Forgiven if forgotten: Dealing with deviations in dosing consistency

In both clinical trial environments and in the post-approval real world, problems with adherence to a given drug’s dosing schedule can carry important implications.?

In the closely controlled conditions of a clinical trial, non-adherence can, if unmonitored or undetected, impact on the validity of results by corrupting the ability to accurately measure the relationship between drug exposure and therapeutic effect.??

And in the real world, non-adherence is an inevitable risk that has the potential to impair patient outcomes. This can range from merely delaying recovery at one end of the spectrum to introducing more serious health problems at the other.?

But the fact that isolated instances of non-adherence do not always have immediate drastic consequences can be explained by the concept of forgiveness. This pertains to a drug’s ability to accommodate deviations in adherence without its effectiveness being significantly impacted (1). Essentially, it acknowledges the drug’s capacity to continue its beneficial action even if patients deviate from their prescribed dosing schedule.?

Forgiveness is determined by the therapeutic window of the drug in question, but it can vary between individuals and over time, and often relies on the chosen dose and dosing regimen. Therefore, during a drug’s development process, it is important to define the therapeutic window and identify the most common variations in adherence so that the optimal level of forgiveness can be determined.?

Knowledge of a drug’s forgiveness allows for the establishment of an adherence threshold, separating acceptable deviations from those that will have more significant impact. Take, for instance, cardio-aspirin (acetylsalicylic acid), commonly administered once daily. Despite its plasma half-life being a mere 20 minutes, its effect persists for the duration of the platelets’ lifespan, which spans several days – a characteristic that offers a degree of forgiveness for patients since occasional lapses of one or two consecutive missed doses will fall within the acceptable range.?

In stark contrast, direct oral anticoagulants (DOACs), some of which are also administered once daily, exhibit an unforgiving nature, where even a single missed dose has the potential to disrupt the continuous anticoagulant effect (2).?

These examples underline the critical importance of understanding precisely how an approved drug behaves within the body, both for patients who diligently follow their prescribed regime and for those who occasionally fail to meet their dosing obligations.?Discovering the ideal dosing regimen that promotes optimal forgiveness for the most common lapses in medication adherence enables the maximization of clinical benefits without heightening the risk of side effects, which often serve as the primary reason for treatment discontinuation.?

In the real world, the idea of eradicating non-adherence altogether remains an unrealistic vision, but by improving the measurement of non-adherence in trials, there is potential to enhance the insights that underpin knowledge of a drug’s therapeutic effect. This, in turn, provides clearer knowledge of how it might forgive those patients who, on occasion, might delay or miss a dose.?

(1) Osterberg LG, Urquhart J, Blaschke TF. Understanding forgiveness: minding and mining the gaps between pharmacokinetics and therapeutics. Clin Pharmacol Ther. 2010 Oct;88(4):457-9. doi: 10.1038/clpt.2010.171. PMID: 20856243.

(2) Vrijens B, Heidbuchel H. Non-vitamin K antagonist oral anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace. 2015 Apr;17(4):514-23. doi: 10.1093/europace/euu311. Epub 2015 Feb 17. PMID: 25694538.