¹GlaxoSmithKline, Cambridge, United Kingdom (Great Britain)

Abstract

Background: LTG and OXC may be coadministered during the treatment of epilepsy or bipolar disorder. In vitro, OXC and its active 10-monohydroxy metabolite (MHD) are weak inducers of UDP-glucuronyl transferase, which may increase LTG conjugation. In a retrospective study OXC reduced LTG concentrations by 29% [May et al, 1999]. Purpose: To investigate the pharmacokinetics (PK) and tolerability of the combination of LTG and OXC. Methods: 49 healthy, non-smoking, adult males were randomized to receive LTG (titrated to 200mg/day) or placebo (PBO) on days 1|[ndash]|53. OXC (titrated to 600 mg bd) or PBO were added on days 43 - 53 resulting in 3 parallel cohorts receiving the combinations of LTG+OXC, LTG+PBO or OXC+PBO. PK profiles were obtained at steady state on day 53. Results: AUC_(0-24) and C_max of LTG, OXC and its active metabolite MHD were not significantly affected by cotherapy, all being less than 10% lowered compared to monotherapy. AEs were reported more frequently with OXC+LTG than with either monotherapy. Most frequent AEs were headaches, dizziness, nausea and somnolence. Most AEs were mild to moderate in intensity except for severe dizziness in two subjects receiving OXC+LTG. Conclusions: Co-administration of LTG and OXC does not affect the PK of either drug. The PK results support co-administration in patients who may benefit from combination therapy. In this healthy volunteer cohort AE frequency was higher with the combination therapy than with either of the monotherapies.