Multiple-dose pharmacokinetics and safety of two regimens of quinupristin/dalfopristin (Synercid (R)) in healthy volunteers

Quinupristin/dalfopristin (Q/D) is a novel streptogramin antibiotic for the treatment of severe gram-positive infections. The purpose of this open, no nrandomized, parallel-group, phase I trial was to evaluate Q/D pharmacokine tics after single and repeated doses under the two different dosing regimen s corresponding to the effective doses and to evaluate tolerability. Two gr oups of 10 healthy volunteers received multiple I-hour intravenous infusion s of 7,5 mg/kg Q/D either every 8 or 12 hours for 4 or 5 days, respectively . Plasma concentrations of Q, D, and metabolites were determined using high -performance liquid chromatography and selective microbiological assays. Th e two regimens q8h and q12h lead to the same disposition profile after sing le and repeated administration. Single-dose data confirmed the high plasma clearances of Q and D (about 0.90 I/h/kg) obtained previously. Unchanged dr ugs were the main components in plasma, with each of the three metabolites representing about 20% (in terms of the AUC ratio) of the parent drugs. Com parable steady-state concentrations were reached from day 2 of both regimen s. A similar moderate increase in C-max and AUC (about 20%) of parent drugs was observed between the first and lost day of treatment. This phenomenon, which was also observed for the metabolites, was not expected considering the short terminal disposition half-lives of the parent drugs and trough pl asma concentrations of all components mostly below the limits of quantitati on at steady state, whatever the dosing regimen. The clearances of parent d rugs at steady state were about 20% lower as compared with that observed fo llowing the first drug administration (statistically significant difference ). No trend suggesting a treatment effect on any laboratory parameter, vita l signs, or electrocardiographic parameters was identified. However, 80% of subjects reported venous adverse events probably related to treatment. sto ol the American College of Clinical Pharmacology.