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Year 3 Sem 2 > 4. Delivery Of Medicines Oncology > Flashcards

4. Delivery Of Medicines Oncology Flashcards

1
Q

Why do we change the route or method of administration for pain management?

A
  1. Different drug exposure profiles
    - need to have a quicker onset (high Cmax and low Tmax) for breaking pain
    - to have sustained blood levels (controlled or sustained release) over days
    - to change the formation of metabolites
  2. To avoid 1st pass metabolism in the GI tract
  3. To have efficient, non-invasive delivery
    - transmembrane approaches such as rectal, buccal, nasal, transdermal
  4. Patient factos
    - convenience, age, dexterity, support
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2
Q

Describe Oral Opioid products regarding its 2 release methods

A 
Immediate release (IR) for acute pain & breakthrough cancer pain
- dosed every 2 to 6 hrs

Sustained release (SR) or Controlled release (CR) for chronic pain

  • patient should have alrdy been receiving opioids and developed some tolerance
  • depending on product, dosed every 12 to 24 hrs continuously
  • provides more stable blood level PK profile
  • must closely follow patient information instruction
  • larger doses per unit are more prone to abuse
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3
Q

Describe principles of Dosing for pain management in oncology

A
  • Better to schedule medication instead of waiting for pain
  • Short acting (intermediate release) every 4h
    : steady state plasma level ~ 1day
  • Long acting (sustained release) every 12h
    : steady state plasma level within 2~4 days
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4
Q

What are Abuse-deterrent Formulations (ADFs) of opioids?

A
  • As the use of opioids reaches an all-time high, concern for their misuse and abuse has risen simultaneously
  • There has been a high surge in deaths from overdoses of opioids as non-medical users and dealers obtain prescription opioids or opioids via illicit sources and divert to the illegal market
  • To reduce overdosing and black market supply, there is a focus on promoting temper-resistant or abuse-deterrent formulations (ADF)s)
  • Aim is to render diverted opioids unusable if there is an attempt to extract the drugs
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5
Q

Describe Abuse and Tampering of Opioid analgesics

A

The potential for abuse of an opioid is essentially predicated on its pharmacokinetics (PK) profile

  • drug abusers prefer a large concentration (High Cmax) in the shortest time (Low Tmax)
  • PK properties of increasing Cmax and decreasing Tmax correlate with the pharmacodynamic property of euphoria

Immediate release formulations offer the easiest dosage form from which to recover the opioid

  • Routes of abuse, other than ingestion, are inhalation, injection and smoking
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6
Q

Describe the ADF(Abuse-Deterrent Formulations) strategies

  • Physical barrier
  • Aversion
A

Physical barrier (gel formation)

  • This tablet formulation has a structure that is highly viscous or semisolid
  • It also includes solids that become viscous and gelatinous upon adding water or attempting an extraction with alcohol
  • A gel formulation may also limit abuse if it is deemed too difficult to overcome the delivery system

Aversion
- Utilises a noxious component added to the powder formulation to discourage abuse because of unwanted adverse events e.g subtherapeutic niacin to deter oral abuse

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7
Q

Describe ADF of oxycodone

A
  • No drug release if crushed or ingested
  • Forms a viscous gel if wetted, cannot be injected
  • Releases less drug if attempt to dissolve in vodka
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8
Q

Describe the ADF(Abuse-Deterrent Formulations) strategies

  • Agonist/Antagonist
  • Pro-drug
A

Agonists/Antagonists

  • Pellets of morphine sulphate surrounding a central core of sequestered naltrexone hydrochloride in a ratio of 100:4
  • If the capsules are chewed, ground, or otherwise tempered with, the orally available naltrexone will be released, causing decrease in the euphoria acticipated from the opioid

Pro-drug

  • Prodrugs are biologically inactive substances that are metabolised in vivo to their active form
  • The GI biotransformation is the rate-limiting step
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9
Q

How are patches being abused?

A
  • The gel is removed and boiled to extract the opioid
    : liquid is either injected or drunk
  • Patches are chewed to release 3 days of equivalent dose for mucosal delivery
  • Multiple patches are placed on the skin
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10
Q

Define Breakthrough Cacner Pain (BTcP) and impact of it to patients

A

Transient increases in pain in a cancer patient who has stable, persistent pain treated with opioids

Patients with BTcP pain have higher levels of

  • Background pain
  • Peak pain
  • Depression
  • Anxiety
  • Functional impairment

BTcP pain has a significant negative effect on quality of life

  • Requires an additional dose
    : not replacing administration of regular dose - that is short acting
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11
Q

What is required from Breakthrough Cancer Pain opioids?

A
  • Analgesic closely matching time profile of BTcP
  • Rapid onset of action controlling BTcP
  • Short duration of action minimising systemic exposure
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12
Q

Describe Breakthrough Pain Treatment

A

Medication for BTcP is taken as needed as soon as the pain begins
- patient advised ‘not to wait it out’

The most common drugs used include morphine, oxycodone, hydromorphone and fentanyl

Fentanyl is unique as it comes in three different immediate release (IR) forms
: sublingual lozenge
: tablet (either buccal or sublingual
: nasal spray

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13
Q

Describe characteristics of Fentanyl Citrate

A

Fentanyl is a potent u-opioid analgesic with rapid onset of analgesia

The most lipophilic of the clinically available IR opioids

  • well-suited to a number of different routes of administration (nasal, buccal)
  • quickly crosses cellular barriers, providing broad tissue distribution and rapid onset of action

Oral transmucosal fentanyl citrate (OTFC)

  • the first rapid-onset opioid (ROO) to be approved for the treatment of BTcP
  • recommended by the European Association of Palliative Care
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14
Q

Describe Buccal/Sublingual administration

A
  • Convenient and easy to use
- Takes advantage of oral mucosa characteristics that facilitate rapid absorption
\: large surface area
\: high permeability
\: high vascularity
\: uniform temperature
  • High bioavailability, due to avoidance of 1st pass metabolism
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15
Q

SUMMARY of Drug Delivery in Pain management of Oncology

A
  • Effectiev drug products to control pain, and especially breakthrough pain, are available
  • Needs/preferences of different patients can be met by these products
  • Desirable PK profiles can be achieved
  • Abuse and tampering of opioid drug products is an ongoing problem
  • Abuse-deterrent formulations (ADF) have been developed and can be effective
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16
Q

What are the Variabiliy in patients?

A
  • Age of patient
  • Body size & composition
  • Gender
  • Ethnicity
  • Disease state
  • Hepatic & renal function
  • Pregnancy
  • Genetics
17
Q

Describe Genetic variability

A

Many of the genes encoding proteins involved in PD and ADME display genetic polymorphism (enzymes, transporters, receptors)

Genetic polymorphisms (variation in the gene structure)

  1. SNP (single nucleotide polymorphism)
    - the nucleotide sequence at one specific position is changed, inserted, deleted
    - depending on region affected: silent or have functional consequences
  2. CNV (copy number variations)
    - gene deletion: loss of function
    - gene duplication: increased expression and hyperactivity
Allele: gene variant. Each cell has 2 copies of same gene
- two copies of same allele 
= homozygous genotype
- combination of 2 different alleles
= heterozygous genotype
18
Q

What is Haplotype?

A
  • known as DNA signature, genetic signature
  • group of alleles across different genes on a single chromosome that are located closely together on the same chromosome and tend to be inherited together
19
Q

What is Germline genetic variation?

A
  • variation in the DNA present at conception and passed on to offspring
20
Q

What is Somatic genetic variation?

A
  • changes arising spontaneously within cells after conception
  • passed to descendants of the original cell but not to offspring
  • genes in cancer cell have thousands of somatic variations; some specifically targeted by anticancer drugs
21
Q 
Define Pharmacogenetics (PGt)
and Pharmacogenomics (PGx)
A

Pharmacogenetics (PGt)

  • variability in drug response due to hereditary factors or
  • genetic causes of individual variations in drug repsonse

Pharmacogenomics (PGx)
- Much broader approach
- whole-genome application of pharmacogenetics
: genome-wide analysis of the genetic determinants of drug efficacy and toxicity or
- Infleunce of genes on drug response. Combined effect of a number of genes on a particular phenotype

22
Q

Describe Germline genetic variability and prescribing

A
  • ~15% of EMA and FDA approved drugs contain PGx information in their label
  • About 7% approved FDA
  • About 18% of US prescriptions
    = have actionable agents
  • only 17 of 18000 human genes are considered clinically actionable for germline PGx
23
Q

What are Genotype and Phenotype?

A

Genotype

  • an individual’s full hereditary information
  • born with it

Phenotype
- the individual’s actual expressed properties or the physical characteristics of an organism or the organism’s actually observed properties

24
Q

Describe implications in therapy of Tamoxifen regarding CYP2D6 PGx

A
  • PMs (poor metaboliser) benefit less from therapy with tamoxifen than EMs
  • PMs probably do better in therapy with aromatase inhibitor (AI) than with tamoxifen
  • UMs will have higher incidence of hot flushes
  • Comparison between tamoxifen and AI is probably confounded by PGx in un-stratified trials
25
Q

What is the relationship between CYP2D6 and Tamoxifen?

A
  • N-desmethyl TAM and 4-hydroxyTAM believed to be the active moieties when tamoxifen introduced to market
  • Currently known that endoxifen, formed by CYP2D6, is the active compound
26
Q

What is the relationship between CYP2D6 and Tamoxifen?

A
  • 6-MP anad analogues used to treat acute lymphoblastic leukaemia, inflammatory bowel disease and autoimmune disorders
  • Can cause severe haemotoxicity in childhood
  • The gene TMPT encodes thiopurine methyltransferase
27
Q

Describe PGx of TPMT: therapy implications

A
  • TPMT (Thiopurine Methyltransferase) is the only inactivating enzyme in hematopoietic tissues
  • Risk of dose-limiting toxicity
    : 2-20% patients with 1 non functional allele
    : <1% patients with 2 non functional alleles
28
Q

Describe Criteria for a PGx test to be used in clinical care

A
  1. Analytical validity
    : ability of a genetic test to measure accurately and reliably the genotype of interest (test performance in lab rather than clinic
  2. Clinical validity
    - accuracy with which the test can predict the presence or absence of the phenotype and/or clinical diseases
  3. Clinical utility
    - whether use of the test leads to improve health outcomes for patients who are subject to the test and assessment of the risks that occur as a result of testing
29
Q

What are the practical implementation of PGx that needs to be considered?

A

Consider

  • Access
  • Feasibility
  • Cost
  • Evidence
  • Patients and health providers concerns
  • Healthcare providers education
30
Q

Where can you find PGx information and why should you use it ?

A

Regulatory Agencies
- FDA and EMA support integration of PGx tests with drug development to enhance dose selection, efficacy and safety by

  1. Include PGx data in the drug labelling for onfirmation
  2. Use PGx data to choose dose regimen, identify patients at risk
  3. PGx label where PGx data is of high importance for treatment outcome
31
Q

What are the considerations when using Cockcroft-Gault equation?

A

Must be used in steady-state
- if the renal function is changing rapidly the prediction will not be accurate

Prediction not accurate for some populations
- lower/higher than usual muscle mass, marked obesity

ClCr can exceed Cl.inuline when poor renal function and in case of heavy proteinuria

32
Q

Which weight do we use with obese patients?

A
  • ClCr and BSA are used to estimate doses for cancer patients
  • Use of IBW instead of TBW has been proposed for obese patients
  • Evidence suggests that obese patients have often been under dosed
33
Q

JUST READ

- Dosing cancer patients

A
  • PGx variability can improve therapy outcomes of therapy for well-selected applications
  • PGx in CYP2D6 can explain toxicity and lack of efficacy
  • TPMT and 6-MP a good case for proactive testing
  • Implementation of PGx in clinical requires
    : evidence of analytical validity, clinical validity and clinical utility
    : assessment of access, feasibility, cost, evidence, patients and health providers concerns
    : healthcare providers education

Year 3 Sem 2 (12 decks)

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