Population Pharmacokinetic Analysis of Daptomycin in Patients With Osteoarticular Infections

Study Overview
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Brief Summary
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Daptomycin is validated as a treatment of bone and joint infections by the Infectious Disease Society of America. However, most of studies did not investigate daptomycin pharmacokinetics in this indication while it is known that efficacy and toxicity concentration studies show a close therapeutic margin. Evaluation of P-Glycoprotein (P-gp), a transmembrane transport protein, has demonstrated its influence on the concentration and intracellular activity of daptomycin. Recent work has linked the genetic polymorphism of P-gp to the pharmacokinetics of daptomycin, which may explain inter-individual variability but requires further explorations. Previous studies demonstrated existence of interindividual variabilities as sex, renal function and p-glycoprotein polymorphism couple with an intraindividual variabilities unexplained yet. A population approach will be used to determinate the pharmacokinetics factors, their intra and interindividual variabilities, the parameters associated to those variabilities (as the p glycoprotein). The investigator's goal is to evaluate different posology and to try to increase daptomycin efficacy and security in bone and joint infection.

Official Title
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Population Pharmacokinetic Analysis of Daptomycin in Patients With Osteoarticular Infections

Conditions
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Bone Infection, Joint Infection

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients having had a bone or joint infection, with or without implant, having an antibiotherapy with daptomycin between December 2012 and December 2016 at the Croix-Rousse hospital are at least 18 years old Exclusion Criteria: None

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) |  | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve |  | up to 6 months | 
| typical daptomycin clearance and volume of distribution in the population |  | Month 6 | 
| Mean daptomycine plasma clearance | (unit, liters per hour) | Month 6 | 
| Mean daptomycine volume of distribution | (unit, liters) | Month 6 | 
| Inter-individual coefficient of variation of daptomycin clearance | (unit, %) | Month 6 | 
| Inter-individual coefficient of variation of daptomycin volume of distribution | (unit, %) | Month 6 | 
| Intra-individual coefficient of variation of daptomycin clearance | (unit, %) | Month 6 | 
| Intra-individual coefficient of variation of daptomycin volume of distribution | (unit, %) | Month 6 | 
| influence of demographic and biological covariates on pharmacokinetics (e.g. : renal function, gender) | the influence of demographic and biological covariates on pharmacokinetics will be assessed statistically by using the Akaike Information Criterion (AIC, no unit). AIC = -2xLL + 2P, where LL is the log-likelihood computed by the population algorithm and P is the number of parameters in the model. A covariate will be considered as significant if it is associated with a decrease in the AIC value compared with the base model without covariate. | Month 6 | 
| influence of p-glycoprotein pharmacogenetics on daptomycin pharmacokinetics | the influence of P-glycoprotein pharmacogenetics on pharmacokinetics will be assessed statistically by using the Akaike Information Criterion (AIC, no unit). AIC = -2xLL + 2P, where LL is the log-likelihood computed by the population algorithm and P is the number of parameters in the model. The P-glycoprotein genotype will be considered as significant if it is associated with a decrease in the AIC value compared with the base model without covariate. | Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bone and joint infection, daptomycin, population pharmacokinetics, Glycoprotein-P (PgP)