There is evidence to suggest that survivors of breast cancer may experience memory loss and loss of cognitive function after exposure to chemotherapy. Whilst these effects are only slight this does not mean that they do not negatively affect the quality of lives of patients experiencing these consequences on a daily basis1. Breast cancer is currently the most common cancer in the UK, with around 55’000 diagnoses in 2014 alone2 and it is estimated that between 17-50% of these breast cancer survivors experience a decline in cognitive function3. There are currently no treatments options available for memory loss and loss of cognitive function specifically in breast cancer patients after exposure to chemotherapy. This clinical trial is sponsored by Wake Forest University Health Sciences and its aim is to compare the safety and effects of donepezil (Aricept®) as well as its effects on memory loss in patients who have received chemotherapy for breast cancer4. In the UK the only current licenced use of donepezil is in the treatment of Alzheimer’s disease, this is also true for the USA where the trial is taking place.
This trial is a randomized, placebo controlled, double-blind, parallel group Phase 3 design and its primary objective is to determine how well a 24-week course of donepezil improves memory and cognitive function in patients who have reported cognitive dysfunction and demonstrate a decline in memory function 1-5 years after exposure to chemotherapy, compared to a placebo treatment (a sugar pill)5. The trial also has a secondary objective to determine any toxicities and adverse reactions to donepezil after being treated with it for 24 weeks5. There are two arms to this trial to which patients are randomly allocated; Arm 1). Patients will take one 5mg tablet of donepezil daily for 6 weeks followed by two 5mg tablets daily for 18 weeks and after 24 weeks begin a 12-week wash-out period, Arm 2). Patients will follow the same regime but instead take a placebo pill (sugar) rather than donepezil4.
Before patients are selected for the trial they will be asked “How would you rate the change in your ability to think including remembering, organizing your thoughts and speaking since you were first diagnosed with cancer?" and will choose from the following choices; 'No change or better', 'mildly worse', 'moderately worse', 'much worse'. For a patient to be selected for the trial, they must respond with either of the latter two responses as well as scoring less than 7 words recalled in a Hopkins Verbal Learning Test-Revised (HVLT-R) at entry level4. This initial self-assessment limits the trial’s reliability as different patients will have different individual standards for each answer. There are then eight further primary outcome measures including changes in controlled oral word association (COWA) test results which measures speed of mental processing, verbal fluency, and executive function4, which are measured at the baseline of the trial and then 12, 24, and 36 weeks later.
Eligibility criteria for this trial is extensive and includes; patients must be female and aged between 18-75 years old with a history of invasive breast cancer for which they have completed at least 4 cycles of chemotherapy 1-5 years prior to registration, and a self-reported cognitive problem. Patients must be able to speak English and will not be allowed to take part if there is evidence or suspected recurrent or metastatic disease or prior brain irradiation. Patients who currently use donepezil, galantamine, rivastigmine, or any other specific cognition enhancing drug should not have used them within 4 weeks prior to registration. Pregnant and breast feeding women are excluded from the study due to known teratogenic effects of donepezil. These eligibility criteria ensure there are few ethical issues with this trial as it does not include children, and because the trial treatment is not for a life threatening disease there is no ethical issues regarding fairness regarding patients receiving a placebo treatment.
Estimated enrolment for this trial is 276, a 445% increase from a pilot study where there was only 62 enrolled with only 76% of those enrolled actually completing the trial. This pilot study found that there was marked improvement in those who took donepezil compared to the placebo, justifying a further, larger study into the effects of donepezil on memory and cognitive function in breast cancer patients exposed to chemotherapy6. The increase in enrolment will provide much more statistically reliable results.
REFERENCES: 1Munir, F. et al. Cancer Nursing. 34, 389-392. (2011). 2Cancer Research UK. Breast cancer incidence statistics. URL: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive [11/10/17]. 3Cancer Research UK. Chemo Brain. URL: http://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/chemotherapy/side-effects-chemotherapy/chemo-brain/about [11/10/17]. 4ClinicalTrials.gov. Phase 3 Radomized Placebo Controlled Clinical Trial of Donepezil. URL: https://clinicaltrials.gov/ct2/show/study/NCT02822573 [11/10/17]. 5National Cancer Institute. Donepezil in improving cognitive performance in Breast cancer patients after receiving chemotherapy. URL: https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=782321 [13/10/17]. 6Lawrence, J. A. et al. Journal of Cancer Survivorship. 10, 176-184. (2016).
Chemistry of the API
Donepezil hydrochloride is the salt form of the donepezil and is what is used in this trial; however, the active moiety is donepezil alone and its 2D structured is presented on the right of the page. Donepezil has the molecular formula C24H29NO3 and it may also be identified by its IUPAC name 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one. It has a molecular weight of 379.5g/mol, a LogP value of 3.6, zero hydrogen bond donors, and four hydrogen bond acceptors, meaning the molecule adheres to Lipinski’s ‘rule of 5’ meaning that good absorption or permeation across the blood brain barrier is more likely1. However, since Donepezil contains a basic tertiary amino group2 with a pKa of approximately 8.82 it will mean that at a physiological pH of 7.4 most of the molecule will be protonated3 and therefore ionised3 by the HCl to form the salt version of donepezil hydrochloride which is less likely to be able to cross the blood brain barrier, where the drug will be acting.
Donepezil has a chiral centre at the second carbon of the indanone moiety, as pointed out in the diagram above, meaning donepezil exists as a pair of enantiomers with both R and S conformers4. This is a stand out feature of donepezil as both enantiomers have nearly the exact same molecular shape displaying high intramolecular stability and is currently produced as a racemic mixture as both enantiomers are pharmacologically active and display extremely similar pharmacological properties4.
There are many routes of synthesis of donepezil, many producing a low yield for example Sugimoto, H. et al. describe a route with a yield of only 27.4%5. R. Rao et al. experimented however to find a synthesis method with a much more cost efficient yield of 75-80%. Their synthesis begins with a condensation reaction of 5,6‐dimethoxy‐1‐indanone and 1‐benzyl‐4‐piperidinecarboxaldehyde to produce 1‐benzyl‐4‐[(5,6‐dimethoxy‐1‐indanone)‐2‐yidenyl] methyl piperidine, which is the key intermediate in the synthesis of donepezil, in order for this reaction to be successful it must be carried out at a high temperature and in the presence of alkalimetal carbonates. 1‐benzyl‐4‐[(5,6‐dimethoxy‐1‐indanone)‐2‐yidenyl] methyl piperidine is then hydrogenated to produce donepezil5. This is summarised in figure 1 below.
Hydrate, crystalline, and anhydrous polymorphic forms of donepezil hydrochloride are known to exist6, however this does not appear to be important in the synthesis of donepezil as it is seemingly difficult to find literature that may suggest otherwise. There also appears to be few problems regarding stability of donepezil hydrochloride.
Other acetylcholinesterase inhibitors include Rivastigmine and Galantamine, the structures of which are shown below. They all contain a tertiary amine but apart from this there are few structural similarities with the exception of donepezil and rivastigmine both containing a relatively long carbon backbone chain.
REFERENCES: 1Lipinski, C.A. et al. Advanced Drug Delivery Reviews. 46, 3-26 (2001). 2Francis, S.A. et al. “Integrated Pharmacy Case Studies”, Pharmaceutical Press (2014). 3Angelantonio, S.D. et al. British Journal of Pharmacology. 141(4), 644-652 (2004). 4Sugimoto, H. et al. Current Medicinal Chemistry. 7, 303-339 (2000). 5Roa, R.J. et al. An International Journal for Rapid Communication of Synthetic Organic Chemistry. 37, 2847-2853 (2007). 6MHRA. Donepezil hydrochloride Public Assessment Report. URL: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con036291.pdf [15/10/17] 7Cacabelos, R. et al. Neuropsychiatric Disease and Treatment. 3, 303-333 (2007).
Pharmacology of the API
Whilst the use of donepezil in this trial is not for Alzheimer’s disease (AD), it is still being used for the same symptoms as in AD; memory loss and decline of cognitive function. Acetylcholine is involved in the activation of post-synaptic muscarinic and nicotinic receptors leading to transmission of nerve impulses responsible for cognitive function4. People suffering with AD have been found to have reduced amounts of acetylcholine in the brain5 namely the hippocampus and the cortex, so, since breast cancer patients exposed to chemotherapy are experiencing the same symptoms as in AD, this might also be the cause of their memory loss and decline of cognitive function.
Donepezil, also known as E2020, is a derivative of piperidine1, and is a reversible, selective, non-competitive acetylcholinesterase inhibitor2. Memory loss and cognitive function are thought to be a result of a lack of acetylcholine, donepezil works to inhibit the effects of acetylcholinesterase, thereby increasing the amount of available acetylcholine, by binding to hydrophobic binding sites of the acetylcholinesterase enzyme2. This results in an increase in cholinergic activity and therefore and enhancement of cognitive function3.
The potency of donepezil has been thoroughly researched by Sugimoto, H. et al. who have written a comprehensive article on their findings which I have summarised here: Donepezil has been found to have a more specific and longer length of action compared with other acetylcholinesterases such as galantamine and rivastigmine, this is thought to be due to donepezil containing and N-benzypiperidine and an indanone moiety. The indanone ring has been shown to be essential in donepezil’s characteristically high potency for acetylcholinesterase, as when this was replaced with other substituents there was a marked decrease in the potency of the drug. More specifically it is the carbonyl group of this indanone ring that proved to be most essential to donepezil’s activity as when it was replaced by an indanol group and then an indene group, there was again another marked decrease in potency of donepezil. Moreover, donepezil was found to bind much less strongly to acetylcholinesterase’s active site when the methoxy group of the carbonyl group at the para position was removed3. The mechanism of action is summarised in the diagram to the side.
Donepezil appears to have many advantages over other APIs of its class including a much higher selectivity for acetylcholinesterase compared to tacrine, an acetylcholinesterase inhibitor that was withdrawn due to concerns over hepatotoxicity6 as well as its many side effects such as vomiting and diarrhoea becoming a concern for safety.
When donepezil is administered orally as it is in the trial, it is absorbed in the gastrointestinal tract9. The metabolism, distribution, and elimination profiles of donepezil have been discussed extensively by Jann et al. and are summarised here. CYP3A4 and CYP2D6 were found to be the primary enzymes by which donepezil is metabolised before it undergoes extensive first-pass metabolism in the gut and liver. The key metabolites formed for donepezil are 6-O-desmethyldonepezil and donepezil-cis-N-oxide, resulting from hydrolysis and oxidation reactions respectively7, with only the former metabolite displaying equal pharmacological activity to donepezil. Donepezil has a volume of distribution of 12L/kg8 meaning that the majority of the drug, 96%, is protein bound in the plasma. More specifically 75% is bound to albumin and 21% to α1-acid glycoprotein. The half-life of donepezil is estimated to be around 70-80 hours7.
References: 1Greunen, D.G. et al. European Journal of Medicinal Chemistry. 126, 671-690 (2017). 2 Jelic, V. et al. Clinical Medicine Insights: Therapeutics. 2, 771-788 (2010). 3Sugimoto, H. et al. Current Medicinal Chemistry. 7, 303-339 (2000). 4Wilkinson, D.G. et al. Drugs and Aging. 21, 453-478 (2004). 5Tabet, N. Age and Ageing. 35, 336-338 (2006). 6Mehta, M. et al. International Journal of Alzheimer’s Disease. 2012, 1-8 (2011). 7Jann, M.W. et al. Clinical Pharmacokinetics. 41, 719-739 (2002). 8Drugbank. Donepezil. URL: https://www.drugbank.ca/drugs/DB00843 [01/11/17]. 9Heydorn, W.E. Expert Opinion on Investigational Drugs. 6, 1527-1535 (1997).
Formulation of the API
In this trial, donepezil is being delivered orally using 5mg standard release tablets. In the UK donepezil is only available as oral administration forms, namely, tablets, orodispersible tablets, and oral solution, this is also true for the USA where the trial is taking place, where modified release tablets with a 23mg strength are also available there exclusively.
Aricept is formulated as donepezil hydrochloride, a salt preparation. Donepezil alone is a base so with the addition of the hydrogen chloride acid molecule it is able to form a salt, via protonation of the nitrogen atom.
Formulating donepezil, a weak base, as a salt; donepezil hydrochloride will increase its solubility and dissolution rate at biological pH 7, i.e. the conditions of the intestine, due to the buffering action of the salt1. However, donepezil hydrochloride may be less well absorbed in the stomach due to the precipitation of any free base at the bottom of the tablet which will cause a decrease in dissolution rate and decrease in solubility1. However, this should not be a problem in this trial as donepezil when administered orally in tablet form is absorbed mainly in gastrointestinal tract2.
Excipients in Aricept 5mg tablets
Role of Excipient
Lactose monohydrate
Filler
Maize starch
Disintegrant
Cellulose microcrystalline
Diluent
Hyprolose
Binder
Magnesium stearate
Lubricant
Hypromellose
Solution binder
Talc
Glidant/Lubricant
Macrogol
Binder
Titanium dioxide (E171)
Opacifier
As well as containing 5mg of donepezil hydrochloride in each 5mg Aricept tablet, there is also an extensive list of excipients which are summarised in table 1.
Manufacturing donepezil as a salt i.e. donepezil hydrochloride poses manufacturing problems such as degradation of the tools used to punch the tablets1.
References: 1Makary, P. UK Journal of Pharmaceutical and Biosciences. 2, 1-4 (2014). 2Wright, P. Core Psychiatry. Saunders Elsevier (2012). 3Aricept Tablets, PIL, Eisai (2016).
Use of the API in Practice
Whilst donepezil is used to treat a decline in cognitive function and memory loss, in practice it is only licensed for this when the cause of these symptoms is Alzheimer’s disease; that is to say, the use of donepezil to treat decline in cognitive function and memory loss in breast cancer patients exposed to chemotherapy, is not a current licensed indication of donepezil.
For the treatment of mild to moderate dementia in Alzheimer’s disease in adults the dosage is initially one 5mg tablet every night for one month, and then if necessary the dose can be increased up to 10mg every night1; this is not dissimilar to the dosing regimen being used in the clinical trial as discussed in the trial overview. Donepezil is currently only available as oral dosage forms including tablets, orodispersible tablets, and oral solution. Specific directions for administration for donepezil orodispersible tablets advise that the orodispersible tablet should be placed on the patient’s tongue, allowed to disperse, and then swallowed, patients and carers should be given advice, either by a pharmacist or doctor, on how to properly administer donepezil orodispersible tablets, this information is available in the BNF1. Orodispersible tablets are usually given to patients who have difficulties swallowing as they do not require water 2 whilst this may be more common in the use by Alzheimer’s patients as these patients are often older, it is unlikely that patients from the trial would require orodispersible tablets and they are given normal tablets regardless.
CYP3A4 Inhibitors
CYP2D6 Inhibitors
Enzyme Inducers
Ketoconazole
Fluoxetine
Rifampicin
Itraconazole
Quinidine
Phenytoin
Erythromycin
Carbamazepine
Diarrhoea, nausea, and headache are the most common side effects of donepezil with one or more out of every ten patients taking donepezil experiencing these side-effects3. Patients who are taking beta-blockers are more at risk of experiencing bradycardia if they take donepezil concomitantly, this is also true for digoxin and fluoxetine4. As beta-blockers are a relatively commonly prescribed drug, this may limit the size of the trial in order to find patients who are not taking beta-blockers. Due to the cholinometic actions of donepezil, donepezil should be prescribed with care in patients with asthma or obstructive pulmonary disease3, this is not an exclusion criterion for participation in the trial and may therefore be a limit on the safety of the trial. Patients taking NSAIDs, or who have a history of gastric ulcers, should be monitored for symptoms of the development of gastric ulcers when taking donepezil3. These symptoms may include stomach pain shortly after eating, indigestion, nausea, and in serious cases vomiting blood and passing dark blood stained stools5. If patients of the trial do experience these symptoms and are taking NSAIDs or have a history of gastric ulcers, they should stop taking donepezil and/or their NSAID and withdraw from the trial. If patients are likely to need to undergo surgery requiring anaesthesia, this should be done so with caution as donepezil is likely to enhance muscle relaxation during the anaesthesia3. Plasma concentration levels of donepezil may be raised by drugs inhibiting the CYP3A4 and CYP2D6 isoenzymes, and reduced by enzyme inducers6, examples can be found in table 1 below. Patients taking ketoconazole and quinidine are not allowed to take part in this trial, presumably due to their inhibitory effect.
Currently there is no data on the use of donepezil in patients with hepatic impairment therefore no comment can be made on its safety in these patients so use should be avoided7. Donepezil should not be taken by women who are breastfeeding as donepezil was found to be excreted in the breast milk of rats when studied and pregnant women should only take donepezil if it absolutely necessary due to animal studies highlighting peri- and post-natal toxicity3. In the context of this trial, this may limit participant numbers as 15% of breast cancer cases occur in women of childbearing age8.
References: 1Meds Complete, BNF: Donepezil. URL: https://www.medicinescomplete.com/mc/bnf/current/PHP3239-donepezil-hydrochloride.htm?q=donepezil&t=search&ss=text&tot=64&p=1#PHP43988-indications-and-dose [30/10/17] 2Hannan, P.A. et al. Indian J Pharm Sciences. 78, 2-7 (2016). 3Aricept 5mg and 10mg tablets, SPC, Pfizer (2016). 4NICE, Donepezil Interactions. URL: https://bnf.nice.org.uk/interaction/donepezil.html [30/10/17]. 5NHS Choices, Stomach Ulcer symptoms. URL: https://www.nhs.uk/conditions/stomach-ulcer/ [30/10/17]. 6Meds Complete, Martindale:Donepezil. URL: https://www.medicinescomplete.com/mc/martindale/current/3627-b.htm?q=donepezil&t=search&ss=text&tot=274&p=1#m3627-a3-l [31/10/17]. 7Meds Complete, BNF: Donepezil. URL: https://www.medicinescomplete.com/mc/bnf/current/PHP3239-donepezil-hydrochloride.htm?q=donepezil&t=search&ss=text&tot=64&p=1#PHP43994-hepatic-impairment [30/10/17]. 8RCOG, Pregnancy and Breast Cancer, (2011).