title: Assessing impact of real-world dosing irregularities with lamotrigine extended-release and immediate-release formulations by pharmacokinetic simulation.
abstract: OBJECTIVE
  To assess the effect of common dosing irregularities on serum concentrations of antiepileptic drug (AED) lamotrigine for the extended-release (XR) formulation, which is recommended for once-daily dosing (QD), and the immediate-release (IR) formulation, which is typically dosed twice daily (BID).
  
  
  METHODS
  A pharmacokinetic model was constructed for lamotrigine XR and IR formulations in the presence and absence of comedications. The model was then used to simulate concentration time profiles in scenarios of full compliance and various forms of nonadherence such as a delayed dose, a missed dose, and a doubled dose.
  
  
  RESULTS
  Lamotrigine steady-state serum concentrations stayed in a narrower range for XR-QD than for IR-BID, despite the more frequent dosing of the latter. At the same daily dose, concentrations with IR-BID were outside the range seen with XR-QD for the majority of the day. For XR-QD, concentration decrease due to dosing delay was small (<15%) when the delay was up to 4, 8, and 16 hours in patients receiving enzyme-inducing AEDs, neutral AEDs, and enzyme inhibitor valproate, respectively. For IR-BID, similar concentration decrease was caused by shorter delay. A single missed dose caused a notable 16%-68% trough concentration reduction, which was broadly comparable between XR-QD and IR-BID for each AED group. A doubled dose after a missed dose did not lead to excessive peak concentration for either treatment.
  
  
  CONCLUSIONS
  Simulations have provided quantitative insight, showing that XR formulation is generally more forgiving in nonadherence. They also suggest that in a typical patient, a missed dose should be made up by doubling the next dose. The approach illustrates how a model constructed on clinical trial data can be used to simulate real-world dosing scenarios and guide therapeutics.
authors.affiliation: Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Uxbridge, United Kingdom. chao.c.chen@gsk.com
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: James
authors.initials: J
authors.lastname: Wright
authors.forename: Barry
authors.initials: B
authors.lastname: Gidal
authors.forename: John
authors.initials: J
authors.lastname: Messenheimer
mesh_terms: D000927:Anticonvulsants / Q000737:chemistry* / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003199:Computer Systems / Q000592:standards; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D057915:Drug Substitution / Q000379:methods / Q000592:standards; D006801:Humans; D000077213:Lamotrigine; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D014227:Triazines; D000077213:Lamotrigine