Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Abstract

The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (ϳ20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (ϳ9 h), volume of distribution (ϳ0.1 liters/kg), systemic clearance (ϳ8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (ϳ54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.Daptomycin is a novel lipopeptide antibiotic that possesses several pharmacologic advantages over other gram-positive antimicrobial agents (3,12). It is a fermentation product of Streptomyces roseosporus that was discovered in the early 1980s (12). Daptomycin exhibits potent in vitro bactericidal activity against most clinically relevant strains of gram-positive bacteria, including antimicrobial-resistant pathogens (5). The MICs at which 90% of the microbes tested are inhibited are Յ1 g/ml, with the exception of those for enterococci, which are approximately 2 to 4 g/ml (5, 7, 8, 10-13). The spontaneous acquisition of resistance to daptomycin is rare in gram-positive bacteria in vitro, and the emergence of resistance to daptomycin is rare during clinical trials.Daptomycin appears to bind to the gram-positive bacterial cell membrane by its fatty acid tail, followed by calcium-dependent insertion (6). The resulting decrease in membrane potential causes cell death by rapidly stopping DNA, RNA, and protein synthesis (1). Because daptomycin does not appear to penetrate into cells, the interactions with the plasma membrane are most likely the basis for its pharmacologic actions...

Daptomycin use in infants: report of two cases with peak and trough drug concentrations

“…2 Daptomycin 6 mg kg À1 every day is approved for treatment of MRSA bacteremia. 1 Preliminary data on the pharmacokinetic properties of daptomycin in children older than 2 years of age indicates that an inverse linear correlation exists between clearance and age when young children are compared with adolescents.…”

The action mechanism of daptomycin

“…However, such daptomycin concentrations still substantially exceed the MICs for clinically susceptible pathogens; they occur in human plasma only immediately after application of the drug; and moreover, 90% of the total amount of daptomycin in plasma is protein-bound, most likely in monomeric form, 43,44 and the unbound remainder would remain well below the experimental aggregation threshold.…”

Pharmacokinetic/pharmacodynamic (PK/PD) considerations in the management of Gram-positive bacteraemia

“…Due to daptomycin's concentration dependence, a once-daily dosing regimen has been proposed to optimize its pharmacodynamic properties and has demonstrated an improved safety profile compared with that of the initially evaluated twice-daily regimen [71][72][73][74][75]. A Monte Carlo prediction model analysis was conducted to determine if AUC/MIC targets could be achieved in a clinical setting [74].…”