Effect of Antiepileptic Drug Comedication on Lamotrigine Clearance

Abstract

To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL).Design: We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication.Results: Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. Conclusion:Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…This observation is similar to the findings of previous studies, with values for this parameter ranging from 0.004 to 0.031 L·h -1 ·kg -1 and a mean of approximately of 0.015 L·h -1 ·kg -1 [26][27][28][29][30][31] .…”

“…The induction effect of PB or CBZ was observed; thus, CL was increased by 1.9-2.4 fold compared to monotherapy. These results are similar to those from previous studies conducted in patients taking these drugs that also reported increased LTG CL with values ranging from 0.044 to 0.084 L·h -1 ·kg -1 [7,[25][26][27] .…”

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…This observation is similar to the findings of previous studies, with values for this parameter ranging from 0.004 to 0.031 L·h -1 ·kg -1 and a mean of approximately of 0.015 L·h -1 ·kg -1 [26][27][28][29][30][31] .…”

“…The induction effect of PB or CBZ was observed; thus, CL was increased by 1.9-2.4 fold compared to monotherapy. These results are similar to those from previous studies conducted in patients taking these drugs that also reported increased LTG CL with values ranging from 0.044 to 0.084 L·h -1 ·kg -1 [7,[25][26][27] .…”

Steady‐state Pharmacokinetics of Lamotrigine when Converting from a Twice‐daily Immediate‐release to a Once‐daily Extended‐release Formulation in Subjects with Epilepsy (The COMPASS Study)

“…May reported that, in the presence of PHT, LTG concentrations were reduced by 71.1% compared with those observed for LTG alone; however, LTG concentrations were reduced by only 48.9% in the presence of CBZ. Similar findings were reported by Weintraub et al (2005). In our study, 53% of subjects in the enzyme-inducing group were taking PHT and 47% were taking CBZ.…”

Influence of the clinical profile of patients with refractory epilepsy on lamotrigine plasma concentration

“…These results corroborate those from Weintraub and colleagues (2005), that revealed an increase of 125% and 50% in LTG clearance when it is associated with PHT and CBZ, respectively, while VPA decreases the LTG clearance in approximately 60% (Weintraub et al, 2005). In addition, May, Rambeck and Jurgens (1996) highlight that PHT is the most powerful AED in terms of decreasing the LTG plasma concentration, followed by PB and CBZ.…”

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…This observation is similar to the findings of previous studies, with values for this parameter ranging from 0.004 to 0.031 L·h -1 ·kg -1 and a mean of approximately of 0.015 L·h -1 ·kg -1 [26][27][28][29][30][31] .…”

“…The induction effect of PB or CBZ was observed; thus, CL was increased by 1.9-2.4 fold compared to monotherapy. These results are similar to those from previous studies conducted in patients taking these drugs that also reported increased LTG CL with values ranging from 0.044 to 0.084 L·h -1 ·kg -1 [7,[25][26][27] .…”

Steady‐state Pharmacokinetics of Lamotrigine when Converting from a Twice‐daily Immediate‐release to a Once‐daily Extended‐release Formulation in Subjects with Epilepsy (The COMPASS Study)

“…May reported that, in the presence of PHT, LTG concentrations were reduced by 71.1% compared with those observed for LTG alone; however, LTG concentrations were reduced by only 48.9% in the presence of CBZ. Similar findings were reported by Weintraub et al (2005). In our study, 53% of subjects in the enzyme-inducing group were taking PHT and 47% were taking CBZ.…”

Influence of the clinical profile of patients with refractory epilepsy on lamotrigine plasma concentration

“…These results corroborate those from Weintraub and colleagues (2005), that revealed an increase of 125% and 50% in LTG clearance when it is associated with PHT and CBZ, respectively, while VPA decreases the LTG clearance in approximately 60% (Weintraub et al, 2005). In addition, May, Rambeck and Jurgens (1996) highlight that PHT is the most powerful AED in terms of decreasing the LTG plasma concentration, followed by PB and CBZ.…”

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…This observation is similar to the findings of previous studies, with values for this parameter ranging from 0.004 to 0.031 L·h -1 ·kg -1 and a mean of approximately of 0.015 L·h -1 ·kg -1 [26][27][28][29][30][31] .…”

“…The induction effect of PB or CBZ was observed; thus, CL was increased by 1.9-2.4 fold compared to monotherapy. These results are similar to those from previous studies conducted in patients taking these drugs that also reported increased LTG CL with values ranging from 0.044 to 0.084 L·h -1 ·kg -1 [7,[25][26][27] .…”

Steady‐state Pharmacokinetics of Lamotrigine when Converting from a Twice‐daily Immediate‐release to a Once‐daily Extended‐release Formulation in Subjects with Epilepsy (The COMPASS Study)

“…May reported that, in the presence of PHT, LTG concentrations were reduced by 71.1% compared with those observed for LTG alone; however, LTG concentrations were reduced by only 48.9% in the presence of CBZ. Similar findings were reported by Weintraub et al (2005). In our study, 53% of subjects in the enzyme-inducing group were taking PHT and 47% were taking CBZ.…”

Influence of the clinical profile of patients with refractory epilepsy on lamotrigine plasma concentration

“…These results corroborate those from Weintraub and colleagues (2005), that revealed an increase of 125% and 50% in LTG clearance when it is associated with PHT and CBZ, respectively, while VPA decreases the LTG clearance in approximately 60% (Weintraub et al, 2005). In addition, May, Rambeck and Jurgens (1996) highlight that PHT is the most powerful AED in terms of decreasing the LTG plasma concentration, followed by PB and CBZ.…”