Patient adherence: the true costs

FOR THE majority of clinical conditions, rapid diagnosis followed by fast and effective treatment is vital to a patient’s continued quality of life and potentially their ongoing survival. However, a major impediment to the efficacy of any medical treatment is the patient’s failure to take the medicine in accordance with the patient insert leaflet (PIL) or physician’s recommendations. Even in countries with good healthcare systems and knowledgeable patient populations, patient adherence can still be low, with 40 percent failing to follow dosing instructions.¹ This can rise to 70 percent when dosing regimens are complex and/or necessitate changes in lifestyle, such as dietary changes.²

Patient non-adherence (or non-compliance) is a multi-faceted issue; the physician’s advice is often followed with the best of intentions and/or ability, but intermittently forgotten, ignored, misconstrued or misinterpreted.³ Pill burden is often a significant factor in non-compliance, particularly for older individuals.⁴ Another factor causing patient confusion, and resulting in poor adherence, is the dosing interval of the medicinal product. Meta-analyses across multiple clinical studies suggest that within acute and chronic disease states, decreasing dosage frequency from multiple daily dosing (ie, twice and thrice daily – bid and tid, respectively) to daily dosing (ie, od) may radically improve patient adherence.⁵ This confusion is also exacerbated if patients are taking multiple drug regimens where drugs have different dosing frequencies (ie, some are tid, some are bid, while others are od).⁶

One of the main factors contributing to bacterial resistance is non-compliance; whereby the patient often follows the dosing instructions until they feel better, then discontinue the medication before the dosing regimen is fully complete.⁷ The healthcare cost repercussions are also significant. In the US alone, the cost is estimated at over $100 billion per year.⁸ In 2015, the annual “disease-specific economic cost of non-adherence per person ranged from $949 to $44,190”.⁹ Non-adherence also increases patient mortality rates in many disease states.¹⁰

Therefore, reducing the pill burden by developing fixed dose combinations (FDC) of therapeutically related drugs¹¹ can be an attractive proposition. FDCs can offer convenience to patients and simplify complex dosing regimens in various disease areas such as HIV, cardiovascular diseases, TB and diabetes.¹² FDCs can also be easier to pack and distribute, improve reliability and be less expensive than the corresponding single-dose formulations. A single tablet FDC regimen of all treatment therapies was found to be linked with “higher adherence rates, decreased hospitalisations and more patients with an undetectable viral load” than patients taking multiple tablets for treatment of HIV/AIDS.¹³ The main chemistry, manufacturing and control) (CMC) challenges with development and manufacture of FDCs are the physical and chemical compatibility of two or more drugs; for instance, combining an anionic drug – ie, dolutegravir sodium – with a cationic drug – ie, abacavir sulfate in Triumeq^TM14 – is challenging. This is often addressed by separating the incompatible components and manufacturing bi- or tri-layer tablets, compression-coated tablets, multi-particulates, etc. Decision trees are useful aids in determining formulation strategies.¹⁵ The other related CMC problem is the necessary high drug loading within the formulation. For many HIV combinations, the active dose is ≥1g (eg, TriumeqTM)¹⁴ and with added excipients the compression weight of the resultant tablets is often ≥1.2g. As such, the flow and compression properties of the combination drugs must all be “fit for purpose”. The size of such FDC dosage forms often necessitates a functional break-line to facilitate swallowing.

The other strategy for reducing pill burden is reducing the dosing interval by developing longer acting therapies. Moving beyond the once daily dosing paradigm will be important in the future. As such, once weekly oral¹⁶ or once monthly (or longer)¹⁷ injectable dosing regimens would significantly enhance treatment outcomes.

References

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