Lecture 4: Molecularly Targeted Therapeutics for Cancers PDF

Lecture 4. Molecularly targeted therapeutics for cancers CH3 N H3C O Tamoxifen PHAR3003 MPharm Year 3 Cancers...

Lecture 4. Molecularly targeted therapeutics for cancers CH3 N H3C O Tamoxifen PHAR3003 MPharm Year 3 Cancers Pharmaceutics Lead: Professor Cameron Alexander [email protected]  Targeted cancer therapies – hormone- dependent pathways Endocrine therapy to slow / stop growth of hormone-related cancers Not a cytotoxic therapy– range of administration routes and formulations possible Tamoxifen – weak base (pKa8.8) - Low aqueous solubility (< 0.01 % at 20 0C) CH3 N - Converted to citrate salt (solubility 0.5 mg/mL) H3C O to be given orally Tamoxifen - Originally screened in a drug development OH program to discover new contraceptive agents…. Is a pro-drug - antagonist of estrogen CH3 N H3C O receptor in breast via active metabolite 4- 4- Hydroxytamoxifen hydroxytamoxifen.  How biopharmaceutics affects therapy Tamoxifen –PK driven by metabolism (CYP3A4, CYP2C9, CYP2D6) Metabolites of tamoxifen are key in antineoplastic CH3 effect H3C N O - Bind to estrogen receptor but do not activate it Tamoxifen - 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4- hydroxytamoxifen (endoxifen) have 30-100 times greater affinity with estrogen receptor than tamoxifen itself - Mode of action is tissue dependent - Strongly antiestrogenic on mammary epithelium, but Has proestrogenic on uterine been described epithelium – hence as a ‘self-formulating drug’ is a Selective due to different activity in different Estrogen Different tissue Receptor locations dose Modulator responses to patients with different CYP 450 OH isoenzyme profiles OH CH3 CH3 CH3 HN HN N O O H3C O 4- Hydroxytamoxifen N- Desmethyltamoxifen 4- Hydroxy-N-desmethyltamoxifen (Endoxifen)  How biopharmaceutics affects therapy Patient responses and CYP 450 profiles Variant forms of CYP 2D6 gene can lead to delayed CH3 metabolism of tamoxifen into active metabolites H3C N O - Recommend genotyping of patients for CYP 2D6 variants Tamoxifen SSRIs – e.g. paroxetine, fluoxetine can decrease effectiveness of tamoxifen via competition for the CYP2D6 enzyme Not just CYP activity - Antiestrogen 450 – other via ERαfactors in targetcause tissuesvariable patient response - Although ~75% of all breast tumors are ERα-positive, Tamoxifen effective in ~ 2/3 of this population OH OH CH3 CH3 CH3 HN HN N O O H3C O 4- Hydroxytamoxifen N- Desmethyltamoxifen 4- Hydroxy-N-desmethyltamoxifen (Endoxifen)  Fulvestrant – long acting targeted endocrine therapy OH More potent than tamoxifen H – ERα binding affinities compared to estradiol O F F H H S F – Fulvestrant ~ 90%; Tamoxifen ~ 3 % HO F F Mode of action different to SERMs – Impairs dimerisation and translocation of ERα; also blocks cofactor recruitment at both activating sites. – ERα–fulvestrant complex unstable - rapidly degraded  reduction of cellular ERα, and negation of oestrogen signalling Not suitable for oral formulation – Water insoluble, high binding to plasma proteins (VLDL, LDL etc) – Administration is via injection every two weeks for first three doses, then 1 x per month  Formulation and biopharmaceutics of fulvestrant IM route allows for sustained dosing OH – Peak plasma concentration in 5-7 days, terminal t1/2 = 40-50 H days O F F H H S F – Repeated monthly administration results in ~2-3 fold HO F accumulation. F – Steady state reached after ~ 6 months with most accumulation after 3-4 doses. – High volume of distribution, Vss is 4.1±1.6 l/kg – Triphasic decline in plasma concentration and rapid distribution into peripheral tissues Formulation constraints for intramuscular (IM injection) – Sterilisable components, acceptable viscosity at required dose – Castor oil and co-solvents (benzyl alcohol, ethanol and benzyl benzoate) added to dose fulvestrant at 50 mg/ml.  Formulation of peptide drugs for hormone- dependent cancers Goserelin is a decapeptide agonist of luteinising hormone releasing hormone. Initial exposure to goserelin increases release of testosterone or oestrogen Long-term exposure blocks testosterone or oestrogen release. CHEMICAL CASTRATION due to desensitisation. Used to treat prostate cancer (>50k deaths in US per year) and early onset puberty. But goserelin has to be injected and has a 2 hour half-life How do you dose the patient chronically without daily injections?  Formulation concept for sustained peptide release A single dose that releases goserelin over 3 month period Use a polymer material that dissolves slowly to allow a peptide therapeutic to be liberated continually. =  Achieving Slow Dissolution Option 1 – High molecular weight water-soluble polymer Dense and entangled Disentangling gel Polymer chain in solution polymer solid  Achieving Slow Dissolution Option 2 – Chemical breakdown of the polymer Dense and entangled Chain scission of Dissolution of low polymer solid polymer molecular weight products  Problems with Option 1 Unreliable as dependent on entanglement Most polymers will dissolve quicker than required for goserelin What happens to the polymer after dissolution? Glomerular excretion does not occur with polymers of larger size than threshold value  ~ 40 kDa for water-soluble linear polymers  Particles of > 6-8 nm Poor renal excretion at high molar mass Option 2 - Polymers that slowly breakdown in the body Need a chemical group that hydrolyses Ester group O O O HO- 1 1 1 R R R R O R O R OH - O O H O O O O O O O O O O O O O O O O O O O O O O O O Poly(lactic acid)  Polymers that slowly breakdown in the body Polymer must be water-insoluble but low molecular weight degradation products must be water soluble. O HO M M M M M M M OH Water O insoluble 1 O R = M HO M M M M R O OH Water n swellable n O Water insoluble - High molar mass HO M Water OH soluble Low molar mass monomers water soluble Degradation is the chemical breakdown of polymer chains Erosion only starts when polymer chains have decreased in molecular weight sufficiently to create enough hydrophilic end groups to drive water solubility.  Poly(lactic acid) and related polymers Chemical structure O O n Polymerised from dimer called lactide CH3 O O O H3C H3C H3C O O O * H H H H O O O * CH3 CH3 CH3 O O O 3S, 6S- Lactide 3R, 6S- Lactide L, L- Lactide D, L- Lactide Effect of stereochemistry on PLA degradation Poly(DL-lactic acid) (PDLLA) takes approx 1 year to fully degrade Poly(L-lactic acid) (PLLA) takes more than 2 years to Dense fully degrade Low water penetration Explained by crystallinity. Slow hydrolysis – PLLA is semi- crystalline Lower density Loose packed chains More rapid water penetration – PDLLA is Faster hydrolysis amorphous  PLA undergoes bulk erosion Water penetration and chain scission is more rapid than erosion Hydrated Polymer Polymer Water Water Note: drug release occurs faster than polymer erosion as some drug can escape when the polymer hydrates Tailoring PLA degradation kinetics to match clinical need Add glycolic acid monomer to make a co-polymer CH3 O O No methyl side-chain O Less hydrophobic O O n O n n Poly(glycolic acid) - PGA Poly(lactic acid-co-glycolic acid) Usually polymerised by ring opening of PLGA lactide dimer analogue, glycolide GA component is more susceptible to hydrolysis due to lack of hydrophobic methyl group Therefore, increasing GA in PLGA should increase degradation rate (decrease degradation time) in the patient  Degradation Kinetics of PLGA 1 year Time to Predicted complete degradation kinetics degradatio n in body 6 months Note: LA is in DL form Actual All polymer in 3 months degradation small particle kinetics morphology PGA PLGA 50:50 PLGA 65:35 PLGA 85:15 PDLLA 0 % PLA 100 % PLA Polymer Type  Zoladex formulations Zoladex – 1 month depot system, 3.6 mg goserelin – PLGA with 50% DL-lactic acid and 50% glycolic acid – Mixture of high and low molecular weight polymer to fine tune controlled release. – Cylindrical rod of 11 x 1.1 mm Zoladex LA – 3 month depot system, 10.8mg goserelin – PLGA with 95% DL-lactic acid and 5% glycolic acid – Mixture of high and low molecular weight polymer to fine tune controlled release. – Rod of 18 x 1.5 mm Both subcutaneous injection Mature technology – review of development in Clinical Pharmacokinetics 2000, 39 (1), 27-48 Ian Cockshott  Zoladex release kinetics and testosterone suppression 10 Testosterone (nmd/L) Goserilin (mg/L Goserilin (mg/L 1.0 0.1 Time after initial injection (days) Time (weeks)  Zoladex LA and Zoladex release rates in practice Dosing is more rapid than predicted from polymer degradation alone Autocatalytic degradation is pronounced Increased local acidity as lactic acid oligomers cannot escape in rod systems H+ Hydration and fragmentation of the rod allows drug to release by a diffusion mechanism before full degradation of the polymer. Low molecular weight chains increase early erosion Plasticisation by lower molar mass components Drug release  Targeting therapeutics for signalling pathways Molecularly targeted drugs – Originally developed for cancers – Small molecule inhibitors or antibodies – Specifically inhibit signal transduction pathways – Prevent cancer growth, proliferation, and survival – Estrogen receptor (ER) antagonists and aromatase inhibitors – Immune checkpoint inhibitors Min, HY., Lee, HY. Molecular targeted therapy for anticancer treatment. Exp Mol Med 2022, 54, 1670–1694. Cho, H-S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003, 421,756–760  Targeting therapeutics for signalling pathways Molecular targeting – Initially, mainly small molecule drugs, – Major class - small molecule kinase inhibitors (SMKIs) – Most SMKIs suppress protein kinases involved in transformation, growth, proliferation, and survival of cancer cells. – Successful class of drugs, – Oral route many – advantageous examples for patients (gefitinib, palbociclib, – dasatinib, But, resistance can develop imatinib, lapatinib….) Min, HY., Lee, HY. Molecular targeted therapy for anticancer treatment. Exp Mol Med 2022, 54, 1670–1694.  Summation for lecture 4 Drugs can be targeted to signalling pathways implicated in cancers Lack of cytotoxicity can have benefits for patients Properties of the drugs can alter formulation requirements Need for sustained dosing rather than frequent injections requires innovative formulations New generation of oral-dosed molecularly targeted drugs offer many further benefits for cancer patients  Questions you should now be able to answer What are the key classes of molecularly targeted cancer drugs Why can tamoxifen be dosed orally but fulvestrant cannot? What are the advantages in terms of clinical practice of having different types of formulation (oral, IM)? What are the key factors in choosing a polymer for encapsulating a peptide-based therapeutic? What parameters can be varied in polymer formulations to control the release of drugs?