Using l‐Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis

Abstract

Objective The objective of this review is to discuss the therapeutic use and differential treatment response to Levo‐carnitine (l‐carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l‐carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity. Methods A narrative review was conducted that focused on explaining interpatient variability in l‐carnitine treatment response. Relevant biological and patient‐level characteristics considered include genetic, metabolic, and morphomic phenotypes; potential drug interactions; and pharmacokinetics (PKs). Main Results Despite promising results in a phase I study, a recent phase II clinical trial of l‐carnitine treatment in septic shock showed a nonsignificant reduction in mortality. However, l‐carnitine treatment induces significant interpatient variability in l‐carnitine and acylcarnitine concentrations over time. In particular, administration of l‐carnitine induces a broad, dynamic range of serum concentrations and measured peak concentrations are associated with mortality. Applied systems pharmacology may explain variability in drug responsiveness by using patient characteristics to identify pretreatment phenotypes most likely to derive benefit from l‐carnitine. Moreover, provocation of sepsis metabolism with l‐carnitine offers a unique opportunity to identify metabolic response signatures associated with patient outcomes. These approaches can unmask latent metabolic pathways deranged in the sepsis syndrome and offer insight into the pathophysiology, progression, and heterogeneity of the disease. Conclusions The compiled evidence suggests there are several potential explanations for the variability in carnitine concentrations and clinical response to l‐carnitine in septic shock. These serve as important confounders that should be considered in interpretation of l‐carnitine clinical studies and broadly holds lessons for future clinical trial design in sepsis. Consideration of these factors is needed if precision medicine in sepsis is to be achieved.

The effects of l-carnitine supplementation on inflammatory factors, oxidative stress, and clinical outcomes in patients with sepsis admitted to the intensive care unit (ICU): study protocol for a double blind, randomized, placebo-controlled clinical trial

“…l -carnitine (lysine + methionine) is involved in beta-oxidation [ 29 ]. Its anti-inflammatory and antioxidant effects have already proven though its effects on septic patients are not conclusive [ 12 , 30 ].…”

Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

“…The long-chain acylcarnitine C16:2(OH) was reduced in septic patients compared to SIRS [ 20 ], suggestive of reduced uptake of fatty acids into mitochondria as carnitines are involved in the transportation of long-chain fatty acids from cytoplasm [ 31 ]. In addition, studies focusing on adults and children also showed that patients with sepsis had increased levels of acetylcarnitine compared to SIRS [ 25 , 32 ] or healthy subjects [ 23 ], reflecting enhanced conversion of free carnitine and excess acetyl-CoA from metabolic stress into acetylcarnitine ( Figure 1 ) via carnitine acetyl-transferase [ 33 ]. Moreover, sugars including glucose, mannose and lactitol dehydrate were reduced in septic patients compared to SIRS [ 25 , 32 , 34 ] whilst sucrose was elevated [ 25 ].…”

Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness

“…The study was powered to predict a posterior probability of the high dose (18 g) levocarnitine being superior to placebo, and only reached 0.78 rather than the 0.9 a priori benchmark. These results are confounded by the multitude of sepsis phenotypes, and variability in patient drug response to L-carnitine supplementation, several of the authors have suggested pharmacologic probes using L-carnitine to target subgroups of septic patients more likely to respond to therapy [ 144 ]. The variability of these data highlight the need for further research into pharmacogenomics and personalized medicine approaches to sepsis therapeutics.…”