Abstracts

Rationale: "Forgiveness" is defined as the difference between a drug's post-dose duration of action (D) and the prescribed dosing interval (I): F=D-I. Forgiveness is therefore a measure of the latitude in therapeutic effect if doses are missed. However, the concept assumes that 1) D is well-defined and constant and 2) a longer I will always result in lower forgiveness (shorter time to loss of therapeutic effect) if a dose is missed. For antiepileptic drugs (AEDs), the risk of breakthrough seizures is purportedly greater with missed doses of an XR AED dosed QD than with the immediate-release (IR) formulation dosed BID. However, this oversimplifies the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug and ignores the impact of increased drug load as well as an XR formulation's release profile on the product's duration of action. Computer simulation allows testing of forgiveness associated with an IR-AED and its XR counterparts reformulated for less frequent daily dosing. Methods: Plasma concentration-time profiles were simulated for a hypothetical AED. Simulations used a one-compartment model with first-order absorption and first-order elimination. IR and XR formulations were modeled at same total daily dose and same systemic parameters (clearance and volume, thus half-life) but different absorption rate constant (k_a). Simulations compared forgiveness when IR was dosed TID (I=8 hr), BID (I=12 hr), and QD (I=24 hr) and when suitably designed XR formulations were dosed BID and QD. D was calculated following abrupt discontinuation of dosing and was defined as the time from last administration to the time plasma drug concentration fell below a hypothetical threshold therapeutic AED concentration. Results: In simulations with a hypothetical AED (180 mg/day) with 8.7 hr half-life, the duration of action (D) increased for both IR and XR formulations as the total daily dose was administered in increasingly larger individual doses (60, 120, 180 mg) at correspondingly shorter dosing intervals (I=8, 12, 24 hr). However, for the IR AED, which had the same k_a regardless of I, the small increase in D could not offset the effect of increased dosing interval, causing the forgiveness period (F) to shorten. In contrast, with XR formulations specifically designed so that k_a decreased as the dosing interval increased, the duration of action was longer than with the corresponding IR regimen. As a result, forgiveness was longer for the XR vs IR AED given at the same dose and dosing interval. Furthermore, forgiveness was no shorter and perhaps even longer with QD or BID dosing of the XR AED than TID dosing of the IR AED. Conclusions: While the traditional view of forgiveness - impact of missed doses is greater with QD vs BID administration - may be true for IR AEDs considered alone, computer simulation shows that forgiveness can remain the same or even increase with an appropriately designed XR AED. Controlled drug release with XR reformulation prolongs drug input and changes the PK profile that determines duration of action, thereby extending post-dose duration of therapeutic concentrations.