Sunday, February 21, 2016

Extended-release antiepileptic drugs

Seizures may result in physical, psychological, and social repercussions. One might assume that people with epilepsy would adhere rigorously to their medication regimens in order to prevent these deleterious outcomes. However, epilepsy patients, like patients with other illnesses, do not always take their medications as prescribed.

Furthermore, an inverse relationship exists between the number of doses prescribed per day and adherence: The more frequently medication must be taken, the less likely it is the patient will consume all doses. Many patients fail to achieve 100% adherence even with once-a-day dosing. Although 100% medication adherence does not guarantee seizure control, lack of adherence, not surprisingly, may result in increased seizure frequency.
More than 25 years ago, Cramer and colleagues  used a medication event monitoring system to measure adherence in several groups of people with epilepsy. The system records the time that the medication bottle is opened on a computer chip contained within the cap. The results can then be printed and analyzed when the patient returns for follow-up.
Even though patients had consented to the study and knew they were being monitored, only 76% of doses were taken as prescribed. Adherence was 87% for once-a-day medications, 81% for twice-daily medications, 77% for medications taken three times daily, and only 39% for those taken four times daily.
Other adherence studies have revealed similar results.  These findings provide a clear rationale for clinicians to limit the number of daily medication doses for each patient in order to optimize adherence.
Extended-release (ER) preparations offer a means to decrease dosing frequency compared with immediate-release (IR) medications. In addition, ER preparations offer more consistent serum drug levels with higher troughs, which may protect against breakthrough seizures, and lower peaks, which may mitigate dose-related side effects…
Although compliance may be enhanced by a once-a-day ER product, clinicians may hesitate to prescribe such preparations because the consequences of a missed dose may be more severe owing to the extended interval before the next dose.  Pellock and Brittain  recently addressed this issue in an industry-sponsored computer-modeling pharmacokinetics study. Defining "forgiveness" (F) as the "margin of therapeutic effect following a missed dose," the authors calculated F as the difference between duration of action (D) and dosing interval (I), or F = D – I.
Concentration/time curves were calculated for IR and ER formulations (called "XR" in their study). For both formulations, duration of action increased with larger doses. The duration of action was longer post-dose for ER than IR products, which tended to mitigate the drop in level from a missed dose.
The authors observed, "Compared with TID [three times daily] dosing of the IR formulation, the forgiveness interval was the same (XRBID) or even longer (XRqd) with the XR AEDs." They attributed this effect to the slower release rate and prolonged time of absorption of the ER product.
The choice of an AED must be individualized for each patient, taking into account such factors as patient age, comorbidities, seizure type, epilepsy syndrome, adverse events, genetic profile, formulation (liquid, tablet, capsule, sprinkle), insurance coverage, and medication cost.
A choice must also be made between IR and ER preparations, and sometimes between different ER preparations. Pharmacokinetic modeling by Pellock and Brittain suggests that patients may benefit from ER products without necessarily suffering a larger drop in serum level compared with an IR product after a missed dose. More detailed in vivo comparative studies between ER and IR products that include seizure counts, adverse effects, and serum levels would fortify their argument.
Nonetheless, ER preparations offer the possibility of improved tolerability, more stable serum levels, and enhanced adherence and should be considered for appropriate patients. In addition, all patients with epilepsy should be educated regarding the importance of not missing a dose, whether they are taking an IR or ER product.

1 comment:

  1. Pellock JM, Brittain ST. Use of computer simulations to test the concept of dose forgiveness in the era of extended-release (XR) drugs. Epilepsy Behav. 2016


    "Forgiveness" - the difference between a drug's postdose duration of action and its prescribed dosing interval - estimates the margin of therapeutic effect following a missed dose. Because this margin presumably decreases as dosing becomes less frequent, QD dosing of an antiepileptic drug (AED) is expected to be less forgiving than more frequent (e.g., BID) dosing of that same AED. However, if the AED is reformulated as an extended-release (XR) preparation, drug input may be prolonged relative to its immediate-release (IR) counterpart. It therefore stands to reason that forgiveness could be increased by an XR AED that extends the period during which therapeutic plasma concentrations are maintained if a dose is missed. Computer simulation was used to estimate forgiveness for an IR formulation of a hypothetical AED and its XR counterparts reformulated for less frequent dosing. Simulations determined forgiveness when the hypothetical IR AED was dosed TID, BID, and QD and when suitably designed XR formulations were dosed BID and QD. Simulations showed that forgiveness for an XR formulation can equal or exceed that for an IR formulation dosed more frequently.