L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships

Abstract

Background Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score. Results Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32–47]) (median [25th–75th percentiles]; SOFA score, 4 [1–6]) were included. The presumed VPA ingested dose was 15 g [10–32]. Plasma VPA concentration on admission was 231 mg/L [147–415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7–4.9]) and hyperammonemia (127 mmol/L [92–159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [$$E={E}_{0}\times {e}^{k\cdot C}$$ E = E 0 × e k · C ; with baseline E0 = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2–2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction. Conclusions VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.

Drug-associated hyperammonaemia: a Bayesian analysis of the WHO Pharmacovigilance Database

“…Time to onset of hyperammonaemia was not limited to the introduction period in the first few days following the liable drug start and could be delayed. Several mechanisms might explain this delayed reaction that has also been found in previous studies [ 16 , 28 , 29 ]. First, it cannot be ruled out that hyperammonaemia is a dose-dependent adverse effect occurring at a "supratherapeutic" cumulative dose for some medications such as chemotherapies.…”

The serum acylcarnitines profile in epileptic children treated with valproic acid and the protective roles of peroxisome proliferator-activated receptor a activation in valproic acid-induced liver injury

“…Based on this potential risk, carnitine therapy should be avoided during acute metabolic disorders ( Spiekerkoetter et al, 2009 ). Although carnitine supplementation has been widely used to prevent and treat fatty liver toxicity caused by VPA, recent studies have shown that carnitine supplementation has a minimal therapeutic effect in patients with acute toxicity caused by VPA( Nguyen et al, 2022 ). On the other hand, since carnitine supplementation may increase ACs accumulation, the search for a potential protective agent against VPA-induced hepatotoxicity that both upregulates fatty acid β-oxidation in mitochondria and does not cause ACs accumulation is necessary.…”

Valproate-Induced Encephalopathy Presenting at Therapeutic Blood Concentrations: A Case Report and Literature Review

“…However, the literature is mixed on the efficacy of using L-carnitine for acute toxicity. Nguyen et al note that while L-carnitine reduces peak serum lactate levels in acute valproate toxicity, it does not speed up the return of blood lactate to normal levels nor help in valproate clearance [12], meaning that L-carnitine may help reduce the extent of organ damage in severe valproate toxicity, but may not improve prognosis and length of hospital stay.…”