Bioequivalence and pharmacokinetic comparison of a single 200-mg dose of meclofenoxate hydrochloride capsule and tablet formulations in healthy Chinese adult male volunteers: a randomized sequence, open-label, two-period crossover study.
BACKGROUND
Meclofenoxate hydrochloride is a psychostimulant in the nootropic agent group available in capsule and tablet formulations approved for traumatic cataphora, alcoholic poisoning, anoxia neonatorum, and children's enuresis in China. Although these 2 generic formulations are marketed in China, information regarding their pharmacokinetics and bioequivalence in humans has not been published.


OBJECTIVE
The aim of this study was to compare the pharmacokinetic properties and bioequivalence of the capsule (test) and tablet (reference) formulations of meclofenoxate hydrochloride 200 mg in healthy Chinese volunteers.


METHODS
This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. As a prodrug, meclofenoxate is hydrolyzed into 4-chlorophenoxyacetic acid and is not detected in plasma. The active metabolite of meclofenoxate, chlorophenoxyacetic acid, was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity, blood samples were obtained at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 14, and 24 hours after administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Subjects were interviewed concerning the occurrence of adverse events including excitement, insomnia, lassitude, and headache. Tolerability was assessed at baseline (before administration) and at 1, 2, 6, and 12 hours after administration by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis).


RESULTS
Twenty-four Chinese male subjects (mean [range]age,23.5[22-30]years;weight,63.3[56-68]kg; height, 171 [165-184] cm) were enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of chlorophenoxyacetic acid Cmax, AUC0-24, and AUC0-infinity were 95.7 to 122.9, 97.6 to 111.9, and 97.8 to 111.7, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No adverse events were reported or observed during this single-dose study.


CONCLUSIONS
In this small study in healthy Chinese adult male volunteers, a single 200-mg dose of the capsule formulation was found to be bioequivalent to a single 200-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.
Zou
Jian-Jun
JJ
Department of Clinical Pharmacology, Nanjing First Hospital of Nanjing Medical University, Nanjing, China.
Ji
Hong-Jian
HJ
Wu
Ding-Wei
DW
Yao
Jing
J
Hu
Qin
Q
Xiao
Da-Wei
DW
Wang
Guang-Ji
GJ
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D044466:Asian People; D001682:Biological Availability; D002214:Capsules / Q000493:pharmacokinetics; D002681:China; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D002504:Meclofenoxate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D033281:Nontherapeutic Human Experimentation; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012016:Reference Values; D013607:Tablets / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
D002214:Capsules; D018697:Nootropic Agents; D013607:Tablets; D002504:Meclofenoxate