Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

Abstract

Epilepsy and bipolar disorder are commonly treated by combination drug therapy, such as lamotrigine and oxcarbazepine. To ensure the safety of this combination, information on pharmacokinetics and tolerability must be available. The objective of study was to evaluate the pharmacokinetics and tolerability of coadministered lamotrigine and oxcarbazepine in healthy subjects. This randomized, single-blind, parallel-group study comprised three cohorts: lamotrigine (200 mg daily) plus oxcarbazepine (600 mg twice daily), lamotrigine (200 mg daily) plus placebo, and oxcarbazepine (600 mg twice daily) plus placebo. Serial blood samples were collected at steady state to determine serum concentrations of lamotrigine and plasma concentrations of oxcarbazepine and its active metabolite 10-monohydroxy metabolite (MHD). Pharmacokinetic parameters were determined by noncompartmental methods. Tolerability was monitored through adverse event reports, clinical laboratory results, vital signs, and electrocardiograms. A total of 47 male volunteers received study drugs. At steady state, lamotrigine AUC and C max were not significantly affected by oxcarbazepine cotherapy, nor were MHD AUC (0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and C max significantly affected by lamotrigine cotherapy. The most common adverse events, headache, dizziness, nausea, and somnolence, occurred more frequently during lamotrigine and oxcarbazepine combination therapy than during the monotherapy. No significant changes in clinical laboratory parameters, vital signs, or electrocardiograms were reported. In conclusion, the combination of lamotrigine and oxcarbazepine does not require dose adjustments based on pharmacokinetic data. However, it is important to recognize that the combination therapy was associated with more frequent adverse events.

No impact of neuropathy on pharmacokinetic of lamotrigine in rat model

“…Furthermore the results clears that there were no alterations in basic pharmacokinetic parameters such as the obtained elimination rate constant, elimination t 1/2 and Cl T obtained results were in correlation with those of the results already reported. The data for LMT revealed that the maximum drug concentration obtained was found to be similar to that demonstrated by Theis et al, [10] but the time to peak concentration was at 1h probably this was obtained from large population between 0.5 h and 2.5 h. From early trial phase 3 studies performed, the therapeutic anticonvulsant serum concentration was between 1-4 µg/mL and 3-14 µg/ mL has proven to be quite safe but few [11][12][13] reported that concentration above 12 µg/mL was optimum probably such a high concentration may be required depending upon patients and their side effects. There was a direct relationship between daily dose, plasma level of LMT and analgesic effects, which was previously explained by Lunardi et al [14] Although only a few animals were used per treatment group, the effects seen were consistent across the groups and based on ethical grounds.…”

The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy

“…We did not demonstrate a significant effect of OXC on LTG CL, but our sample size was small, with only 10 serum levels among older adults and 8 serum levels in younger adults taking LTG in combination with OXC. Some (May et al., 1999; Weintraub et al., 2005), but not all (Theis et al., 2005), larger prior studies have shown that OXC increases LTG CL modestly (15–30%).…”

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

“…Oxcarbazepine and methsuximide may enhance the metabolism of lamotrigine, resulting in lower serum lamotrigine concentrations (May et al, 1999; Besag et al, 2000; Wellington & Goa, 2001). A lowering effect of oxcarbazepine on serum lamotrigine levels, however, has not been confirmed in all studies (Theis et al, 2005).…”