Multiple‐Dose Pharmacokinetics and Bioequivalence L-Carnitine 330-mg Tablet versus 1-g Chewable Tablet versus Enteral Solution in Healthy Adult Male Volunteers

Abstract

The bioavailability and bioequivalence of three oral dosage forms ofL‐carnitine were studied in 15 healthy volunteers. Recently, an intravenous (iv) dosage form ofL‐carnitine has been approved to be marketed in the United States. The purpose of this study was to determine after multiple dose administration of the three oral dosage forms (marketed solution, chewable tablet, and marketed tablet) the pharmacokinetics and absolute bioavailability of each of the dosage forms at steady state and compare them with those following administration of a single iv dose. The relative bioavailability and bioequivalence of the chewable and marketed tablet relative to the marketed solution at steady‐state replicate design conditions were also studied. Bioavailability based on data that was not corrected for the baseline (uncorrected data) was compared with bioavailability determined from data corrected for baseline. Steady‐state conditions, based on free or totalL‐carnitine plasma concentrations, were achieved by Day 3, and products were bioequivalent based on the analysis of variance and comparisons by the two one‐sidedttest. Pharmacokinetic evaluations were found to be powerful tools for bioequivalence determinations; the power to detect 20% differences in AUC,Cmaxtmax, andCmin0was >80%. Mean absolute bioavailabilities (based on free or totalL‐carnitine plasma concentrations) on Day 4 (fraction of the dose absorbed) of Carnitor (levocarnitine) tablet, Carnitor (levocarnitine) oral solution, and levocarnitine chewable tablet relative to the first iv dose were ∼18%. Similarly, absolute bioavailability compared with the last iv dose was ∼18% for all three oral formulations. However, if AUCs for oral and iv dosage forms were corrected for baseline (endogenous) plasma concentrations, the absolute bioavailability ranged between 14.4 and 16%, based on free or totalL‐carnitine concentrations. Based on amounts of free or totalL‐carnitine excreted in the urine, the three products were also found to be bioequivalent. Correcting for baseline endogenous concentrations ofL‐carnitine did not significantly influence absolute bioavailability determinations.