Lamotrigine Serum Concentration-to-Dose Ratio: Influence of Age and Concomitant Antiepileptic Drugs and Dosage Implications

Abstract

Using bivariate and multivariate methods, we retrospectively analyzed the influence of patient age and the use of concomitant antiepileptic drugs (AEDs) on the lamotrigine (LTG) concentration-to-dose (C/D) ratio in samples from 164 patients (68 children, 96 adults) with epilepsy receiving LTG alone (n = 28) or in combination with various antiepileptic drugs (n = 136). The LTG C/D ratio increased with age in children receiving LTG alone (r = 0.60, p < 0.01), but decreased with age in adults receiving LTG and inducers (r = -0.42, p < 0.001). In patients receiving LTG and inducers, the ratio was statistically lower in those younger than 9 years of age (0.23 +/- 0.08) and older than 30 years of age (0.32 +/- 0.15) than it was in those between 9 and 30 years of age (0.44 +/- 0.15). The mean LTG C/D ratio was 0.37 +/- 0.15 in patients receiving LTG and inducers (n = 92), 0.84 +/- 0.41 in patients receiving LTG alone (n = 28), 1.09 +/- 0.44 in those receiving LTG with VPA plus inducers (n = 17), and 3.41 +/- 1.18 in those receiving LTG and VPA (n = 27). Differences in the LTG C/D ratio between treatment groups were similar in children and in adults. We reached the following conclusions: The LTG C/D ratio increased with age in children but may decrease with age in adults receiving concomitant enzyme-inducing AEDs; the LTG C/D ratio was 10 times lower in patients receiving LTG and inducers than in those receiving LTG and VPA (in both children and adults), and this difference was higher than the four-fold difference described for LTG half-life and the two-fold differences currently used in LTG dosage.

Influence of Concomitant Antiepileptic Drugs on Plasma Lamotrigine Concentration in Adult Japanese Epilepsy Patients

“…receiving LTG+VPA (group II), which was lower than the ratios of 3.84±1.1 19) and 4.04±0.9 12) in Spanish patients, 3.4±1.7 in Italian patients, 16) or 3.66±1.7 in German patients.…”

“…In contrast, a higher CD ratio was observed in adult patients with the TT genotype than in those with the CC or CT genotype among patients receiving LTG monotherapy (1.98±0.5 vs. 1.10±0.3, p<0.001), but only 3 patients had the TT genotype. 19) In Japanese patients on LTG monotherapy (49 out of 96 patients in group I), the CD ratio was 1.43±0.4, which was higher than the values of 1.30±0.5 19) and 1.05±0.4 12) reported in Spanish patients or 0.98±0.4 in German patients. 10) These results suggest that clearance of LTG may be slower in nonCaucasians than in Caucasians.…”

“…To our knowledge, four studies about the CD ratio of LTG in European patients have been published. 10,12,16,19) Among them, Sánchez et al 19) reported a significant association between the CD ratio of LTG and UGT2B7 (−161C>T) polymorphism. They found a CD ratio of 1.65±1.5 in patients with the CC genotype (wild-type), which was higher than the ratios of 1.24±1.2 and 1.20±1.0 in patients with the CT and TT genotypes, respectively.…”

“…6,12,13,17,18) We classified the subjects by different inducer combinations and compared the CD ratios for LTG in these groups (Figs. 2, 3).…”

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…Despite LTG's wide clinical use, standard npg dosage regimens continue to be used even though they may often be suboptimal because of the high variability found in CL values in the target population [7,10,[13][14][15][16][17][18] . This observation, together with previous studies that have established definable relationships between LTG blood concentrations and therapeutic and toxic effects [19][20][21] , justify TDM as an indicator of drug exposure for the individualization of LTG doses [4][5] .…”