Romain Garreau1,2, Damien Montange3,4, Antoine Grillon5, François Jehl5, Tristan Ferry6,7,8, Laurent Bourguignon9,10,7, Sylvain Goutelle9,10,7. 1. Service Pharmaceutique, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France. romain.garreau@chu-lyon.fr. 2. UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, Université Lyon 1, Villeurbanne, France. romain.garreau@chu-lyon.fr. 3. Laboratoire de Pharmacologie Clinique et Toxicologie, Plateforme PACE, Centre Hospitalier Universitaire de Besançon, Besançon, France. 4. EA 3920, Marqueurs Pronostiques et Facteurs de Régulations des Pathologies Cardiaques et Vasculaires-SFR FED 4234, Université de Franche Comté, Besançon, France. 5. Institut de Bactériologie, Hôpitaux Universitaires, Strasbourg, France. 6. Service des Maladies Infectieuses et Tropicales, Centre Interrégional de Référence Pour la Prise en Charge des Infections Ostéo-Articulaires Complexes (CRIOAc Lyon), Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, Lyon, France. 7. ISPB, Facultés de Médecine et de Pharmacie de Lyon, Université Lyon 1, Lyon, France. 8. CIRI-Centre International de Recherche en Infectiologie, Inserm, U1111, Université́ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Lyon, France. 9. Service Pharmaceutique, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France. 10. UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, Université Lyon 1, Villeurbanne, France.
Abstract
BACKGROUND AND OBJECTIVE: Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue. METHODS: A PBPK model of daptomycin was built using PK-Sim®. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments. RESULTS: The final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy. CONCLUSIONS: We developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.
BACKGROUND AND OBJECTIVE: Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue. METHODS: A PBPK model of daptomycin was built using PK-Sim®. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments. RESULTS: The final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy. CONCLUSIONS: We developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.
Authors: Douglas R Osmon; Elie F Berbari; Anthony R Berendt; Daniel Lew; Werner Zimmerli; James M Steckelberg; Nalini Rao; Arlen Hanssen; Walter R Wilson Journal: Clin Infect Dis Date: 2013-01 Impact factor: 9.079
Authors: D Montange; F Berthier; G Leclerc; A Serre; L Jeunet; M Berard; P Muret; L Vettoretti; J Leroy; B Hoen; C Chirouze Journal: Antimicrob Agents Chemother Date: 2014-05-05 Impact factor: 5.191
Authors: Friederike Traunmüller; Michael V Schintler; Julia Metzler; Stephan Spendel; Oliver Mauric; Martin Popovic; Karl Heinz Konz; Erwin Scharnagl; Christian Joukhadar Journal: J Antimicrob Chemother Date: 2010-04-07 Impact factor: 5.790