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.

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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.
    Preview · Article · Feb 2012 · Therapeutics and Clinical Risk Management
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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.
    Full-text · Article · Nov 2010 · European journal of medical research
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    • "Drug elimination occurs through the renal mechanism and it is excreted largely unchanged in the urine. The normal 8 h halflife of daptomycin increases to as high as 30 h when there is renal impairment, hence dose adjustment is mandatory for patients with renal failure [11]. As daptomycin does not induce or inhibit the activities of cytochrome P450 or other hepatic enzymes and because of its unique mechanism of action, no antagonistic drug interactions have been observed [12]. "
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    ABSTRACT: Serious infections caused by Gram-positive bacteria are currently difficult to treat because many of these pathogens are now resistant to standard antimicrobial agents. As a result of the emergence and spread of multidrug-resistant Gram-positive pathogens, new antimicrobial agents are urgently needed for clinical use. In recent years, there has been an increase in the number of drugs that have activity against these Gram-positive pathogens. Daptomycin, tigecycline, linezolid, quinupristin/dalfopristin and dalbavancin are five antimicrobial agents that are useful for the treatment of infections due to drug-resistant Gram-positive cocci. This review focuses on their mechanism of action, pharmacokinetics, spectrum of activity, clinical effectiveness, drug interaction and safety. These antimicrobial agents provide the clinician with additional treatment options among the limited therapies for resistant Gram-positive bacterial infection.
    Preview · Article · Dec 2009
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