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J Antimicrob Chemother. 2019 Jan 9. doi: 10.1093/jac/dky541. [Epub ahead of print]

Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing daptomycin pharmacokinetics: a population analysis in patients with bone and joint infection.

Author information

Hospices Civils de Lyon, Department of Infectious Diseases, Lyon, France.
Hospices Civils de Lyon, Groupement Hospitalier Nord, Service de Pharmacie, Lyon, France.
Univ Lyon, Université Claude Bernard Lyon 1, ISPB - Facultés de Médecine et de Pharmacie de Lyon, Lyon, France.
Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.
Hospices Civils de Lyon, Groupement Hospitalier Sud, Laboratoire de Pharmacologie, Lyon, France.
Univ Lyon, Université Claude Bernard Lyon 1, International Centre for Research in Infectiology, CIRI, INSERM U1111, CNRS UMR5308, ENS de Lyon, Lyon, France.



Daptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK).


We aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI.

Patients and methods:

We analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets.


Data from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy.


Daptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements.


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