POPULATION PHARMACOKINETICS OF LAMOTRIGINE MONOTHERAPY IN PATIENTS WITH EPILEPSY - RETROSPECTIVE ANALYSIS OF ROUTINE MONITORING DATA

Aims To examine the population pharmacokinetics of lamotrigine in pati ents newly diagnosed with epilepsy and receiving oral lamotrigine mono therapy for up to 48 weeks. Methods The population consisted of 158 Ca ucasians and 5 Asians of whom 81 were males and 82 females. Age and we ight ranged between 14 and 76 years and 41-107 kg, respectively. A one -compartment compartment model with first-order absorption and elimina tion was fitted to plasma lamotrigine concentration-time profiles from retrospective drug monitoring, using non-linear mixed effect modellin g (NONMEM), with first-order estimation. Oral clearance (CLo), apparen t volume of distribution (V/F) and absorption rate constant (K-a) were the main pharmacokinetic parameters. Results CLo was not significantl y influenced by body weight, age, gender, oral contraceptives and dose . However, due to auto-induction CLo increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28 l h(-1), and was 28.7% lower in As ians than Caucasian. The final magnitude in interpatient variability w as 32%. The effect of the covariates weight, age, race and gender on V /F was examined and none was statistically significant. The final popu lation estimate of V/F was 77.41 with an interpatient variability of 3 4%. Conclusions In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto-induction on clearance are unlike ly to be clinically significant and, thus, no dosage adjustment is war ranted for these effects.