The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation

Abstract

Objectives To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Methods Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. Results The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. Conclusions The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician’s justification of the patient’s seizure control.

Handling Delayed or Missed Dose of Antiseizure Medications

“…The recommendations in this study were consistent with those in previous studies for carbamazepine, 16 valproic acid, 17 lamotrigine, 18 levetiracetam, 20 and phenobarbital. 21 However, previous studies were limited to only typical patients or scenarios. In our study, we went further to systematically assess the remedial regimens in both children and adults on various concomitant medications and at different pathophysiologic statuses.…”

“…Population pharmacokinetic (PK) modeling and simulation are regarded to be efficient and have been applied to develop remedial dosing regimens for ASMs, including carbamazepine, 16 valproic acid, 17 lamotrigine, 18 eslicarbazepine acetate, 19 levetiracetam, 20 and phenobarbital. 21 However, because the prediction and simulation by the gold-standard population PK software (NONMEM) used in previous studies is too time consuming, only typical patients with commonly used regimens were investigated. [16][17][18][19]21 Optimal remedial regimens for various delayed or missed dose scenarios were incompletely explored.…”

“…21 However, because the prediction and simulation by the gold-standard population PK software (NONMEM) used in previous studies is too time consuming, only typical patients with commonly used regimens were investigated. [16][17][18][19]21 Optimal remedial regimens for various delayed or missed dose scenarios were incompletely explored.…”

Managing delayed or missed pregabalin doses in patients with focal epilepsy: a Monte Carlo simulation study

“…The Monte Carlo simulation economically and systematically evaluates various dosing regimens and has been used to assess the PK impact of irregular AED dosing [10,16,19,20,28,29]. Here, we employed a therapeutic instead of a xed reference range to investigate the effects of delayed or missed pregabalin doses.…”

“…Here, we employed a therapeutic instead of a xed reference range to investigate the effects of delayed or missed pregabalin doses. A therapeutic range is more realistic than a xed reference range as it provides a dynamic goal based on patient demographics and the indicated dose regimen [19,20,29]. In the present study, deviation time was used to assess the optimal remedial strategy as it more comprehensively described patient risk outside the therapeutic range than the trough and peak concentrations.…”