Population Pharmacokinetics of Daptomycin

Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 09/2004; 48(8):2799-807. DOI: 10.1128/AAC.48.8.2799-2807.2004
Source: PubMed


Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.


Available from: Robert D. Arbeit, Jan 01, 2014
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    • "Compared with healthy volunteers, clearance in subjects on dialysis is approximately one-third of that in nondialysis subjects (0.27 vs 0.81 L/hour).55 While there is no dose adjustment recommended for patients with renal impairment and creatinine clearance >30 mL/minute, in patients with <30 mL/minute, the dose recommendation is 4 mg/kg every 48 hours in patients on hemodialysis or continuous ambulatory peritoneal dialysis, dose administration is recommended postdialysis on dialysis days.56 "
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    ABSTRACT: Daptomycin is a lipoglycopeptide antibacterial drug that is rapidly bactericidal for methicillin-resistant Staphylococcus aureus (MRSA) infection and has antibiotic activity against a wide range of Gram-positive organisms. It has been approved by the Ministry of Health, Labor and Welfare in Japan for the treatment for bacteremia, right-sided endocarditis, and skin and skin-structure infections, such as necrotizing fasciitis, due to MRSA on the basis of a Phase III trial conducted in Japan since July, 2011. In Japanese Phase I and III trials, daptomycin therapy given at 4 mg/kg and 6 mg/kg once per day was well tolerated and effective as standard therapy for the treatment of acute bacterial skin and skin-structure infections and bacteremia caused by MRSA, but side effects remain to be evaluated in large-scale trials.
    Therapeutics and Clinical Risk Management 02/2012; 8:79-86. DOI:10.2147/TCRM.S23875 · 1.47 Impact Factor
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    • "The half life of daptomycin is approximately 8 hours [75,76,79,80]. The reason for this long half-life is the restricted glomerular filtration due to the high protein binding. "
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    ABSTRACT: The rapid antibiotic resistance development has created a major demand for new antimicrobial agents that can combat resistant strains such as methicillin-resistant S. aureus (MRSA). Until a short time ago, the glycopeptide vancomycin was the only therapeutic choice in this situation. However, in recent years some newer agents with different mechanisms of actions have been added to the arsenal, and more are on the horizon. For a successful therapy it is of vital importance that these compounds are used judiciously and dosed appropriately. The present article reviews the pharmacokinetic properties of vancomycin, linezolid, tigecycline and daptomycin. The first major difference between these compounds is their oral bioavailability. Only linezolid can be administered orally, whereas vancomycin, daptomycin and tigecycline are limited to parenteral use. Once in the body, they show very different disposition. Daptomycin has a very small volume of distribution of 7L indicating very little tissue distribution whereas tigecycline has a very large volume of distribution of 350-500 L. Vancomycin and linezolid are in-between with volumes of distribution of approximately 30 and 50 L, close to total body water. However, studies have shown that linezolid shows better tissue penetration than vancomycin. Newer studies using microdialysis, a new technique that allows direct monitoring of unbound tissue levels, support this finding. As far as drug elimination, daptomycin and vancomycin are mainly eliminated into the urine and require dosing adjustments in renally impaired patients, whereas tigecycline is eliminated into the bile and linezolid is metabolized so that in renal patients no dosing adjustments are needed for these compounds. Although the elimination pathways are very different, the resulting half-lives of linezolid, vancomycin, and daptomycin are not greatly different and vary from 4-8 h. Tigecycline, however, has a much longer half-life of up to 1-2 days due to the slow redistribution from tissue binding sites.
    European journal of medical research 11/2010; 15(12):533-43. DOI:10.1186/2047-783X-15-12-533 · 1.50 Impact Factor
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    • "The currently approved method of administration for daptomycin is as a once-daily 30 min intravenous (iv) infusion, and the efficacy, safety and pharmacokinetics of this dosing regimen have been established in healthy subjects10,11 as well as in patients with Gram-positive infections.12 In Phase III clinical trials, the majority of adverse events (AEs) experienced by patients were of mild or moderate intensity and not attributed to the study drug.13,14 "
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    ABSTRACT: Two randomized Phase I studies in separate populations of healthy adult volunteers investigated the pharmacokinetics, safety and tolerability of daptomycin (Cubicin; Novartis Pharma AG, Basel, Switzerland) administered as a 2 min intravenous (iv) injection, relative to the currently licensed 30 min iv infusion. Study 1 was an open-label, single-dose, two-period, crossover study in which each subject received 6 mg/kg daptomycin administered as a 30 min iv infusion (n = 15) and as a 2 min iv injection (n = 16). In Study 2, a single-blind, multiple-dose, parallel-group study, subjects received a once-daily 2 min iv injection of 6 mg/kg daptomycin (n = 12), 4 mg/kg daptomycin (n = 8) or placebo (n = 4) for 7 days. Single-dose pharmacokinetics were assessed at various timepoints up to 36 and 24 h post-dose in Study 1 and Study 2, respectively, and multiple-dose pharmacokinetics were assessed in Study 2 at day 7 for 48 h post-dose. In Study 1, pharmacokinetic comparability between the two administration regimens was demonstrated by meeting the bioequivalence criteria for the exposure parameters, AUC(0-t), AUC(0-infinity) and C(max). In Study 2, time-invariant pharmacokinetic properties as well as dose-proportional pharmacokinetics were demonstrated for the daptomycin 2 min iv injection regimen. In both studies, daptomycin was well tolerated and the majority of treatment-emergent adverse events were of mild intensity and considered to be unrelated to daptomycin. The similar pharmacokinetic and safety profiles of the two administration regimens suggest that the 2 min iv injection may be a convenient treatment option for both patients and healthcare professionals.
    Journal of Antimicrobial Chemotherapy 05/2009; 64(1):151-8. DOI:10.1093/jac/dkp155 · 5.31 Impact Factor
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