Population Pharmacokinetic Analysis of Daptomycin in Patients With Osteoarticular Infections

• Conditions: Bone Infection; Joint Infection

• Registration Number: NCT03134521
• Lead Sponsor: Hospices Civils de Lyon

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-12-01
• Study First Submitted: 2017-03-29
• Study First Submitted QC: 2017-04-28
• Status Verified: 2017-05
• Study First Posted: 2017-05-01
• Last Update Submitted: 2017-05-10
• Last Update Posted: 2017-05-11
• Primary Completion: 2017-06-30
• Study Completion: 2017-06-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 189

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

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Exclusion Criteria

• None

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Peak plasma concentration (Cmax)	Month 6

Secondary Outcome Measures

Name	Time	Method
Intra-individual coefficient of variation of daptomycin clearance	Month 6	(unit, %)
Mean daptomycine volume of distribution	Month 6	(unit, liters)
Inter-individual coefficient of variation of daptomycin clearance	Month 6	(unit, %)
influence of demographic and biological covariates on pharmacokinetics (e.g. : renal function, gender)	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.
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	Month 6	(unit, liters per hour)
Inter-individual coefficient of variation of daptomycin volume of distribution	Month 6	(unit, %)
Intra-individual coefficient of variation of daptomycin volume of distribution	Month 6	(unit, %)
influence of p-glycoprotein pharmacogenetics on daptomycin pharmacokinetics	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.