CARNITOR® (Levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, therefore delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle they serve as major fuel. Primary systemic carnitine deficiency is characterized by low plasma, A.C. and/or tissue levels. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to the underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with carnitine. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acyl CoA esters.^1,6

Secondary levocarnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect was demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acyl CoA dehydrogenase deficiency. ^7,8 Autointoxication occurs in these patients due to the accumulations of acyl CoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acyl CoA compound to its free acid results in acidosis that can be life threatening. Levocarnitine clears the acyl CoA compound by formation of acyl carnitine which is quickly excreted. Levocarnitine deficiency is defined biochemically as abnormally low plasma levels of free carnitine, less than 20 µM/ Lat age greater than one week post term and may be associated with low tissue and or urine levels. Further, this condition may be associated with a ratio of plasma ester/ free levocarnitine levels greater than 0.4 or abnormally elevated levels of esterified levocarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma free levocarnitine levels below age related normal levels.

Bioavailability/ Pharmacokinetics

In a relative bioavailability study in 15 healthy adult male volunteers CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following the administration of 1980 mg bid., the maximum plasma concentration level (C_max) was 80 nmol/mL and the time to maximum concentration (T_max) occurred at 3.3 hours. There were no significant differences for AUC and urinary excretion observed between these two formulations.

In the same bioavailability study of 15 healthy adult males, CARNITOR® (Levocarnitine) Injection administered as a slow 3 minute bolus intravenous injection at a dose of 20 mg/Kg showed that free levocarnitine plasma profiles are best fit by a two compartment model. Approximately 76% of free levocarnitine is eliminated in the urine. Using plasma levels uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours following a single intravenous dose.

The absolute bioavailability of L-carnitine from CARNITOR® Tablets and Oral Solution was determined cornpared to the bioavailability of L-carnitine from CARNITOR® (Injection) Intravenous in 15 healthy male volunteers. After correction for circulating endogenous levels of L-carnitine in the plasma, absolute bioavailability was 15.1% ±5.3% for L-carnitine from CARNITOR® Tablets and 15.9% ±4.9% from the Oral Solution. Total body clearance of L-carnitine (Dose/AUC including endogenous baseline levels) was a mean of 4.00 L/hr. Endogenous baseline levels were not subtracted since total body clearance of L-carnitine does not distinguish between exogenous sources of L-carnitine and endogenously synthesized L-carnitine. Volume of distribution of the intravenously administered dose above baseline endogenous levels was calculated to be a mean of 29.0 L ±7.1 L (approximately 0.39 L/kg) which is an underestimate of the true volume of distribution since plasma L-carnitine is known to equilibrate slowly with, for instance, muscle L-carnitine.

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