title: Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens.
abstract: Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009-2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy.
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Azienda USL di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address: manuela.contin@unibo.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Contin
authors.affiliation: Pharmaceutical Department, Maggiore Hospital, Azienda USL di Bologna, Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Alberghini
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Azienda USL di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Carmina
authors.initials: C
authors.lastname: Candela
authors.affiliation: Pharmaceutical Department, Maggiore Hospital, Azienda USL di Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Benini
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Azienda USL di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Riva
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood*; D001774:Blood Chemical Analysis; D062313:Databases, Pharmaceutical; D057915:Drug Substitution; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy; D005260:Female; D005500:Follow-Up Studies; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D007297:Inpatients; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D011446:Prospective Studies; D012189:Retrospective Studies; D000077236:Topiramate; D014227:Triazines / Q000008:administration & dosage / Q000097:blood
chemical_list: D000927:Anticonvulsants; D016568:Drugs, Generic; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D000077287:Levetiracetam; D000077213:Lamotrigine; D010889:Piracetam
keywords: Antiepileptic drugs; Generic substitution; Plasma drug concentration; Therapeutic drug monitoring