MODELING AND SIMULATION OF THE PHARMACOKINETICS OF ONCE DAILY LAMOTRIGINE EXTENDED RELEASE TO SUPPORT THE EVALUATION OF DOSING SCENARIOS AND COMPARISONS WITH TWICE DAILY IMMEDIATE-RELEASE LAMOTRIGINE
Abstract number :
3.222
Submission category :
7. Antiepileptic Drugs
Year :
2008
Submission ID :
8305
Source :
www.aesnet.org
Presentation date :
12/5/2008 12:00:00 AM
Published date :
Dec 4, 2008, 06:00 AM
Authors :
Robert Kustra, D. Tompson, J. Wright and J. Messenheimer
Rationale: The objective of this investigation was to evaluate the potential impact of delayed dosing on the steady-state pharmacokinetics (PK) profile of lamotrigine (LTG) once-daily extended-release (LTG-XR) in patients with epilepsy. Methods: LTG PK data were collected in patients with epilepsy in an open-label, conversion study between LTG immediate release (IR) and LTG XR, who were taking concomitant anti-epileptic drugs (AEDs) and classified as either on enzyme inhibiting, neutral, or enzyme-inducing AEDs [Tompson DJ et al, 2007]. A pharmacokinetic model was developed to simultaneously describe the steady-state LTG serum concentration-time course following either LTG-XR or IR, taking into account the known differences in clearance in the three AED groups. The model was used to simulate the changes in LTG steady-state pharmacokinetic profile if a dose of the XR formulation was delayed by 4, 8, 12, 16 or 24 hours. The impact of taking a double dose having either taken the previous dose or having missed the previous dose was explored. Results: : If a dose of LTG-XR were to be delayed by 12 hours in an inhibited patient, serum concentrations would not fall more than 20% below the usual Cmin until the next dose was taken. In an induced patient, concentrations would not fall more than 20% below the usual Cmin for approximately 5.5 hours, and by 12 hours after the missed dose concentrations would have fallen to approximately 41% of the usual Cmin. Concentration close to the usual Cmin will be achieved following administration of the next scheduled dose, 12 hours later. If a patient misses a dose and takes a double dose the following day, concentrations are predicted to exceed the usual Cmax by less than 5% for approximately 100 hours for inhibited patients and by up to 25% for 60 hours in induced patients. Conclusions: Delayed dosing with LTG-XR is predicted to lead to clinically manageable fluctuations in lamotrigine serum concentration time course. Optimal strategies for dealing with missed or delayed doses will be presented.
Antiepileptic Drugs