PRELIMINARY POPULATION PHARMACOKINETICS OF LAMOTRIGINE IN INFANTS AGED 1-24 MONTHS
Abstract number :
1.295
Submission category :
Year :
2002
Submission ID :
76
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Jagdev Sidhu, Jonathan Bullman, David Onks, Paul Caldwell, John Messenheimer. Clinical Pharmacokinetics, GlaxoSmithKline, Harlow, Essex, United Kingdom; Epilepsy Clinical Development, Research Triangle Park, NC
OBJECTIVE: To evaluate the population pharmacokinetics model (PK) for lamotrigine (LTG) in an on-going study of infants with partial seizures aged 1-24 months.
RATIONALE: A population pharmacokinetic model developed with adult data has previously been validated in children (median age 7.6 years). This model has presently been used to evaluate preliminary data from a clinical study in infants (1-24 months).
METHODS: The population consisted of 65 infants (wt range: 3.4-16 kg; 30 males) with partial seizures uncontrolled by one or more antiepileptic drugs (AED). Serum LTG (LAMICTAL[tm]) concentrations (N=187) were determined at week 2 (1 sample) and approximately at the end of week 5 (typically 3-7 samples; N=25 infants). Serum LTG PK data were analysed using NONMEM. In addition to demographic factors, the influence of concomitant AEDs on LTG PK was evaluated. A 1-compartment model with first-order absorption and elimination (parameterised in terms of apparent clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka)) was used to describe LTG PK.
RESULTS: Parameter values for the final population PK model are given in the table below: [table1]For an infant with the population median weight of 10.9 kg not receiving an enzyme-inducing AED (EIAED), the above model estimates a LTG CL/F and V/F of 0.762 L/h and 84 L, respectively. Coadministration of an EIAED is predicted to cause a 1.77-fold increase in LTG CL/F. The median predicted LTG half-life (T1/2) across all infants was 80 h and 48 h for those without and with concomitant EIAED intake, respectively. Importantly, there was still a large degree of unexplained variability in CL/F (53%).
CONCLUSIONS:
[bullet] Compared with older children and adults, substantially longer LTG T1/2s were encountered in this group of infants, which could primarily be attributed to very large volumes of distribution.
[bullet] The large unexplained variability in LTG CL/F indicated that factors other than weight or EIAED intake contribute to metabolic variations in this group.
[Supported by: This study is funded by GlaxoSmithKline]; (Disclosure: Salary - Glaxo SmithKline - employee)