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