Clinical pharmacokinetics of quinupristin/dalfopristin

Quinupristin/dalfopristin is a streptogramin antibacterial with a wide spectrum of Gram-positive antibacterial activity. The drug has minimal oral absorption and is administered intravenously as a fixed 30 : 70 ratio of quinupristin to dalfopristin. A linear relationship has been observed between the dose administered and maximum plasma concentrations. Single-dose administration of 7.5 mg/kg produced a maximal plasma concentration of 2.3-2.7 mg/L for quinupristin and 6.1-8.2 mg/L for dalfopristin. The area under the concentration-time curve (AUC) obtained with the same dose was 2.7-3.3 and 6.5-7.7 mg (.) h/L for quinupristin and dalfopristin, respectively. Repeated administration results in 13-21% increases in maximum plasma concentrations and 21-26% increases in AUC for both quinupristin and dalfopristin. Quinupristin and dalfopristin exhibit steady-state volumes of distribution of 0.46-0.54 and 0.24-0.30 L/kg, respectively. Quinupristin exhibits higher protein binding (55-78%) than dalfopristin (11-26%), though both entities distribute well into tissues. Concentrations exceeding those in blood have been reported for the kidney, liver, spleen, salivary glands and white blood cells of primates. Extravascular penetration, as measured in blister fluid, is 40-80%. Both quinupristin and dalfopristin are extensively metabolised via nonenzymatic reactions. Quinupristin is conjugated to form two active compounds, a cysteine moiety and a glutathione moiety. Dalfopristin is hydrolysed to the active metabolite pristinamycin IIA. The metabolites exert antibacterial activity similar to that of the parent compounds. Quinupristin/dalfopristin is excreted primarily in the faeces (75-77%), with lesser renal excretion (15-19%). The elimination half-lives of quinupristin and dalfopristin are similar, and are 0.7-1.3 hours after single doses. The metabolites have slightly longer half-lives, ranging from 1.2 to 1.8 hours. With repeated doses, plasma clearance of quinupristin and dalfopristin is reduced by approximately 20% compared with single doses, resulting in clearances of 0.7-0.8 L/h/kg. Saturable protein binding has been hypothesised as a causative mechanism. Quinupristin/dalfopristin is an inhibitor of cytochrome P450 3A4, resulting in multiple drug interactions. Ciclosporin AUC increased by 5-222% when coadministered with quinupristin/dalfopristin. Careful monitoring of patients receiving drugs that are substrates of cytochrome P450 3A4 is suggested. Quinupristin/dalfopristin is administered at 7.5 mg/kg every 8-12 hours, depending upon the severity of infection. The pharmacodynamic parameter linked with antibacterial activity for quinupristin/dalfopristin appears to be the ratio of AUC to the minimal inhibitory concentration. The additional activity of a prolonged post-antibiotic effect may also be important for efficacy.