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.
© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.