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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

1
Hospices Civils de Lyon, Department of Infectious Diseases, Lyon, France.
2
Hospices Civils de Lyon, Groupement Hospitalier Nord, Service de Pharmacie, Lyon, France.
3
Univ Lyon, Université Claude Bernard Lyon 1, ISPB - Facultés de Médecine et de Pharmacie de Lyon, Lyon, France.
4
Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.
5
Hospices Civils de Lyon, Groupement Hospitalier Sud, Laboratoire de Pharmacologie, Lyon, France.
6
Univ Lyon, Université Claude Bernard Lyon 1, International Centre for Research in Infectiology, CIRI, INSERM U1111, CNRS UMR5308, ENS de Lyon, Lyon, France.

Abstract

Background:

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).

Objectives:

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.

Results:

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.

Conclusions:

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.

PMID:
30629193
DOI:
10.1093/jac/dky541

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