PHARMACOKINETIC AND CLINICAL STUDIES WITH L-627 (BIAPENEM) IN THE PEDIATRIC FIELD

Abstract

To conduct pharmacokinetic and clinical studies on newly developed L-627 (biapenem) against various infections in pediatrics, a study group was organized and a joint research by 15 institutions and their related hospitals was undertaken. Informed consents of subjects were obtained prior to the study. The obtained results are as follows.
1. Plasma concentrations and urinary excretion
Pharmacokinetics of L-627 in children was studied in 29 subjects using 30 minutes intravenous drip infusion of 6mg/kg and 12mg/kg. Maximum plasma levels of L-627 was observed at the completion of drip infusion and were 25.1μg/ml with administration of 6mg/kg and 39.2μg/ml with administration of 12mg/kg on average. Dose dependency was noted in C_max. and AUC with these doses. Maximum blood levels in all of the 5 participated sucklings under the age of one year were similar to the average. As for urinary excretion, L-627 was excreted 66.0% with administration of 5mg/kg and 62.3% with 12mg/kg.
2. Cerebrospinal fluid concentrations
Cerebrospinal fluid concentrations ranged from 0.76 to 8.54μg/ml in 30-240 minutes after the completion of drip infusion with dose of 20-40mg/kg in 9 subjects with purulent meningitis, when they were measured within 3 days after the initiation of the treatment with L-627.
3. Clinical results Thirty-three cases of exclusion and drop-out were deducted from a total of 330 cases, hence 297 cases were evaluated as the subjects in the study for analysis of clinical effects. As for clinical effects in group A where pathogenic bacteria were detected, 166 out of 173 were rated as effective or above, hence the efficacy rate of 96.0% was obtained. In group B where pathogenic bacteria were not detected, 114 out of 124 cases were rated as effective or above, thus the efficacy rate was 91.9%, which is similar to that of the group A. The overall efficacy rate was 94.3% in the entire 297 cases. The rates of “excellent” responses out of the cases rated as effective or above were 62.7%(104/166) in the group A and 55.3%(63/114) in the group B, thus the rate was markedly high in the former group.
Efficacy rate for each pathogenic strain was also high, and that in subjects infected by a single pathogenic strain was 96.7%(145/150) and that in subjects infected by two or more pathogenic strains was 91.3%(21/23).
As for the bacteriological effect 74 (94.9%) out of 78 strains of Gram-positive bacteria and 115 (93.5%) out of 123 strains of Gram-negative bacteria disappeared. Even among examples of poor responses, the eradication rates were high: including 57.1% for MRSA and 71.4% for Pseudomonas aeruginosa. Besides, 2 out of 3 strains of Bordetella pertussis were eradicated. The overall bacterial eradication rate was 94.0%.
The efficacy rate of L-627 was 93.0%(93/100) in cases where other antibacterial drugs were administered for more than 3 days and proved to be ineffective. The rate of “excellent” response out of the 93 cases was 51.6%(48/93). The bacterial eradication rate for Gram-positive bacteria was 96.6%(28/29) and that for Gram-negative bacteria was 93.9%(31/33).
4. Side effects and abnormal laboratory data
A study on the safety was conducted in 316 cases to evaluate side effects and in 313 cases to evaluate abnormalities in laboratory data. Side effects were noted in 10 cases (3.2%), consisting of 11 events: skin rash in 4, diarrhea in 4, erythema in 1, abdominal pain in 1 and pyrexia in 1.
Abnormalities in laboratory data were found in 46 cases (14.7%), consisting mainly of elevations in platelet count, increases in eosinophils and elevations of transaminase. Side effects and abnormalities in laboratory data were not particularly serious and disappeared or returned to normal with discontinuation or completion of the treatment with L-627.