Abstracts

RATIONALE: Enzyme induction is a process by which either the quantity or activity of a cytochrome (CYP) enzyme is increased above its baseline. CYP induction results from an increase in gene transcription triggered by selected substances and drugs. This results in increased drug clearance and a lower drug plasma level. Once an enzyme inducer is started, it generally takes 2-4 weeks to reach the higher drug clearance although the time course of induction has not been well characterized. When an inducing drug is stopped, the effect is lost and drug clearance returns to baseline. This process is known as de-induction and the time course has been assumed to be the same as induction. However, there has been no studies which have looked at the time course and the effect of dose of the inducer on de-induction. The pupose of this project is to determine the time course and the dose at which induction effect is lost.
METHODS: The antiepileptic drugs (AEDs) which are potent CYP 3A4/5 and uridine-diphosphate glucuronyl transferase (UGT) inducers include carbamazepine and phenytoin. LTG is a substrate for primarily for UGT. Patients selected for the study were on stable doses of one of the enzyme inducing AEDs (CBZ or PHT) and were also taking LTG. Patients were included who were to have the inducer discontinued and maintained on LTG monotherapy. Two trough plasma levels for the inducer and LTG were drawn before any changes in dose were made. Unit dose reduction was done weekly (PHT 100 mg, CBZ 200 mg) and plasma samples were obtained weekly during the taper. Plasma samples were three times a week for two weeks after the inducer was stopped and then weekly for three more weeks. Plasma concentrations were assayed using HPLC.
RESULTS: Ten patients taking LTG were studied. Plasma levels of LTG did not decline as CBZ or PHT doses were initially reduced. The plasma concentrations increased by 20-30% when CBZ or PHT was reduced to the last tablet/capsule. Further de-induction did not occur while low levels of inducer were present. LTG levels did not increase with plasma levels of PHT as low as 0.4 ug/ml and CBZ as low as 0.3 ug/ml. LTG levels increased progressively over a two week period after the plasma concentration of the inducing agent reached zero (0). Plasma levels of LTG increased 70-80% after the inducer was discontinued. For both PHT and CBZ, it takes 4-5 days to completely clear the system once the agent has been discontinued (ie, plasma levels of 0). It takes an additional 2-3 weeks for the phenomenon of de-induction to be completed. Overall the LTG plasma level increase was approximately 100%.
CONCLUSIONS: Loss of induction (de-induction) was not observed as the dose of an AED inducer was initially reduced. A small loss of induction occurred as the plasma level of the inducer approached zero and the majority of de-induction occurred in the two weeks after the inducer cleared the system. The time course of de-induction was similar for both CBZ and PHT.