ecancer.2015.521

Product Monograph: PrSPORANOX® itraconazoleoral solution 10 mg/mL Antifungal Agent. (2015). Janssen Inc.Extracted from Health Canada Drug Directorate. DIN number: 02047454.

Product Monograph: PrSPORANOX® itraconazolecapsules 100 mg Antifungal Agent. (2015). Janssen Inc. Extracted fromHealth Canada Drug Directorate. DIN number: 02231347.

Rudin, Charles M. et al. (2013). Phase 2 Study of Pemetrexed and Itraconazole as Second-Line Therapy for MetastaticNonsquamous Non–Small-Cell Lung Cancer. Journal of Thoracic Oncology , 8 (5) , 619 – 623http://www.jto.org/article/S1556-0864(15)32820-3/abstract

Stella, V. J., He, Q. (2008). Cyclodextrins. Toxicologic Pathology. 36(1), 30-42.

http://tpx.sagepub.com/content/36/1/30.long

Sun, W., Mao, S., Shi, Y., Li, L., Fang., L. (2011). Journal of Pharmaceutical Sciences, 100 (8), 3365-3373.http://jpharmsci.org/article/S0022-3549(15)32030-X/pdf

Types of Fungal Diseases. (2014, December 04). Retrieved April 04, 2016, fromhttp://www.cdc.gov/fungal/diseases/index.html

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proposing a new indication for sporanox tm - in the treatment of cancer

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