Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers.
Josamycin is a macrolide antibiotic with considerable intra- and interindividual variability in kinetics. In the present study bioequivalence of an intact and dispersed josamycin Solutab tablet, containing 1,000 mg of josamycin in the form of josamycin propionate ester, was tested versus a Josacine 1,000 mg reference sachet. The design of this bioequivalence study was adapted to the drug's pharmacokinetic variability, comprising testing in steady-state, testing the reference in replicate, and maintaining a widened bioequivalence margin. The study was performed in a group of 24 male and 12 female healthy subjects, according to a 3-treatment 4-period crossover design. Blood sampling for establishing josamycin propionate and josamycin base serum level profiles were collected during the 12 h dosing interval on day 4. Steady-state serum levels were reached on day 4. With the reference sachet mean peak levels of 1.02 micrograms/ml and 0.36 microgram/ml were observed for parent drug and metabolite, respectively, reached at peak times of 1.5 h and 1.8 h. Comparable profiles were observed with the intact and dispersed Solutab tablets, both tending towards higher serum levels than the sachet. In terms of josamycin propionate levels as well as josamycin base levels, the intact and dispersed Solutab tablet was bioequivalent with the referent sachet within the preset 0.70-1.43 margins. Variability in josamycin kinetics proved to be substantial, maximum differences in peak levels and AUC values being about 10-fold between individuals, and 3-fold within individuals. Retrospectively, the multiple dosing regimen appeared not to result in a clear reduction of intrasubject variability.
Van Hoogdalem
E J
EJ
Yamanouchi Europe B.V., Research Labs Leiderdorp, The Netherlands.
Terpstra
I J
IJ
Krauwinkel
W J
WJ
Volkers-Kamermans
N J
NJ
Baven
A L
AL
Verschoor
J S
JS
D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D015570:Josamycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D012016:Reference Values; D015203:Reproducibility of Results; D012189:Retrospective Studies; D013056:Spectrophotometry, Ultraviolet; D013607:Tablets; D013810:Therapeutic Equivalency
D000900:Anti-Bacterial Agents; D013607:Tablets; D015570:Josamycin