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European Pharmaceutical Contractor

Beyond a Single Pill

‘Demographic shift’, ‘ageing population’ and ‘silver tsunami’ are just a few phrases widely used to refer to the growing number of people aged 65 and over. The images associated with these terms often depict active, older adults who are enjoying their ‘golden years’ in good health. While this is true for the majority, it neglects another important impact of this demographic change: the dramatic rise of a patient population that reaches beyond 75 years, 85 years and even 95 years – many of whom have increasingly complex health issues.

This patient group faces a unique set of challenges, and the traditional ‘one-size-fits-all’ approach to drug design and development is not always appropriate for them. For example, with increased age, the likelihood of living with chronic disease rises (1). According to the US Centers for Disease Control and Prevention, chronic illnesses and conditions such as heart disease, stroke, cancer, diabetes, obesity and arthritis are among the most common, costly and preventable of all health problems (2).

Therapy Needs

The good news is that with the medicines introduced in recent decades, the majority of chronic diseases can be managed effectively today. For instance, to prevent cardiovascular events like myocardial infarction, low-density lipoprotein cholesterol-lowering drugs combined with antihypertensive medicines of different drug classes are prescribed together to significantly reduce risk (3).

Managing chronic diseases effectively, and earlier in the ageing process, can reduce the risk of fatal events and extend life expectancy. But this also gives the diseases that occur later in life, such as cancer, dementia and rheumatoid arthritis, an increased opportunity to develop. At the same time, advanced age can bring decreasing functional capabilities, making it difficult to live independently or manage medications appropriately.

Consequently, the patient population above 65 years is among the most heterogeneous, with the greatest need for, and use of, effective drug therapies. In light of this, the demographic shift significantly changes the needs of the majority of patients today, and requires a critical reflection on drug development paradigms and processes.

This article examines how a patientcentric approach to drug development and delivery can greatly enhance treatment outcomes for our ageing population.

Drug Development

Cancer

The predisposition to develop cancer grows rapidly with increasing age (4). Cancer is a complex disease process which scientists are starting to understand better through the application of genomics.

In recent years, new oncology drugs have been developed that target patients with a disease-specific biomarker. These drugs are small molecules that are administered orally. Due to the unmet medical needs in oncology, the new compounds were put on a fast-track development path to make them accessible to patients as quickly as possible. Because of the nature of the products, the clinical programme combines Phase 2 and 3 trials, leaving only limited time for pharmaceutical development.

To de-risk product development and clinical supplies, drug-makers often use simple powder blend capsules from early phases through to the marketed product. Simple powder blending and capsule filling is a well-known and understood, commercially-viable process that avoids any implications arising from changes to the product that delay product launch and patient access to innovative therapies.

Alzheimer’s Disease

Dementia, and specifically Alzheimer’s disease, usually become symptomatic at older age through impaired memory, language, motor activity, object recognition, swallowing and the disturbance of executive function required for daily activities.

The administration of medicines to these patients can be quite challenging for caregivers, as patients with dementia often refuse or forget to take medicines, or have difficulty swallowing a tablet or capsule (dysphagia). In order to overcome these issues, tablet crushing has become a common practice. This alteration of the drug presents a significant safety issue as the medication’s release and stability can dramatically change, especially in the case of a modified-release product.

However, pharmaceutical developers should anticipate these inappropriate alterations since dysphagia is common in patients with dementia, and factor this potential into the product design and development phase. For example, encapsulated active multiparticulate technology (also known as ‘sprinkles’) can be easily swallowed by adding to food or beverages to safely administer medicines. In addition, adherence-monitoring systems can promote compliance to the therapy, especially in patients with declining memory. As diagnostics are improved to identify Alzheimer’s disease in its earlier stages, adherence-monitoring systems can play an increasingly important role to ensure compliance.

Rheumatoid Arthritis
According to the US Centers of Disease Control and Prevention, rheumatoid arthritis (RA) prevalence is highest in patients aged 65-75 years (5). RA is a systemic inflammatory disease characterised by erosions of the cartilage and bone, and, occasionally, joint deformity with pain, swelling and redness. RA patients can have significant difficulty picking up and holding small objects like tablets. Also, these patients often do not have the dexterity to split tablets to achieve required doses. As a result, drug developers should consider which dosage form works best for these patients. An appropriate dosage form for an RA patient should be medium-sized with an oblong shape and be available in a wide variety of dosages. As RA patients are also often older, and have reduced visual acuity, the dose forms should be clearly differentiated from other products by the use of colour and large print.

Polypharmacy and Multimorbidity

Polypharmacy, or the use of multiple medications, is becoming an inevitable reality for patients with chronic diseases. Drug therapy among older adults is marked by two distinct challenges: the increasing complexity of the therapeutic regimen, and the decreasing functional capabilities of patients required for successful medication management and administration (1,2).

A typical example includes a 75-year-old patient’s medication schedule. This multimorbid patient has several medical conditions: asthma, type 2 diabetes, coronary heart disease, restless leg syndrome, leg oedema and lumbosciatica. Given the multiple chronic health conditions, this patient is prescribed 13 different drugs. The example clearly demonstrates that polypharmacy leads to very complex medication schedules that require a high level of management to ensure the patient adheres to the regimen.

To reduce complexity for patients with more than one chronic medical condition, drug products need to be designed and developed using a patient-centric approach to decrease the number of medicines that need to be taken, and provide dosage forms that are easier to identify, handle and swallow. For instance, the use of fixed dose combination (FDC) products that utilise flexible manufacturing technology platforms is a potential solution.

FDCs are able to convert varying dose strengths of different products into a single solid-dosage form. This can significantly reduce the number of medicines and simplify the dosing schedule to help prevent medication errors that may result from tablet splitting or forgetting to take individual medications. Combining FDCs with multiparticulates (for example, sprinkle capsule formulations) will further increase safety and effectiveness by addressing swallowing or administration issues in patients with dysphagia.

Facing Functional Declines

Being old in itself is not a disease, but its physical and cognitive impacts are just as important. Looking beyond the wrinkles and grey hair, bodies change in many ways, as evidenced by vision loss, reduced dexterity and impaired memory, to name a few.

By the time a person reaches 75 years of age, these changes can interfere with daily activities. For instance, loss in muscle strength might lead to sarcopenia, which reduces a person’s mobility to the point where he or she may not participate in social activities anymore. These patients may also stop drinking liquids to avoid going to the toilet, leading to dehydration, or they may stop taking their pills altogether as they are unable to open the pill boxes or containers.

The consequences for drug therapy are significant: a patient’s loss of mobility can lead to disconnection from healthcare professionals; dehydration can have a signifi cant effect on drug absorption, metabolism and excretion; and issues opening pill boxes might lead to non-adherence. Furthermore, maintaining a patient’s mobility is a critical prerequisite for independent living and the avoidance of expensive, personalised care. Preventing immobility by developing effective drug therapies against sarcopenia is in the interest of the patient, as well as the healthcare system, and will encourage the industry to invest in the relevant R&D. Therefore, drug therapy will continue to play a predominant role in later life, where patient-centred solutions are required to reduce complexity and allow patients to manage medications independently, in order to achieve desired therapeutic outcomes and quality of life benefits.

Demographic Realities

The reality of the current demographic has led to a new patient population that is very old, and suffering from multiple diseases and disabilities. As the patient ages, the prevalence of the typical age-related diseases and functional deterioration increases, leaving them to face progressively complex medication schedules and polypharmacy, as well as age-related functional declines that impact their daily activities and ability to take medications correctly.

Adherence to a prescribed drug therapy in ageing, multimorbid patients with complex drug therapies is key to achieving positive therapeutic outcomes and the prevention of hospitalisation due to medication-related errors. Therefore, drug therapy will need to move from the ‘single standard drug’ concept to integrated patient-centric therapies that are tailored to the needs and capabilities of targeted patients. By reducing complexity, patient-centric drug products increase adherence, safety and effectiveness – benefiting patients, as well as society and the healthcare system.

References


1. Centers for Disease Control and Prevention, NCHS data brief, Multiple chronic conditions among adults aged 45 and over: Trends over the past 10 years, July 2012. Visit: www.cdc.gov/nchs/data/ databriefs/db100.htm
2. Centers for Disease Control and Prevention, Chronic diseases and health promotion, Chronic diseases: The leading causes of death and disability in the United States. Visit: www.cdc.gov/chronic disease/overview
3. Kronish et al, Circulation 123: pp1,611-1,621, 2011
4. Parry C et al, Cancer survivors: A booming population, Cancer Epidemiol Biomarkers Prev 20(10): pp1,996-2,005, 2011
5. Centers for Disease Control and Prevention, Rheumatoid arthritis, Section VI. Visit: www.cdc.gov/ arthritis/basics/rheumatoid.htm#2


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Sven Stegemann is Director for Pharmaceutical Business Development at Capsugel. He leads common research projects with major pharma companies, as well as small and medium enterprises on a global base. A pharmacist by training, Sven holds a PhD in Pharmacology. His scientific interest areas include improving drug therapy in older adults through multidisciplinary and patient-centred science, and the delivery of affordable medicines through simplified product design and manufacturing.


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