Population Pharmacokinetic Analysis of Daptomycin in Patients With Osteoarticular Infections

Overview

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.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Retrospective
  • Study Primary Completion Date: June 30, 2017

Clinical Trial Outcome Measures

Primary Measures

  • Peak plasma concentration (Cmax)
    • Time Frame: Month 6

Secondary Measures

  • Area under the concentration-time curve
    • Time Frame: up to 6 months
  • typical daptomycin clearance and volume of distribution in the population
    • Time Frame: Month 6
  • Mean daptomycine plasma clearance
    • Time Frame: Month 6
    • (unit, liters per hour)
  • Mean daptomycine volume of distribution
    • Time Frame: Month 6
    • (unit, liters)
  • Inter-individual coefficient of variation of daptomycin clearance
    • Time Frame: Month 6
    • (unit, %)
  • Inter-individual coefficient of variation of daptomycin volume of distribution
    • Time Frame: Month 6
    • (unit, %)
  • Intra-individual coefficient of variation of daptomycin clearance
    • Time Frame: Month 6
    • (unit, %)
  • Intra-individual coefficient of variation of daptomycin volume of distribution
    • Time Frame: Month 6
    • (unit, %)
  • influence of demographic and biological covariates on pharmacokinetics (e.g. : renal function, gender)
    • Time Frame: Month 6
    • 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.
  • influence of p-glycoprotein pharmacogenetics on daptomycin pharmacokinetics
    • Time Frame: Month 6
    • 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hospices Civils de Lyon
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Tristan Ferry, Principal Investigator, Hospices Civils de Lyon – Hopital de la Croix Rousse

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