title: Unexplained spikes in lamotrigine serum concentration: nonlinear elimination?
abstract: OBJECTIVE
  The objective of this study was to evaluate possible nonlinear lamotrigine (LTG) pharmacokinetics at elevated concentration. LTG is reported to have linear kinetics, so that elimination rate is linearly proportional to blood concentration and a change in dose is accompanied by a proportionate change in serum concentration. We encountered patients in whom LTG serum concentration increased dramatically in response to minor or no change in LTG dose. We studied this phenomenon in patients with LTG toxicity in one clinic.
  
  
  METHODS
  Using electronic medical records from 1997 to 2014, we identified patients who developed clinical LTG toxicity with LTG serum concentrations >20 mg/l, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity.
  
  
  RESULTS
  Twenty-two patients had at least one episode of LTG toxicity with levels higher than 20 mg/l (of 922 patients with available levels). The peak serum concentration varied from 21.1 to 40.3 mg/l (mean 28.7). The increase in level was explained in three patients (post-delivery in one, addition of valproate in two). In the 18 others, the increase was not explained or it was disproportionate to an increase in LTG dose.
  
  
  CONCLUSIONS
  Spikes in LTG levels and associated clinical toxicity may occur unexpectedly, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been >10 mg/l.
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ramey
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Osborn
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Lowen
authors.affiliation: Husson University School of Pharmacy, Bangor, ME, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Reed
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Abou-Khalil
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D001259:Ataxia / Q000097:blood / Q000139:chemically induced; D004244:Dizziness / Q000097:blood / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D057286:Electronic Health Records; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D014227:Triazines / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine
keywords: lamotrigine; nonlinear; pharmacokinetics; serum concentration; toxicity