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Questions and Answers
What is a significant problem with using high molecular weight water-soluble polymers for slow dissolution?
What is a significant problem with using high molecular weight water-soluble polymers for slow dissolution?
What must be true for a polymer to slowly break down in the body?
What must be true for a polymer to slowly break down in the body?
Which of the following is a requirement for the degradation products of slow-dissolving polymers?
Which of the following is a requirement for the degradation products of slow-dissolving polymers?
What is a characteristic of polymers used for slow dissolution based on chain scission?
What is a characteristic of polymers used for slow dissolution based on chain scission?
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Why might larger polymers (greater than 40 kDa) exhibit poor renal excretion?
Why might larger polymers (greater than 40 kDa) exhibit poor renal excretion?
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What is a common feature of polymers designed for slow degradation in the body?
What is a common feature of polymers designed for slow degradation in the body?
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What is the primary component of the Zoladex LA depot system?
What is the primary component of the Zoladex LA depot system?
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Which group is essential for creating polymers that can hydrolyze slowly in the body?
Which group is essential for creating polymers that can hydrolyze slowly in the body?
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Which parameter is primarily influenced by the mixture of high and low molecular weight polymers in Zoladex LA?
Which parameter is primarily influenced by the mixture of high and low molecular weight polymers in Zoladex LA?
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Which factor does NOT contribute to the reliability of high molecular weight polymers for slow dissolution?
Which factor does NOT contribute to the reliability of high molecular weight polymers for slow dissolution?
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What causes the autocatalytic degradation in the Zoladex rod systems?
What causes the autocatalytic degradation in the Zoladex rod systems?
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How does drug release happen in the rod system before full degradation of the polymer?
How does drug release happen in the rod system before full degradation of the polymer?
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What is the function of molecularly targeted drugs in cancer treatment?
What is the function of molecularly targeted drugs in cancer treatment?
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Which of the following is a type of molecularly targeted drug mentioned for anticancer treatment?
Which of the following is a type of molecularly targeted drug mentioned for anticancer treatment?
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What dosage form is Zoladex LA administered as?
What dosage form is Zoladex LA administered as?
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What results from the plasticization by lower molar mass components in the drug release mechanism?
What results from the plasticization by lower molar mass components in the drug release mechanism?
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What is the main reason fulvestrant is not suitable for oral formulation?
What is the main reason fulvestrant is not suitable for oral formulation?
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What is the peak plasma concentration time frame for fulvestrant?
What is the peak plasma concentration time frame for fulvestrant?
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How is goserelin typically administered for chronic treatment?
How is goserelin typically administered for chronic treatment?
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What condition does goserelin induce with long-term exposure?
What condition does goserelin induce with long-term exposure?
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What is the terminal half-life of fulvestrant?
What is the terminal half-life of fulvestrant?
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What is the key benefit of the intramuscular route for fulvestrant administration?
What is the key benefit of the intramuscular route for fulvestrant administration?
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What is the volume of distribution (Vss) of fulvestrant?
What is the volume of distribution (Vss) of fulvestrant?
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What component is essential in the formulation of goserelin for sustained release?
What component is essential in the formulation of goserelin for sustained release?
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What impact do paroxetine and fluoxetine have on tamoxifen's effectiveness?
What impact do paroxetine and fluoxetine have on tamoxifen's effectiveness?
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What percentage of breast tumors are ERα-positive?
What percentage of breast tumors are ERα-positive?
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How effective is tamoxifen in patients with ERα-positive tumors?
How effective is tamoxifen in patients with ERα-positive tumors?
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What is the primary mechanism of action of fulvestrant compared to SERMs?
What is the primary mechanism of action of fulvestrant compared to SERMs?
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What is the binding affinity of fulvestrant compared to estradiol?
What is the binding affinity of fulvestrant compared to estradiol?
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What is one of the known metabolites of tamoxifen?
What is one of the known metabolites of tamoxifen?
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Which statement best describes tamoxifen's selectivity in ERα-positive tumors?
Which statement best describes tamoxifen's selectivity in ERα-positive tumors?
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Which of the following is NOT a characteristic of fulvestrant?
Which of the following is NOT a characteristic of fulvestrant?
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What is the primary characteristic of PDLLA compared to PLLA?
What is the primary characteristic of PDLLA compared to PLLA?
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Which component in PLGA increases the degradation rate of the polymer?
Which component in PLGA increases the degradation rate of the polymer?
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How does the degradation time of PLGA typically compare to the time of drug release?
How does the degradation time of PLGA typically compare to the time of drug release?
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What effect does changing the ratio of glycolic acid to lactic acid in PLGA have?
What effect does changing the ratio of glycolic acid to lactic acid in PLGA have?
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Which formulation comprises a mixture of high and low molecular weight polymers?
Which formulation comprises a mixture of high and low molecular weight polymers?
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What is the expected predicted complete degradation time for PLGA 65:35 in the body?
What is the expected predicted complete degradation time for PLGA 65:35 in the body?
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Which statement about the hydrolysis of polymers is accurate?
Which statement about the hydrolysis of polymers is accurate?
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What is the structure of PGA in relation to its side chains?
What is the structure of PGA in relation to its side chains?
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What is the role of 4-hydroxytamoxifen in the action of tamoxifen?
What is the role of 4-hydroxytamoxifen in the action of tamoxifen?
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How do different CYP450 isoenzyme profiles affect tamoxifen therapy?
How do different CYP450 isoenzyme profiles affect tamoxifen therapy?
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Which of the following metabolites of tamoxifen has the highest affinity for the estrogen receptor?
Which of the following metabolites of tamoxifen has the highest affinity for the estrogen receptor?
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What is a key feature of tamoxifen's mode of action?
What is a key feature of tamoxifen's mode of action?
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Why is genotyping recommended for patients undergoing treatment with tamoxifen?
Why is genotyping recommended for patients undergoing treatment with tamoxifen?
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What characteristic makes tamoxifen a 'self-formulating drug'?
What characteristic makes tamoxifen a 'self-formulating drug'?
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Which CYP isoenzyme is least likely to impact tamoxifen's pharmacokinetics?
Which CYP isoenzyme is least likely to impact tamoxifen's pharmacokinetics?
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What is a significant effect of utilizing SSRIs in patients taking tamoxifen?
What is a significant effect of utilizing SSRIs in patients taking tamoxifen?
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Which type of mutation results in the suppression of tumor suppressor genes such as RB1?
Which type of mutation results in the suppression of tumor suppressor genes such as RB1?
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What genetic alteration involves increasing the number of copies of a specific gene?
What genetic alteration involves increasing the number of copies of a specific gene?
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Which of the following is an example of a chromosome rearrangement?
Which of the following is an example of a chromosome rearrangement?
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Single nucleotide mutations at critical sites can affect genes such as which of the following?
Single nucleotide mutations at critical sites can affect genes such as which of the following?
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What is the consequence of RB1 no longer inhibiting the cellular factor?
What is the consequence of RB1 no longer inhibiting the cellular factor?
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Which gene deletion example is correctly matched with its consequence?
Which gene deletion example is correctly matched with its consequence?
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Gene amplifications often involve increased copy numbers of which gene example?
Gene amplifications often involve increased copy numbers of which gene example?
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Which of the following factors typically leads to malignancies when altered?
Which of the following factors typically leads to malignancies when altered?
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Study Notes
Molecularly targeted therapeutics for cancers
- Lecture 4, PHAR3003, MPharm Year 3
- Pharmaceuticals Lead: Professor Cameron Alexander
- [email protected]
Hormone-dependent pathways
- Endocrine therapy slows/stops hormone-related cancer growth
- Not cytotoxic; various administration routes and formulations available
- Tamoxifen: weak base (pKa 8.8)
- Low aqueous solubility (<0.01% at 20°C)
- Converted to citrate salt (solubility 0.5 mg/mL) for oral administration
- Originally screened as a contraceptive agent
- Pro-drug; estrogen receptor antagonist via 4-hydroxytamoxifen metabolite
- Peak plasma concentrations 4-7 hours post-administration
Biopharmaceutics and Tamoxifen
- Tamoxifen PK (Pharmacokinetic) driven by CYP3A4, CYP2C9 metabolism
- Metabolites (e.g., endoxifen) enhance antineoplastic activity
- Binds to estrogen receptor but doesn't activate it.
- 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen have much higher affinity for estrogen receptors
- Mode of action is tissue-dependent; strong anti-estrogenic effect on mammary epithelium
- Patient responses and CYP450 profiles can affect metabolism
- CYP2D6 variants (e.g., paroxetine, fluoxetine) affect tamoxifen efficacy
- 75% of breast tumors are ERα-positive, and tamoxifen is effective in ~2/3 of this population
Fulvestrant
- More potent than tamoxifen
- ERa binding affinity is ~90%, compared to estradiol which is ~3%
- Mode of action differs from SERMs
- Impairs estrogen receptor (ERα) dimerization and translocation, blocks cofactor recruitment, and rapidly degrades ERα-fulvestrant complexes and thereby negates estrogen signaling
- Water-insoluble; high plasma protein binding (VLDL, LDL, etc.)
- Intramuscular (IM) injection every 2 weeks initially, then monthly
- Sustained dosing via peak plasma concentration in 5-7 days; terminal half-life (t1/2) is 40-50 days; accumulation to steady state reached within 6 months
Formulation and Biopharmaceutics of Fulvestrant
- IM route allows for sustained dosing
- Plasma concentration peaks in 5-7 days, with a terminal half life (t1/2) of 40-50 days
- Repeated monthly administration results in ~2-3-fold accumulation
- Steady state reached after about 6 months, with most accumulation occurring after 3-4 doses
- High volume of distribution (Vd) 4.1 ± 1.6 L/kg
- Triphasic decline in plasma concentration, with rapid distribution into peripheral tissues.
- Formulation constraints for IM injection include sterilisable components, acceptable viscosity, and appropriate co-solvents; eg benzyl alcohol, ethanol and benzyl benzoate at 50 mg/ml
Goserelin
- Decapeptide agonist of luteinizing hormone-releasing hormone (LHRH).
- Initial exposure increases testosterone or estrogen release, but long-term exposure blocks release due to desensitization.
- Chemical castration; used to treat prostate cancer, and early onset puberty.
- Two-hour half life; frequently injected; requires sustained release formulations.
Formulation concept for sustained peptide release
- Single dose releases goserelin over 3 months.
- Use a polymer that dissolves slowly, allowing continual release of peptide therapeutic
Achieving Slow Dissolution
- Option 1: High-molecular-weight water-soluble polymers
- Dense and entangled polymer solid dissolves into disentangling gel; polymer chain in solution.
- Option 2: Chemical breakdown of the polymer
- Dense and entangled polymer solid undergoes chain scission, resulting in low molecular weight products in solution
Problems with Option 1
- Unreliable, as dissolution dependent on entanglement.
- Most polymers dissolve before goserelin can be fully released.
- What happens to the polymer after dissolution?
- Glomerular excretion does not occur with polymers larger than 40 kDa
- Particles over 6-8 nm suffer poor renal excretion at high molar mass.
Option 2 - Polymers that slowly breakdown
- Need a chemical group (e.g. ester) that hydrolyzes in the body, leading slower breakdown.
- Polymers (e.g., Poly(lactic acid)) that slowly break down in the body are used.
Polymers that slowly breakdown in the body
- Polymers must be water-insoluble but their degradation products must be low molecular weight.
- Degradation is the chemical breakdown of polymer chains.
- Erosion takes place when polymer chains decrease sufficiently in molecular weight to become water soluble.
Poly(lactic acid) and related polymers
- Polymerised from a dimer called lactide, the chemical structure includes 3S, 6S- Lactide, L, L- Lactide, 3R, 6S- Lactide, D, L- Lactide
- Effect of stereochemistry on PLA degradation
- Poly(DL-lactic acid) (PDLLA) degrades in ~1 year, whereas Poly(L-lactic acid) (PLA) degrades in >2 years.
- PLA is semi-crystalline.
PLA undergoes bulk erosion
- Water penetration and chain scission are more rapid than erosion;
- Note that drug release happens faster than polymer erosion.
Tailoring PLA degradation kinetics
- Add glycolic acid monomer (GA) to make a PLGA co-polymer.
- GA component is more susceptible to hydrolysis due to lack of hydrophobic methyl group.
- Increased GA in PLGA increases degradation rate (shortens degradation time).
Degradation Kinetics of PLGA
- Graph showing how different PLGA ratios degrade and their time to complete degradation.
Zoladex Formulations
- 1-month depot system (3.6 mg goserelin); PLGA with 50% lactic acid + 50% glycolic acid.
- 3-month depot system (10.8 mg goserelin); PLGA with 95% lactic acid + 5% glycolic acid
- Rod-like shape, measured in ~11mm x 1.1 mm and 18mm x 1.5mm (for 3 and 1 month Zoladex respectively).
Zoladex release kinetics and testosterone suppression
- Graph showing release kinetics and testosterone suppression over time,
- Different concentrations of goserelin (measured in mg/month)
Zoladex LA and Zoladex release rates
- Dosing is more rapid than predicted from polymer degradation alone.
- Autocatalytic degradation is pronounced in rod systems.
- Hydration and fragmentation of the rod allows drug release by diffusion mechanism before full degradation of the polymer.
- Low molecular weights of chains increase early erosion, with plasticisation occurring due to lower molar mass components.
Targeting therapeutics for signalling pathways
- Molecularly targeted drugs, originally developed for cancers, are either small molecules or antibodies that specifically inhibit signal transduction pathways.
- Examples, including tyrosine and serine/threonine kinase inhibitors, anti-HER2 or anti-EGFR antibodies and anti-VEGF antibody, that affect cancer growth, proliferation, and survival.
Molecular targeting
- Initially mainly focuses on small molecule drugs such as kinase inhibitors.
- Methods used include inhibiting protein kinases that are involved in transformation, growth, and survival. Cancer cell proliferation.
- Successful classes include inhibitors (e.g., gefitinib, imatinib, lapatinib).
Summation for lecture 4
- Targeting drugs to signalling pathways can be beneficial.
- Lack of cytotoxicity can be a benefit.
- Drug properties influence formulation.
- Sustained dosing needs innovative formulations.
- New oral-targeted drugs offer benefits for patients.
Questions
- Key classes of molecularly targeted cancer drugs: small molecule inhibitors and antibodies.
- Why tamoxifen can be oral but fulvestrant can't: Tamoxifen has much higher water solubility, whereas fulvestrant is water-insoluble with extensive plasma protein binding.
- Advantages of formulation differences: oral formulations are more convenient than repeated injections (e.g., IM)
- Factors in choosing a polymer for encapsulation: water solubility and degradation properties.
- Parameters that can be varied in formulations to control drug release: polymer composition, molecular weight, and degradation mechanisms.
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Description
This quiz covers Lecture 4 of PHAR3003 focusing on molecularly targeted therapeutics for cancer, specifically hormone-dependent pathways and the pharmacokinetics of Tamoxifen. It discusses the administration, metabolism, and action of Tamoxifen in cancer treatment. Test your knowledge on these critical aspects of pharmacotherapy in oncology.
