Pharmacokinetics and Tolerability of Daptomycin at Doses up to 12 Milligrams per Kilogram of Body Weight Once Daily in Healthy Volunteers

Abstract

Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin-(MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.Daptomycin is the first member of the novel cyclicallipopeptide class, which provides rapid, concentration-dependent bactericidal activity against a broad range of gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) (2, 6, 9, 10). Daptomycin causes bacterial cell death by a mechanism unique among available antimicrobial agents (8,11). It binds to the cell membranes of gram-positive bacteria, thereby disrupting their membrane potential, initiating potassium efflux with rapid cell death.The safety and efficacy of daptomycin in treating complicated skin and skin structure infections were demonstrated in two randomized, controlled clinical trials (1). When administered at a dose of 4 mg/kg of body weight intravenously once daily for 7 to 14 days, daptomycin provided clinical success rates comparable to those of vancomycin and penicillinaseresistant penicillins and showed safety and tolerability similar to those of the comparators. On the basis of these studies, daptomycin was approved by the FDA and the European Medicines Agency for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive strains, including MRSA (3). Because of its antibacterial profile, daptomycin may also b...

Intradialytic Administration of Daptomycin in End Stage Renal Disease Patients on Hemodialysis

“…Similar to our findings, they reported achieving lower Cmax values in patients with ESRD than in healthy volunteers. In addition, the percentage of protein binding that we measured (mean unbound fraction 10.8%) was similar to that reported in healthy volunteers (approximately 10%) (10,11) and in patients who were receiving HD (10.70 Ϯ 1.84%; unpublished Cubist data, David P. Benziger, Ph.D., Cubist Pharmaceutical, Inc., Lexington, MA, personal communication, November 19, 2008). The clinical significance of a larger volume of distribution in patients with ESRD and the resultant lower Cmax compared with those achieved in healthy volunteers has yet to be determined.…”

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.…”

Antibiotics Against Endocarditis – Past, Present and Future (Experimental Data)

“…These data support the use of daptomycin dosages exceeding 6 mg/kg to increase bacterial killing and limit the risk of emergence of resistant variants during daptomycin therapy. Case reports have described safe and well tolerated daptomycin treatment at doses up to 12 mg/kg (Benvenuto et al, 2006;Cunha et al, 2006), but adequate dosing of daptomycin remains unresolved. A recent review about clinical utility of daptomycin in infective endocarditis specifies that adequate dosing of daptomycin for the treatment of left-sided or prosthetic valve S. aureus endocarditis should be ≥ 10 mg/kg/day (Cervera et al, 2011).…”