Rapid Switchover to Carbamazepine Using Pharmacokinetic Parameters

Abstract

Summary:Purpose: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the singledose kinetic study can yield the desired concentration at steady state (C,,); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period.Methods: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) andor primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean C,, of 10.2 (&2.2) mgA. On day 2, patients received a CBZ dose equivalent to 10 mgkg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1; PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mgA was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED.Results: All patients completed the switchover to CBZ within a mean time period of 6 days (22), reaching a mean maintenance dose of 1,639 mg/day (rt370) which yielded a mean C,, of 11.3 (k3.2) mg/l. The maintenance dose had to be lowered by 20.4% (28.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients 2-55 years (p = 0.017, Fisher's exact test).Conclusions: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.

Comparative Cognitive Effects of Carbamazepine and Gabapentin in Healthy Senior Adults

“…Arguably, slower titration schedules and lower end‐state dose levels for this study may have reduced the incidence of side effects. In this study, titration times and end‐dose points were both designed to reflect recent experimental findings (22,23). The titration rate used in our study may not be typical of the clinical situation for management of seizures in the elderly and therefore may have contributed to the high study dropout.…”

“…Initial CBZ dose was 200 mg/day for the first 2 days, then increasing by 200 mg/day dosing on day 3, day 5, and then on day 7. Feasibility and pharmacokinetic studies of similar oral loading of CBZ in young adults with epilepsy has resulted in minimal AEs unless accompanied by history of static encephalopathy (22–24). Initial GBP dose was set at 800 mg/day till day 4, at which time dosing increased to 1,600 mg/day and finally to 2,400 mg/day by day 7.…”

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

“…It is of interest to note that in contrast to that with PB, pretreatment with PHT or CBZ did not induce cross‐tolerance to adverse effects of PRM (142). In a rapid switchover study to CBZ in patients receiving treatment with PHT, PB, and PRM, the absence of expected occurrence and severity of side effects to CBZ was hypothetically explained by induction of functional cross‐tolerance to CBZ‐related adverse effects by PHT, PB, and PRM (144).…”