Population Pharmacokinetic Analysis of Daptomycin in Patients With Osteoarticular Infections

Hospices Civils de Lyon189 enrolled

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

OBSERVATIONAL

Enrollment

189

Conditions

Bone Infection Joint Infection

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Peak plasma concentration (Cmax)

Time frame: Month 6

Secondary Outcomes

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

(unit, liters per hour)

Time frame: Month 6

Mean daptomycine volume of distribution

(unit, liters)

Time frame: Month 6

Inter-individual coefficient of variation of daptomycin clearance

(unit, %)

Time frame: Month 6

Inter-individual coefficient of variation of daptomycin volume of distribution

(unit, %)

Time frame: Month 6

Intra-individual coefficient of variation of daptomycin clearance

(unit, %)

Time frame: Month 6

Intra-individual coefficient of variation of daptomycin volume of distribution

(unit, %)

Time frame: 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.

Time frame: 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.

Time frame: Month 6