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Cancer > Pharmaceutics > Flashcards

Pharmaceutics Flashcards

1
Q

Why do we need to formulate cancer drugs?

A

Existing drugs have a low theraputic window?
Cancer drugs are dosed close to the maximum tolerated dose
biological drugs are degraded if taken orally

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2
Q

Why is it an issue to take Nilotinib with food?

A

It has a LogP of 4.4 and is therefore lipid soluble so bioavalibility is largely increased and may be to a toxic level

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3
Q

What are the advantages of giving chemo IV?

A

Accurate, rapid dosing that can be removed instantly if adverse effects are too severe.
It also avoids first pass metabolism and fed or fasting effects on drug don’t apply.
Flexibility of dosing schedule.

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4
Q

Disadvantage of chemo via IV

A

accurate dosing but increased nausea

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5
Q

What are the stringent requirements for IV formulations?

A

Sterile production, formulation stability, no preservatives and low excipients as bypassing body’s natural defence barrier

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6
Q

What would we have to consider when formulating a chemo drug for subcutaneous use? (i.e. IM)

A

Highly vascularised muscles
formulation requirements are less severe
could use implants colloids and suspensions
A high collagen content in the muscle could bind the charged drugs.

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7
Q

Name a topical treatment used for malignant melnoma

A

Tretonoin

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8
Q

Why would you use etoposide phosphate over etoposide?

A

Easier to formulate and handle in vitro cytotoxicity is less

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9
Q

Why should alkaline solutions be avoided with doxorubicin?

A

Promotes hydrolysis

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10
Q

What key properties does etoposide have that make it difficult to formulate IV?

A
  • low solubility in water
  • tendency to crystallize or precipitate
  • Binds strongly to plasma proteins (e.g. albumin has a hydrophobic binding site) - up to 94% can be found bound in human pasma
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11
Q

What can be done about formulating etoposide?

A
  • co planar orientation of aromatic ring in drug and salicylate salt improves solubility in aqueous solution (net charge negative - charge charge repulsion prevents precipiation and protein binding)
  • this all leads to enhanced bioavailability
  • Increased solubility leads to: lower volume of injection and better formulation stability
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12
Q

How can etopside be formulated as a prodrug?

A
  • phosphorylated
  • water-soluble so available as a dry powder for dilution of pre-formed
  • can be infused in 5 minutes
  • easier to formulate and handle
  • but lower cytotoxicity as needs to be dephosphorylated to pro drug - binding site effected so not as active
  • when converted to etoposide it can bin to serum albumin
  • caution needed when administering etopophos with drugs which inhibit phosphatase activities (e.g. levamisole hydrochoride)
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13
Q

Key chemistry point regarding doxorubicin?

A
  • dox can form stacked dimers and polymeric self-assembled aggregates
  • pi-pi interactions strong between aromatic rings (also important in dox-DNA binding)
  • same property but can be blessing or curse
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14
Q

How can we safely formulate doxorubicin?

A
  • formulate with parabens (p-hydroxybenzoic acid esters) - make a complex with dox
  • this disrupts self assembly of drug, enables rapid dissolution from lyophilised formulation, enhances bioavailability and gives more predictable dosing
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15
Q

Why can’t doxorubicin be formulated with alkaline or heparin or 5FU?

A
  • precipitates the drug

- due to covalent bonds in dox dimers

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16
Q

What are the formulation demands of proteins?

A
  • rheology (flow of matter)/viscosity
  • self-aggregation
  • precipitation
  • formulated with buffers, tonicity agents, stabilisers, etc
  • formulation and excipients must be: sterile, pH close to neutral to avoid stinging, stable even at high protein conc
17
Q

What can happen when you shake a high concentration of proteins in a vial?

A
  • proteins are amphiphilic
  • contains charged amino acids and hydrophobic regions
  • if protein is denatured or assembled at the interface, or if shear is created by shaking, association and aggregation can occur
18
Q

How do we avoid systemic toxicity with dox dosing?

A

Encapsulate dox into a virus-sized carrier in stacks

19
Q

What is the criteria for the dox carrier?

A
  • high drug incorporation
  • long-circulation time
  • stable in circulation
  • reisis absorption or plasma proteins
  • ability to release drug in tumour
  • exploit enhanced permeation and retention effect (EPR)
20
Q

What are the factors affecting EPR?

A

Vehicle related: plasma residence time, particle sze (big enough the transpot and not pumped out by efflux pumps), carrier vehicle, polymer architecture
Tumour related: tumour type, microenvironment
External mediators: radiation, bradykinin antagonist, cyclooxygenase inhibitor, nitric oxide scavengers
- note: EPR effect measured mostly in implanted tumours: limited data on epr in metastatic lesions in patients, significant patient and tumour heterogeneity therefore, tumour response alone is not a good predictor of overall survival

21
Q

What are the other factors that define passive targeting?

A
  • prolonged blood circulation of drug carriers is important: drug carriers delivered to target tissue through bloodstream, extravasation considered to be slow and passie manner
  • obstacles to long circulation of partculate or macromolecular carriers: glomerular excretion by the kidney, recognition by reticuloendothelial system (RES) located in the liver, spleen and lung
  • Glomerular secretion can be avoided by using carriers (bigger moleculars wont be filtered out - thershold value 42-50 kDa for water soluble polymers)
  • RES recognitions: not just size but also shapes
22
Q

Describe how dox is formulated as liposomal to solve the problems

A
  • Average particle size 90-100nm ~ virus-size
  • PEG layer prevents attachment of plasma proteins - entropic stabilisation also prevents aggregation
  • Liposomal dox.HCl - half life = 55hrs of 26 hour for HCl salt alone
  • lomger duration time allows passive transport to tumour tissue with disrupted vasculature - accumulation in tumour
  • reduced binding of dox to plasma proteins as it’s encapsulated in transit to tumours
  • total diameter - 200nm = good for transport but limiting factor for drug loading
  • liposomes are highly diluted for injection: drug leakeage during transport and balance of stability of liposome and drug release = BAD
  • changing pH and counter-ion (Dox.HCl vs NH4SO4) allows high loading of drug and self-association of drug in liposome - gives high conc of fibrous gel in liposome
  • may also be a benefit of reduced p\h in solid tumurs - retained liposomes exhibit prolonged time in lower pH environments
  • BUT - EPR effect not present for all tumours: also, unwanted accumulation at sites with poor circulation, palmer-palmar syndrome: damage to fingers, toes, peripheral sites
23
Q

How is Paclitaxel formulated to avoid long infusion times and toxic solvents?

A

Formulate paclitaxel within a nanoparticle pre-formed from albumin & PTX - details are patented but likely a controlled precipitation of albumin in the presence of PTX

24
Q

What is tamoxifen?

A
  • endocrine therapy to slow/stop growth of hormone-related cancers
  • not cytotoxic = range of administration routes and formulations possible
  • weak base: low aqueous solubility, converted to citrate salt to be given orally, originally screened to be a new contraceptive agent
  • is a pro-drug: an antagonist of oestrogen receptor in breast via active metabolite (4-hydroxytamoxifen)
  • peak plasma conc ~ 4-7 hrs after oral dose
25
Q

how is tamoxifen metabolised?

A

PK driven by metabolism (CYP3A4, CYP2C9, CYP2D6)

  • metabolites of tamoxifen are key to antineoplastic effect
  • bind to estrogen receptor but do not activate it: 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen) have 30-100 times greater affinity with estrogen receptor than tamoxifen itself
26
Q

Tamoxifen mode of action?

A
  • tissue-dependent
  • strongly antiestrogenic on mammary epithelium, but proestrogenic on uterine epithelium - hence is a selective estrogen receptor modulator
  • has been described as ‘self-forulating drug’ due to different activity in different tissue locations
  • different dose responses to patients with different CYP 450 isoenxyme profiles
27
Q

How can patient CYP 450 profiles affect tamoxifen?

A
  • variant forms of CYP 2D6 gene can lead to delayed metabolism of tamoxifen into active metabolites
    (recommend genotyping patient for CYP 2D6 variants)
  • SSRIs (can decrease effectiveness of tamoxifen via competition with CYP 2D6 enzyme
  • other factos: antiestrogen activity via ERalpha in target tissues: although around 75% of all breast tumours are ERalpha-positive, tamoxifen effective in ~2/3 of this population
28
Q

Lets talk about fulvestrant

A
  • more potent that tamoxifen

- ERalpha binding affinities compared to estradiol (90% acompared to 3%)

29
Q

Fulvestrant mode of action?

A
  • impairs dimerisation and translocation of ERalpha; also blocks cofactor recruitment at both activating sites
  • ERalpha-fulvestrant complex unstable - rapidly degraded -> reduction of cellular ERalpha, and negation of oestrogen signalling
30
Q

Why can’t fulvestrant be given orally?

A
  • water INsoluble, high binding to plasma proteins (VLDL, LDL etc)
  • administration is via injection every 2 weeks for the first three doses, then 1X per month
31
Q

What is the advantages of IM administration for fulvestrant?

A
  • sustained dosing
  • repeated monthly administration results in ~2-3 fold accumulation
  • peak plasma conc in 5-7 days, terminal half life = 40-50 days
  • steady state reached ~ 6 months with mos taccumulation after 3-4 doses
  • high volume of distribution
32
Q

What are the formulation constraints for IM fulvestrant?

A
  • sterilisable components, acceptable viscosity at required dose
  • castor oil and co-solvents (benzyl alcohol, ethanol and benzyl benzoate) added to dose fulvestrant at 50mg/ml
33
Q

Uses of methotrexate?

A
  • management of acute lymphoblastic leukemia
  • prophylaxis and treatment of meningeal leukemia
  • psoriasis (not UK) and rheumatoid arthritis
34
Q

What are the problems of methotrexate?

A
  • effects of varying doses are very different
  • drug properties very different at different pH
  • low permeability ( C logP = 0.53)
  • poor aqueous solubility (0.01mg/ml) as neutral compound - more soluble in blood stream in salt form (LogP = -1.85)
  • prolonged exposure to drug needed as only kills actively dividing cells
  • short plasma t1/2 (2-10hrs)
  • nonspecific delivery
  • development of resistance
35
Q

What are the formulations for controlling dosing of methotrexate?

A
  • oral tabs: contain MXT sodium, excipients (lactose, Mg stearate, starch, low doses more commonly used for arthritic conditions
  • IM injection: used for rheumatoid arthritis (lower doses than anti-cancer), better absorption, peak conc similar to IV, slower drug absorption and more prolonged expsore to drug than with IV administration
36
Q

Pharmacokinetics of MXT?

A
  • low dose oral MXT rapidly absorbed from GI tract
  • higher doses less well absorbed orally (receptor saturation)
  • IM MXT rapidly and completely absorbed
  • peak serum conc occurs 1-2 hrs after an oral dose, and 30-60 mins after IM
  • distributes to tissues and extracellular fluid
  • MTX enters cells in part by an active transport mechanism
  • converted intracellularly to polyglutamate conjugates
  • ‘conjugate drug’ MTX-pGLu is not actively exported
  • Intracellular processing of this conjugate can liberate MTX
  • hence MTX can remain in the body for several months, particularly in liver, potential hepatic damage
  • development of resistance can occur: decreased transport and increased efflux, impaired poly(glutamylation)
37
Q

Practical issues with MTX treatment?

A
  • MTX pharmacokinetics highly variable: affected by age, renal and hepatic function, limited lipid solubility, does not diffuse across lipid membranes, not transported into CSF after oral or IV administration
  • main route of elimination in renal: glomerular filtration, active tubular secretion, toxicity more dependent on duration of exposure than administered dose
  • MTX can bind to proteins: approx 50% of MTX bound to plasma proteins, variation between oral and IV early elimination rates (first pass metabolism vs renal excretion, protein-bound MTX excreted less quickly?)
  • Negative effects of aspirin and other NSAIDs: displace MTX from protein - increased serum level of free MTX, inhibit MTX secretion in proximal tubule, reduce renal clearance, increasing blood levels, increase in duration of MTX exposure hence increase in toxicity
  • high doses - crystal formation in uring= possible acute renal failure
38
Q

How can mxt crystallisation in urine and nephrotoxicity be minimised?

A
  • risk factors = acid urine, volume depletion, renal impairment
  • minimise nephrotoxicity with hydration + urinary alkalinisation: sodium bicarbonate or acetazolamide
39
Q

How can MTX overdose be treated?

A
  • antidote = folinic acid (leucovorin) given IV
  • timing critical
  • maintain high hydration (avoid acidic urine)
  • in high doses MTX crosses the BBB: danger of severe damage/ death if incorrectly dosed

Cancer (6 decks)

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