Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference
Authors: Garreau Romain , Bricca Romain , Gagnieu Marie-Claude , Roux Sandrine , Conrad Anne , Bourguignon Laurent , Ferry Tristan , Goutelle Sylvain ,   the Lyon Bone and Joint Infection Study Group, Ferry Tristan , Valour Florent , Perpoint Thomas , Miailhes Patrick , Ader Florence , Roux Sandrine , Becker Agathe , Triffault-Fillit Claire , Conrad Anne , Pouderoux Cécile , Benech Nicolas , Chauvelot Pierre , Perry Marielle , Daoud Fatiha , Lippman Johanna , Braun Evelyne , Chidiac Christian , Servien Elvire , Lustig Sébastien , Batailler Cécile , Gunst Stanislas , Schmidt Axel , Malatray Matthieu , Sappey-Marinier Elliot , Fessy Michel-Henry , Viste Anthony , Besse Jean-Luc , Chaudier Philippe , Louboutin Lucie , Ode Quentin , Van Haecke Adrien , Mercier Marcelle , Belgaid Vincent , Walch Arnaud , Martres Sébastien , Trouillet Franck , Barrey Cédric , Mojallal Ali , Brosset Sophie , Hanriat Camille , Person Hélène , Sigaux Nicolas , Céruse Philippe , Fuchsmann Carine , Aubrun Frédéric , Dziadzko Mikhail , Macabéo Caroline , Laurent Frederic , Beraud Laetitia , Roussel-Gaillard Tiphaine , Dupieux Céline , Kolenda Camille , Josse Jérôme , Brevet Marie , Trecourt Alexis , Craighero Fabien , Boussel Loic , Pialat Jean-Baptiste , Morelec Isabelle , Tod Michel , Gagnieu Marie-Claude , Goutelle Sylvain , Mabrut Eugénie 
Published: January 2021

Abstract

Background
Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction.

Objectives
To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration.

Methods
A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety.

Results
A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect.

Conclusions
A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.