Safety, Tolerability and Symptom Outcomes Associated with l-Carnitine Supplementation in Patients with Cancer, Fatigue, and Carnitine Deficiency: A Phase I/II Study

Abstract

Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer. Administration of exogenous L-carnitine may hold promise as a treatment for this common symptom. Little is known about L-carnitine safety, tolerability, and dose-response in patients with cancer. We conducted a Phase I/II open-label trial to assess the safety and tolerability of exogenous L-carnitine and clarify the safe dose range associated with symptom effects for future controlled trials. Adult patients with advanced cancer, carnitine deficiency (free carnitine <35 for males or <25 microM/L for females, or acyl/free carnitine ratio >0.4), moderate to severe fatigue, and a Karnofsky Performance Status (KPS) score > or =50 were entered by groups of at least three into a standard maximum tolerated dose design. Each successive group received a higher dose of L-carnitine (250, 750, 1250, 1750, 2250, 2750, 3000 mg/day, respectively), administered in two daily doses for 7 days. To compare symptom outcomes before and after supplementation, patients completed validated measures of fatigue (Brief Fatigue Inventory [BFI]), depressed mood (Center for Epidemiologic Studies Depression Scale [CES-D]), quality of sleep (Epworth Sleeplessness Scale [ESS]), and KPS at baseline and 1 week later. Of the 38 patients screened for carnitine levels, 29 were deficient (76%). Twenty-seven patients participated ("intention to treat, ITT") (17 males, 10 females), and 21 completed the study ("completers"); 17 of these patients ("responders," mean+/-[SD] age=57.9+/-15) had increased carnitine levels at the end of the supplementation period. The highest dose achieved was 3000 mg/day. No patient experienced significant side effects and no toxicities were noted. Analysis of all the patients accrued (ITT, n=27) showed a total carnitine increase from 32.8+/-10 to 54.3+/-23 microM/L (P<0.001) and free carnitine increase from 26.8+/-8 to 44.1+/-17 microM/L (P<0.001). BFI decreased significantly, from 66+/-12 to 39.7+/-26 (P<0.001); ESS decreased from 12.9+/-12 to 9+/-6 (P=0.001); and CES-D decreased from 29.2+/-12 to 19+/-12 (P<0.001). A separate analysis of the 17 "responders" showed a dose-response relationship for total- (r=0.54, P=0.03), free-carnitine (r=0.56, P=0.02) levels, and fatigue (BFI) scores (r=-0.61, P=0.01). These findings suggest that l-carnitine may be safely administered at doses up to 3000 mg/day and that positive effects may be more likely at relatively higher doses in this range. This study provides the basis for the design of future placebo-controlled studies of l-carnitine supplementation for cancer-related fatigue.

L-Carnitine Reduces Muscle Cramps in Patients taking Vismodegib

“…18 Other studies have confirmed L-carnitine's safety at dosages of 2000mg per day. 19 In these investigations mild adverse events, including nausea and stomach discomfort were noted. Uncommon side effects included muscle weakness in uremic patients and seizures in those with known seizure disorders.…”

The formulation for cancer prevention &amp; therapy

“…No patient experienced significant side effects and no toxicities were noted. These findings suggest that ALC may be safely administered at doses up to 3000 mg where positive effects may be more likely to occur at [129]. Treatments for cancer-related fatigue with an aim to develop directions for future research in large, randomized clinical trials [130].…”

The Effect of Chemotherapy on Serum Carnitine Levels and Fatigue in Chemotherapy Naive Medical Oncology Patients: A Pilot Study. Carnitine, Chemotherapy and Fatigue

“…Serum carnitine measures included total carnitine, free carnitine, acyl: free carnitine ratio ((total-free carnitine)/ free carnitine), and the prevalence of carnitine deficiency as defined by free carnitine (<35 μmol/L for males and <25 μmol/L for females) and acyl: free carnitine ratio (>0.40) [14]. Carnitine was analysed using butyl ester derivatives and electro spray tandem mass spectrometry [15].…”