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 [[Formula: see text]; 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.

Keywords: Antidote; L-carnitine; Lactate; Pharmacokinetics; Poisoning; Valproic acid.

Fig. 1

Validation of the valproic acid (VPA) toxicokinetic model in nineteen poisoned patients with the predicted versus observed plasma VPA concentrations (A), the weighted residuals versus time (B) and the weighted residuals versus predicted plasma VPA concentrations (C)

Fig. 2

Individual toxicokinetics showing the best fit of the observed values in nineteen valproic acid (VPA)-poisoned patients non-treated (panel A) or treated with L-carnitine (designated as LC, panel B)

Fig. 2

Individual toxicokinetics showing the best fit of the observed values in nineteen valproic acid (VPA)-poisoned patients non-treated (panel A) or treated with L-carnitine (designated as LC, panel B)

Fig. 3

Individual relationships between blood lactate and plasma valproic acid (VPA) concentrations in eight valproic acid-poisoned patients. LC means treated with L-carnitine

Fig. 4

Individual time-course of blood lactate concentrations in eight valproic acid-poisoned patients. LC means treated with L-carnitine