Sodium valproate inhibits lamotrigine metabolism

Wellcome Research Laboratories, Beckenham, Kent.
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 06/1992; 33(5):511-3. DOI: 10.1111/j.1365-2125.1992.tb04079.x
Source: PubMed


Concomitant administration of sodium valproate (VPA) reduced lamotrigine (LTG) total clearance by approximately 21% and increased elimination half-life and AUC. Reduced elimination occurred acutely within the first hour. Renal elimination of LTG was not impaired. The most probable explanation for this effect is hepatic competition between VPA and LTG for glucuronidation. Volume of distribution and parameters related to absorption, Cmax and tmax were unchanged.

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    • "A severe and disabling tremor has been reported to occur during treatment with the two drugs [20]. This tremor has been observed not to be consequent to high serum levels of each of these drugs taken alone [19]. Conversely, the VPA-induced rise of serum LTG levels, through the aforementioned metabolic inhibition, might contribute to the onset of skin rash and other more serious consequences, i.e., Stevens–Johnson syndrome and toxic epidermal necrolysis, which may occur during LTG administration especially when starting with high initial doses [21] [22]. "
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    ABSTRACT: The experimental and clinical evidence in support of "rational polytherapy" is sparse, and to date, no clear evidence-based indications can be made to help physicians in their choice of a specific drug combination against specific forms of epilepsy. This article briefly reviews the data available in the literature and obtained from studies conducted in humans to evaluate which main AED combinations might possess supraadditive, synergistic effects in terms of efficacy, with infraadditive toxicity. By far, the most documented association resulting in supraadditive anticonvulsant effects against focal seizures is that of VPA and LTG. There are some indications that combinations of drugs with different primary mechanisms of action may be more effective than combining drugs with the same mechanisms of action. However, further animal and human research studies that focus both on toxicity and anticonvulsant effects of various combinations of AEDs are required.
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    • "When lamotrigine is administered in combination with enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, or primidone), a twofold increase in steadystate clearance (Lamictal XR [PI], 2011) and an approximate 40% reduction in half-life (from 24 to 14 h) is noted (Jawad et al., 1987). Valproic acid is a known inhibitor of glucuronidation, causing a 21% decrease in steady-state clearance, increasing lamotrigine elimination half-life and AUC (Yuen et al., 1992). Therefore, dose adjustment is often necessary in patients who require polypharmacy. "
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    ABSTRACT: Many antiepileptic drugs (AEDs) have short half-lives with large fluctuations in peak-to-trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended-release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (C(max) ) at steady-state that often contribute to AEs during treatment with immediate-release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose-normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([C(max) -C(min) ]/C(avg) ) compared with the IR versions. This results in flatter concentration-time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.
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    • "Thus, the recommended maintenance dose range of LTG taken in combination with EIAEDs is typically twofold greater than that recommended for patients who are receiving " neutral " AEDs. VPA is a known inhibitor of glucuronidation and significantly reduces the CL of LTG (Yuen et al., 1992; Morris et al., 2000). Coadministration of VPA results in an approximate twofold reduction in steady-state LTG CL with a corresponding increase in the t1/2 from ∼24 h to ∼60 h. "
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