title: Population pharmacokinetics of lamotrigine with data from therapeutic drug monitoring in German and Spanish patients with epilepsy.
abstract: This study develops a population pharmacokinetic model for lamotrigine (LTG) in Spanish and German patients diagnosed with epilepsy. LTG steady-state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 600 patients, with a total of 1699 plasma drug concentrations. The data were analyzed according to a one-compartment model using the nonlinear mixed effect modelling program. The influences of origin (Germany or Spain), sex, age, total body weight, and comedication with valproic acid (VPA), levetiracetam, and enzyme-inducing antiepileptic drugs (phenobarbital [PB], phenytoin [PHT], primidone [PRM], and carbamazepine [CBZ]) were investigated using step-wise generalized additive modelling. The final regression model for LTG clearance (CL) was as follows: CL(L/h) = 0.028*total body weight*e(-0.713*VPA)*e0.663*PHT*e0.588*(PB or PRM)*e0.467*CBZ*e0.864*IND, where IND refers to two or more inducers added to LTG treatment; this factor as well as VPA, PHT, PB, PRM, and CBZ take a value of zero or one according to their absence or presence, respectively. The administration of inducers led to a significant increase in mean LTG CL (values of 0.045-0.070 L/h/kg vs. 0.028 L/h/kg being reached in monotherapy), whereas VPA led to a significant decrease in CL (0.014 L/h/kg). Thus, comedication with these analyzed drugs can partly explain the interindividual variability in population LTG CL, which decreased from the basic model by more than 40%. The proposed model may be very useful for clinicians in establishing initial LTG dosage guidelines. However, the interindividual variability remaining in the final model (clearance coefficient of variation close to 30%) make these a priori dosage predictions imprecise and justifies the need for LTG plasma level monitoring to optimize dosage regimens. Thus, this final model allows easy implementation in clinical pharmacokinetic software and its application in dosage individualization using the Bayesian approach.
authors.affiliation: Department of Pharmacy, University Hospital of Salamanca, Salamanca, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Rivas
authors.forename: Dolores Santos
authors.initials: DS
authors.lastname: Buelga
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.forename: José
authors.initials: J
authors.lastname: Santos-Borbujo
authors.forename: María José
authors.initials: MJ
authors.lastname: Otero
authors.forename: Alfonso
authors.initials: A
authors.lastname: Domínguez-Gil
authors.forename: María José
authors.initials: MJ
authors.lastname: García
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D016903:Drug Monitoring; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011153:Population; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology; D014227:Triazines / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine