Population Pharmacokinetic Analysis of Daptomycin in Patients With Osteoarticular Infections

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 Overview

• Status: Unknown
• Conditions: Bone Infection; Joint Infection

• Study Type: Observational
• Enrollment (Actual): 189

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients having bone or joint infection, with or without implant, having an antibiotherapy with daptomycin

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Tristan Ferry, Hospices Civils de Lyon - Hôpital de la Croix Rousse

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Anticipated): June 30, 2017
• Study Completion (Anticipated): June 30, 2017

Study Registration Dates

• First Submitted: March 29, 2017
• First Submitted That Met QC Criteria: April 28, 2017
• First Posted (Actual): May 1, 2017

Study Record Updates

• Last Update Posted (Actual): May 11, 2017
• Last Update Submitted That Met QC Criteria: May 10, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: bone and joint infection; population pharmacokinetics; daptomycin; Glycoprotein-P (PgP)
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases
• Other Study ID Numbers: 69HCL17_0182

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No