Nicolas Gregoire

Alexia Chauzy

Julien Buyck

Blandine Rammaert

William Couet
email: author.william.couet@univ-poitiers.fr

Sandrine Marchand

Clinical Pharmacokinetics of Daptomycin

Due to the low level of resistance observed with daptomycin, this antibiotic has an important place in the treatment of severe Gram-positive infections. It is the first in class of the group of calcium-dependent, membrane binding lipopeptide. It is a cyclic peptide constituted of 13 amino acids and a n-decanoyl fatty acid chain. The antibacterial action of daptomycin requires its complexation with calcium.

Daptomycin is not absorbed from the gastrointestinal tract and needs to be administered parenterally. The distribution of daptomycin is limited (volume of distribution of 0.1 L/kg in healthy volunteers) due to its negative charge at physiological pH and its high binding to plasma proteins (about 90%). Its elimination is mainly renal, with about 50% of the dose excreted unchanged in the urine, justifying dosage adjustment for patients with renal insufficiency. Pharmacokinetics of daptomycin is altered under certain pathophysiological conditions, resulting in high inter-individual variability. As a result, therapeutic drug monitoring (TDM) of daptomycin may be of interest for certain patients such as intensive care unit (ICU) patients, patients with renal or hepatic insufficiency, dialysis patients, obese patients or children. A target for the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC) greater than 666 is usually recommended for clinical efficacy, whereas in order to limit the risk of undesirable muscular effects the residual concentration (Cmin) should not exceed 24.3 mg/L.

Key points:

Daptomycin is highly bound to plasma proteins (90%) and it's unbound fraction may vary considerably between patients with strong impact on its pharmacokinetics. This protein binding of daptomycin should be considered for patients with renal failure, 1 including dialysis patients, as well as children. 2

Introduction

Daptomycin is the first calcium-dependent membrane binding lipopeptide. It was isolated in the 1980s, and found to have impressive activity against Gram-positive, but not Gramnegative bacteria. [START_REF] Eliopoulos | In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic[END_REF] However, Eli Lilly and Company (Lilly) suspended clinical investigation of daptomycin in 1991 because of skeletal muscle toxicity observed at high doses (4 mg/kg every 12h). [START_REF] Tally | Daptomycin: a novel agent for Gram-positive infections[END_REF] In 1997, Cubist Pharmaceuticals, Inc. (Cubist) licensed worldwide rights for daptomycin from Lilly. Yet due to the emergence of multidrug resistant bacteria, daptomycin was revisited. Its side effects were minimized by changing its dosing regimen and it received approval from the U.S. food and drug administration (FDA) in 2003.

Initial FDA authorization was for complicated skin and skin structure infections (cSSSI) in adult and paediatric patients > 1 year old, and Staphylococcus aureus bloodstream infections, including those with right-sided infective endocarditis in adults. Due to low resistance rate, low frequency of side effects and convenient once-a-day administration, daptomycin is currently widely used for Staphylococcus spp. and Enterococcus spp. infections. [START_REF] Tally | Development of daptomycin for gram-positive infections[END_REF]

Chemistry

Daptomycin is produced as a minor component of a complex lipopeptide mixture by the soil actinomycete Streptomyces roseosporus. [START_REF] Debono | Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: the synthesis and evaluation of daptomycin (LY146032)[END_REF] It is a cyclic peptide constituted of 13 amino acids and a n-decanoyl fatty acid chain at the N-terminus with a 1620.7 g/mol molecular weight (Figure 1). It has 4 acids residues (pK a of 1.3, 3.8, 4.1 and 4.4) and 2 basic residue (pK a of 1.3 and 10.7), resulting in a total molecular charge of -3 at neutral pH (the basic residue with pKa of 1.3 is unionized at neutral pH). [START_REF] Totoli | Daptomycin: Physicochemical, Analytical, and Pharmacological Properties[END_REF][START_REF] Qiu | Estimated pKa values for specific amino acid residues in daptomycin[END_REF]. The negative charge at neutral pH contributes to its high solubility in water (17.3 mg/L, logP = -5). [START_REF] Zupancic | Development and in vitro characterisation of an oral self-emulsifying delivery system for daptomycin[END_REF][START_REF] Drugbank | Daptomycin[END_REF] and its lipophilic tail contributes to its amphiphilic character. As a result of its negative charge, daptomycin aggregates into oligomeric structures with calcium, which enables the interaction of the lipophilic tail of daptomycin with the bacterial cell membrane, a prerequisite of its antimicrobial activity [START_REF] Totoli | Daptomycin: Physicochemical, Analytical, and Pharmacological Properties[END_REF].

Mechanism of action

Daptomycin is a membrane-active peptide active against Gram-positive bacteria. [START_REF] Gray | More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin[END_REF] The presence of calcium ions at physiological concentrations (1.25 mM) is a prerequisite for the antibacterial activity of daptomycin, by masking the overall negative charge and stimulating oligomerization of daptomycin. [START_REF] Eliopoulos | In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic[END_REF][START_REF] Scott | NMR structural studies of the antibiotic lipopeptide daptomycin in DHPC micelles[END_REF] The Ca 2+ -daptomycin complex has an increased affinity for negatively charged phospholids of cellular membranes, including phosphatidylglycerol. Yet the exact mechanism of action of daptomycin is still debated, it is admitted that it displays a rapid bactericidal activity by interacting with the cytoplasmic membrane of the bacteria, leading to an efflux of potassium, which in turn should lead to bacterial death. [START_REF] Silverman | Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus[END_REF] However, the simple pore formation may not be the primary antibacterial mechanism of daptomycin, and insertion into fluid membrane microdomains, so-called RIFs (regions of increased fluidity), and subsequent rigidification of those regions seems to play a central role. [START_REF] Gray | More Than a Pore: A Current Perspective on the In Vivo Mode of Action of the Lipopeptide Antibiotic Daptomycin[END_REF]. Furthermore, lipopeptides are known as immunomodulators that interact with pattern recognition receptors such as Toll-like receptors in antigen presenting cells. Daptomycin can also insert into membrane vesicles of immune cells, but further studies are needed to elucidate this possible interaction based on the known immunomodulatory activity of other lipopeptides. [START_REF] Kelesidis | The Interplay between Daptomycin and the Immune System[END_REF] 4 Spectrum of activity.

Daptomycin presents a rapid in vitro bactericidal effect against a wide spectrum of Grampositive bacteria including Staphylococcus aureus (SA, of which methicillin resistant Staphylococcus aureus, MRSA), coagulase-negative staphylococci, streptococci (of which penicillin-resistant streptococci), enterococci (of which vancomycin resistant enterococci, VRE), Peptostreptococcus, Clostridium perfringens and corynebacterium sp. [START_REF]Cubicin: Scientific discussion[END_REF]

Mechanisms of resistance

The prevalence of de novo resistance to daptomycin without prior exposure has been reported to be extremely rare (0.04% in S. aureus). [START_REF] Gonzalez-Ruiz | Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections[END_REF][START_REF] Stefani | Insights and clinical perspectives of daptomycin resistance in Staphylococcus aureus: A review of the available evidence[END_REF] However, even if daptomycin is still quite active, resistance to daptomycin has been widely reported over the past years in Staphylococci and Enterococci. Mutations of various genes are involved in these mechanisms of resistance, e.g. increase of bacterial membrane positive surface charge, alteration in the bacterial membrane fluidity, increased carotenoid pigment content, and increased teicoic acid synthesis in the cell wall have been described [START_REF] Casanova | Mechanisms of resistance to daptomycin in Staphylococcus aureus[END_REF] For more details, a review has described previously the mechanisms and genes involved in resistance to daptomycin. [START_REF] Tran | Mechanisms of drug resistance: daptomycin resistance[END_REF] Depending on the bacteria, two main mechanisms of resistance are used to develop resistance to daptomycin. With Enterococcus faecalis the mechanism corresponds to diversion of the antibiotic from the preferential binding site of daptomycin at the septum of the bacteria, resulting in ineffective binding of daptomycin. With Staphylococcus aureus and Enterococcus faecium, the mechanism is a modification of charge of the cell membrane leading to electrostatic repulsion of the positively charged complex daptomycin-Ca 2+ . Noticeably with Staphylococci, daptomycin resistance is generally observed in high-inoculum infections like endocarditis and abscesses when insufficiently high low doses are used. [START_REF] Dortet | In vivo acquired daptomycin resistance during treatment of methicillin-resistant Staphylococcus aureus endocarditis[END_REF][START_REF] Van Hal | Emergence of daptomycin resistance following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a daptomycin-naïve patient-a review of the literature[END_REF][START_REF] Julian | Characterization of a daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus strain in a patient with endocarditis[END_REF] Furthermore, the vancomycin-intermediate S. aureus (VISA) phenotype is also linked to increased resistance to daptomycin during therapy. [START_REF] Cui | Correlation between Reduced Daptomycin Susceptibility and Vancomycin Resistance in Vancomycin-Intermediate Staphylococcus aureus[END_REF] This cross-resistance is likely induced by modifications in the same molecular pathways. [START_REF] Tran | Mechanisms of drug resistance: daptomycin resistance[END_REF] 6 Indications approved in the marketing authorization Daptomycin is used to treat skin infections, bloodstream infections, right-sided endocarditis, sepsis and urinary tract infections caused by Gram-positive bacteria, such as S. aureus, both methicillin-susceptible and -resistant (MSSA and MRSA), as well as several Streptococcus and Enterococcus species. [START_REF] Heidary | Daptomycin[END_REF] 7 Pharmacokinetic/Pharmacodynamic indices and breakpoints It was shown that area under the curve/MIC (AUC/MIC) ratio is the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with daptomycin activity. [START_REF] Louie | Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection[END_REF] According to target values used by the EUCAST to determine breakpoints, AUC/MIC ratios needed for bacteriostatic or bactericidal effects are >438 or >1061. [START_REF] Safdar | In vivo pharmacodynamic activity of daptomycin[END_REF][START_REF] Falcone | Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia[END_REF][START_REF] Eucast | Daptomycin: Rational for the EUCAST clinical breakpoints, version 1.0.13[END_REF] Although antimicrobial activity depends on unbound antibiotic concentrations, these targets were estimated in mice with thigh infection and rely on total concentrations. Yet since the average unbound fraction (fu) in mice and human are comparable (about 10%), these targets can be used in human. However because it is extensive, even a minor modification of daptomycin protein binding may have a major effect on fu, which may therefore vary widely between subjects or/and due to concentration dependent or disease related effect. [START_REF] Louie | Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection[END_REF][START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF] This protein binding issue could therefore possibly explain that in some cases no link was established between PK/PD indices and clinical efficacy [START_REF] Takesue | Correlation between pharmacokinetic/pharmacodynamic indices and clinical outcomes in Japanese patients with skin and soft tissue infections treated with daptomycin: analysis of a phase III study[END_REF] while in other cases the link was U-shaped [START_REF] Bhavnani | Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations[END_REF]. Yet, in a clinical study with 35 patients, the ratio AUC/MIC>666 was associated with statistically reduced mortality [START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF] and in another study, a residual total concentration (Cmin) of less than 3.2 mg/L was associated with reduced efficacy. [START_REF] Galar | Current use of daptomycin and systematic therapeutic drug monitoring: Clinical experience in a tertiary care institution[END_REF]. At that point the clinical relevance of these target values based on total concentrations is not guarantee.

Clinical breakpoints have been fixed by EUCAST at 1 mg/L for Staphylococcus spp. and Streptococcus spp. (except S. pneumonia for which the use of daptomycin is not recommended). [START_REF] Eucast | Breakpoint tables for interpretation of MICs and zone diameters[END_REF] The EUCAST did not determined clinical breakpoint for Enterococcus spp. but determined epidemiological cut-off values of 4 mg/L for E. faecalis and 8 mg/L for E. faecium, whereas the Clinical and Laboratory Standards Institute (CLSI) determined a susceptible breakpoint of <2 mg/L for E. faecalis and a separate susceptible dose-dependent breakpoint of <4 mg/L for E. faecium. [START_REF] Avery | Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint[END_REF] Regarding toxicity, a total trough concentration (Cmin) of daptomycin >24.3mg/L was shown to be associated with an increased probability of creatine phosphokinase (CPK) elevation. [START_REF] Tally | Daptomycin: a novel agent for Gram-positive infections[END_REF][START_REF] Tally | Development of daptomycin for gram-positive infections[END_REF][START_REF] Bhavnani | Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis[END_REF][START_REF] Oleson | Once-daily dosing in dogs optimizes daptomycin safety[END_REF] However, for some authors this threshold could be exceeded without increasing the risk of toxicity. [START_REF] Ando | Observational retrospective single-centre study in Japan to assess the clinical significance of serum daptomycin levels in creatinine phosphokinase elevation[END_REF] 8 Bioanalysis Chromatographic Methods. Chromatographic methods for the determination of daptomycin in plasma [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF][START_REF] Gika | Daptomycin determination by liquid chromatography-mass spectrometry in peritoneal fluid, blood plasma, and urine of clinical patients receiving peritoneal dialysis treatment[END_REF][START_REF] Naito | Simple and validated UHPLC method coupled to UV detection for determination of daptomycin in human plasma and urine[END_REF][START_REF] Verdier | Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry[END_REF][START_REF] Baietto | Development and validation of an UPLC-PDA method to quantify daptomycin in human plasma and in dried plasma spots[END_REF][START_REF] Luci | A new validated HPLC-UV method for therapeutic monitoring of daptomycin in comparison with reference mass spectrometry[END_REF], dry plasma spots [START_REF] Baietto | Development and validation of an UPLC-PDA method to quantify daptomycin in human plasma and in dried plasma spots[END_REF], serum [START_REF] Tobin | An HPLC assay for daptomycin in serum[END_REF], whole blood [START_REF] Szultka | Simultaneous determination of selected chemotherapeutics in human whole blood by molecularly imprinted polymers coated solid phase microextraction fibers and liquid chromatography-tandem mass spectrometry[END_REF], urine [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Gika | Daptomycin determination by liquid chromatography-mass spectrometry in peritoneal fluid, blood plasma, and urine of clinical patients receiving peritoneal dialysis treatment[END_REF][START_REF] Naito | Simple and validated UHPLC method coupled to UV detection for determination of daptomycin in human plasma and urine[END_REF], plasma ultrafiltrate [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF], and peritoneal fluid [START_REF] Gika | Daptomycin determination by liquid chromatography-mass spectrometry in peritoneal fluid, blood plasma, and urine of clinical patients receiving peritoneal dialysis treatment[END_REF] can be found in the literature.

Methods using UV detection have quantitation limits ranging from 2 to 5 mg/L [START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF][START_REF] Naito | Simple and validated UHPLC method coupled to UV detection for determination of daptomycin in human plasma and urine[END_REF][START_REF] Luci | A new validated HPLC-UV method for therapeutic monitoring of daptomycin in comparison with reference mass spectrometry[END_REF][START_REF] Tobin | An HPLC assay for daptomycin in serum[END_REF], higher than those using mass detection with positive electrospray ionization, with quantitation limits ranging from 1 to 2 mg/L in plasma and of 0.05 mg/L in plasma ultrafiltrate. [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Gika | Daptomycin determination by liquid chromatography-mass spectrometry in peritoneal fluid, blood plasma, and urine of clinical patients receiving peritoneal dialysis treatment[END_REF][START_REF] Verdier | Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry[END_REF][START_REF] Szultka | Simultaneous determination of selected chemotherapeutics in human whole blood by molecularly imprinted polymers coated solid phase microextraction fibers and liquid chromatography-tandem mass spectrometry[END_REF][START_REF] Barco | A liquid chromatography-tandem mass spectrometry platform for the routine therapeutic drug monitoring of 14 antibiotics: Application to critically ill pediatric patients[END_REF] Another characteristic of LC-MS/MS methods is that they allow the use of small test samples (50µL), which can be an advantage for concentrations determinations in paediatrics. [START_REF] Barco | A liquid chromatography-tandem mass spectrometry platform for the routine therapeutic drug monitoring of 14 antibiotics: Application to critically ill pediatric patients[END_REF] Stability. Because of temperature dependent proteases activity, daptomycin is unstable in serum at body temperature and decreases by more than 50% after only 24h. [START_REF] Ogami | Evaluation of pharmacokinetics and the stability of daptomycin in serum at various temperatures[END_REF] However, daptomycin is stable at room temperature in whole blood and in plasma for at least 2 h and 6 h respectively. [START_REF] Barco | A liquid chromatography-tandem mass spectrometry platform for the routine therapeutic drug monitoring of 14 antibiotics: Application to critically ill pediatric patients[END_REF] Concentration loss in serum at room temperature is approximately 5% after 12h and more than 10% after 24 h. [START_REF] Ogami | Evaluation of pharmacokinetics and the stability of daptomycin in serum at various temperatures[END_REF] Concentrations in serum samples stored at 4°C decrease by 10% after 7 days. [START_REF] Ogami | Evaluation of pharmacokinetics and the stability of daptomycin in serum at various temperatures[END_REF] Daptomycin is stable in stock solution and in plasma for at least one year at -20°C, it is also stable after 3 freeze/thaw cycles. [START_REF] Verdier | Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry[END_REF][START_REF] Tobin | An HPLC assay for daptomycin in serum[END_REF][START_REF] Barco | A liquid chromatography-tandem mass spectrometry platform for the routine therapeutic drug monitoring of 14 antibiotics: Application to critically ill pediatric patients[END_REF] After extraction, daptomycin is stable in auto-sampler at room temperature for at least 6 h. [START_REF] Verdier | Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry[END_REF][START_REF] Barco | A liquid chromatography-tandem mass spectrometry platform for the routine therapeutic drug monitoring of 14 antibiotics: Application to critically ill pediatric patients[END_REF] Protein binding estimation. Protein binding of daptomycin can be determined by ultracentrifugation. [START_REF] Woodworth | Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers[END_REF], ultrafiltration [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF], or microdialysis [START_REF] Kim | In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers[END_REF]. As daptomycin adheres to ultrafiltration membranes, non-specific binding should be assessed. Furthermore non-specific binding reported in the literature increases as concentrations decrease, ranging from 5% for concentrations of 70 mg/L to 75% for concentrations of 1 mg/L. This relationship between the concentration of daptomycin and non-specific binding must be taken into account when correcting the concentrations measured in the ultra-filtrates. [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Kim | In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers[END_REF] 9 Clinical pharmacokinetics

Dosage regimens approved in the marketing authorization

It is indicated that daptomycin should be administered once daily as a 30-min infusion at a dose of 4 mg/kg/day (complicated skin and soft tissue infections) or 6 mg/kg/day (other indications). In case of renal insufficiency (creatinine clearance<30 mL/min), the interval of dose should be extended to 48h. At initiation of treatment, and then at least once weekly, CPK levels should be measured in order to monitor the occurrence of muscular adverse events. [START_REF]Cubicin: Summary of product characteristics[END_REF] EMA and FDA approved the use of daptomycin for treatment of paediatric patients with complicated skin and soft tissue infections (cSSTI) at dosages of 5, 7, 9, and 10 mg/kg every 24 h for patients aged 12-17, 7-11, 2-6, and 1-2 years old, respectively [START_REF]Cubicin: Summary of product characteristics[END_REF][START_REF] Purandare | Clinical Review NDA 021572. Cubicin (daptomycin for injection)[END_REF] and at dosages of 7, 9, and 12 mg/kg every 24 h for patients aged 12-17, 7-11, and 1-6 years old, respectively for treatment of S. aureus bacteraemia [START_REF]Cubicin: Summary of product characteristics[END_REF][START_REF] Rister | Clinical Review NDA 021572. Cubicin (daptomycin for injection)[END_REF]. Due to peak concentration toxicity observed in preclinical studies, it is recommended to extend the infusion time from 30 min to 1 hour for children under 11 years of age. [START_REF]Cubicin: Summary of product characteristics[END_REF][START_REF] Purandare | Clinical Review NDA 021572. Cubicin (daptomycin for injection)[END_REF][START_REF] Rister | Clinical Review NDA 021572. Cubicin (daptomycin for injection)[END_REF]

Absorption

Due to its very low lipophilicity (logP=-5), daptomycin is poorly absorbed orally with >90% excreted in the faeces in animal models. [START_REF]Cubicin: Scientific discussion[END_REF] There is no clinical information about subcutaneous administration but in animals a relatively high bioavailability was observed using this route of administration. [START_REF]Cubicin: Scientific discussion[END_REF] Peritoneal, intrathecal or intraventricular administration of daptomycin were also used. [START_REF] Paul | Pharmacokinetics of 300 mg/d Intraperitoneal Daptomycin: New Insight from the DaptoDP Study[END_REF][START_REF] Lee | Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin[END_REF]

Distribution

The extravascular distribution of daptomycin is limited due to its negative charge at physiological pH, its low lipophilicity and its high binding to plasma proteins. The volume of distribution of total daptomycin is around 0.1 L/kg for healthy volunteers. [START_REF] Benvenuto | Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers[END_REF][START_REF] Dvorchik | Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects[END_REF].

Daptomycin is substrate of the efflux transporter p-glycoprotein (P-gp). [START_REF] Lemaire | Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells[END_REF] In patients (n=81) with bone and joint infection, the volume of distribution of daptomycin was reported to be 25% lower in individuals having the CGC/CGC haplotype for pgp compared with any other haplotype, which, according to the authors, could be due to a greater efflux of certain tissues. [START_REF] Bricca | Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing daptomycin pharmacokinetics: a population analysis in patients with bone and joint infection[END_REF] However, in another study conducted on 12 healthy volunteers, neither rifampicin administration nor pgp single nucleotide polymorphism were associated with significant differences in daptomycin disposition. [START_REF] Benefield | Comparison of the Drug-Drug Interaction Potential of Daptomycin in Combination with Rifampin in Healthy Adult Volunteers[END_REF] Distribution within cells. In vitro, it has been shown that daptomycin can penetrate within cells, with a 60% ratio between intracellular and extracellular concentration in neutrophils. [START_REF] Lemaire | Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells[END_REF][START_REF] Van Der Auwera | Intraphagocytic penetration of antibiotics[END_REF] However, it was shown in mice that achievable plasma levels were insufficient to eliminate an intracellular strain of MRSA. [START_REF] Lehar | Novel antibodyantibiotic conjugate eliminates intracellular S. aureus[END_REF] Distribution into soft tissue interstitial fluid. After administration of daptomycin at 4 mg/kg it has been shown in healthy volunteers and diabetic patients that daptomycin diffuses into the soft tissue interstitial fluid, with concentrations in the range of 70 to 90% of free plasma concentrations. [START_REF] Kim | In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers[END_REF] Distribution within lung. While daptomycin is effective against S. pneumoniae in vitro, this does not translate in vivo into sufficient therapeutic activity for treatment of lung infections.

This may be due to a weak distribution of daptomycin in the lungs, but also to its sequestration by lung surfactant, which contains phosphatidylglycerol.. [START_REF] Taylor | The action mechanism of daptomycin[END_REF] For now, information regarding lung distribution is missing.

Distribution within central nervous system. After IV infusion of daptomycin 10 mg/kg to patients with meningitis, daptomycin has a minimal penetration into central nervous system (<1% which was corrected to 11.5% after accounting for protein binding). [START_REF] Lee | Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin[END_REF][START_REF] Piva | Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis[END_REF] By contrast, daptomycin can be an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. [START_REF] Lee | Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin[END_REF] Distribution into peritoneal fluid. After IV administration, Gika et al. reported good daptomycin distribution within peritoneal fluid, although the ratio between area under the curve (AUC) was not indicated. [START_REF] Gika | Daptomycin determination by liquid chromatography-mass spectrometry in peritoneal fluid, blood plasma, and urine of clinical patients receiving peritoneal dialysis treatment[END_REF] Intraperitoneal administration of daptomycin has been reported for peritoneal dialysis patients with peritonitis. [START_REF] Paul | Pharmacokinetics of 300 mg/d Intraperitoneal Daptomycin: New Insight from the DaptoDP Study[END_REF][START_REF] Bahte | Therapeutic serum concentrations of daptomycin after intraperitoneal administration in a patient with peritoneal dialysis-associated peritonitis[END_REF][START_REF] Saint | Pharmacokinetics of Intraperitoneal Daptomycin in Patients with Peritoneal Dialysis-Related Peritonitis[END_REF] A 300 mg dose allowed to reach effective concentrations in dialysate, and the systemic bioavailability was high (70%). However, this should be considered with caution since peritonitis may have increase peritoneal permeability and thus increase the bioavailability. [START_REF] Paul | Pharmacokinetics of 300 mg/d Intraperitoneal Daptomycin: New Insight from the DaptoDP Study[END_REF] Distribution into bone and synovial fluid. The penetration of daptomycin into bone is good, with a ratio of unbound AUC of daptomycin in bone and plasma of about 1. [START_REF] Montange | Penetration of daptomycin into bone and synovial fluid in joint replacement[END_REF] This makes daptomycin an attractive antibiotic for treatment of staphylococcal prosthetic joint infection.

[65] Similarly, bone penetration has been shown to be sufficient for the treatment of the diabetic foot infections. [START_REF] Grillon | Bone penetration of daptomycin in diabetic patients with bacterial foot infections[END_REF][START_REF] Traunmüller | Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections[END_REF] Cardiac distribution. Daptomycin is used for the treatment of infectious endocarditis due to its good diffusion within the vegetations [START_REF] Caron | Daptomycin or teicoplanin in combination with gentamicin for treatment of experimental endocarditis due to a highly glycopeptide-resistant isolate of Enterococcus faecium[END_REF] as well as at the level of the cardiac valves [START_REF] Tascini | Daptomycin concentrations in valve tissue and vegetation in patients with bacterial endocarditis[END_REF].

Elimination

Daptomycin is primarily eliminated by the kidney. In a radiolabelled study in healthy volunteers, 78 % of the dose was recovered in urine, of which 52% were biologically active; the rest was proposed to be peptide fragments produced during renal excretion or within urinary bladder. [START_REF]Cubicin: Scientific discussion[END_REF][START_REF] Woodworth | Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers[END_REF] Indeed, the kidney is known to be an active site of peptide degradation due to the presence of peptidases, and it can be noted that in rats, high concentrations of daptomycin have been found in the kidneys where it can be degraded. [START_REF] Kreft | Experimental studies on nephrotoxicity and pharmacokinetics of LY 146032 (daptomycin) in rats[END_REF][START_REF] Diao | Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides[END_REF] Based on PK results in healthy volunteers, unbound renal clearance of daptomycin can be estimated to vary between 60 and 80 mL/min, which is less than the glomerular filtration rate and therefore suggests tubular reabsorption. [START_REF] Dvorchik | Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects[END_REF] It is of note that probenecid had no effect on the PK of daptomycin, suggesting that organic anion transporters (OAT) are not involved in renal elimination of daptomycin. [START_REF]Cubicin: Scientific discussion[END_REF] Non-renal elimination of daptomycin does not involve cytochrome P450 enzymes, and preclinical PK studies indicated that daptomycin does not appear to inhibit or induce any of the key cytochrome P450 isoenzymes. [START_REF]Cubicin: Scientific discussion[END_REF] In healthy volunteers, after IV administration of radiolabelled daptomycin ( 14 C-daptomycin), 5% of the 14 C dose was recovered in faeces. [START_REF] Woodworth | Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers[END_REF] It has been shown in a clinical case that after administration of daptomycin at 8 mg/kg/day the concentrations of daptomycin in bile were comparable to those in plasma. [START_REF] Tascini | Case report of a successful treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and MRSA/vancomycin-resistant Enterococcus faecium cholecystitis by daptomycin[END_REF]

Drug-drug interactions

Since daptomycin has little or no metabolism by cytochrome P450, metabolic drug-drug interactions are unlikely. On the other hand, its renal elimination poses a possible risk of decreased clearance when given concomitantly with drugs that reduce glomerular filtration rate, such as non-steroidal anti-inflammatory drugs. [START_REF]Cubicin: Scientific discussion[END_REF] So far, no interactions requiring precautionary measures have been reported due to its high protein binding.

Protein binding.

In plasma, daptomycin binds reversibly and primarily to albumin with an averaged bound fraction of about 90-95% in healthy volunteers. [START_REF] Woodworth | Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers[END_REF][START_REF] Schneider | Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin[END_REF] This high protein binding would justify to measure unbound concentrations, which can be done by different methods but which is complicated by the fact that daptomycin binds to the separation membranes (see bioanalysis section). If measurement of free concentrations is not possible, at least the factors that may alter protein binding should be considered. In that respect, it was shown that the fraction of daptomycin bound to proteins in plasma depends little on the level of daptomycin concentrations but increases with albuminemia. [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF] A change in protein binding has theoretically no effect on average free drug concentration at steady-state, but it does affect average total concentration at steady-state. [START_REF] Zeitlinger | Protein binding: do we ever learn?[END_REF][START_REF] Benet | Changes in plasma protein binding have little clinical relevance[END_REF][START_REF] Toutain | Free drug fraction vs free drug concentration: a matter of frequent confusion[END_REF] Thus, while the total concentration at steady-state (Css) depends on the free fraction (f u ) and on the clearance of unbound concentration (CL u ) (Eq.1), the unbound concentration at steady-state (Css u ) is independent of fu (Eq. Thus, the area under the curve of free concentrations (AUC u ), which is the parameter related to the efficacy of daptomycin, is also independent of f u (Eq.3). u ss nt rva ai y dos nt rva u (Eq.3)

Since daptomycin is strongly bound a relatively small change in protein binding (eg: from 90% to 95%) will have a much higher effect on fu (in that case from 10% to 5%). As an illustration, in a study in intensive care unit (ICU) patients with variable renal function, the f u varied by 8 fold between patients (from 4% to 33%). Therefore, different values of total concentrations may correspond to the same free concentration (Eq.2). For example, in case of low albuminemia (and high f u ), a low total concentration of daptomycin could lead to the erroneous belief that a patient is underdosed. [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF] In vitro, the presence of calcium at physiological concentrations increases the binding of daptomycin to serum albumin from 85% to 96%. [START_REF] Schneider | Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin[END_REF] It is therefore important to control calcium concentration when performing protein binding experiments with daptomycin. The clinical impact of this observation has not been evaluated. Finally, it should be noted that in vitro, the effective concentration could differ from the free concentration. [START_REF] Garonzik | Defining the Active Fraction of Daptomycin against Methicillin-Resistant Staphylococcus aureus (MRSA) Using a Pharmacokinetic and Pharmacodynamic Approach[END_REF] Whether this is confirmed in vivo remains to be established.

PK in healthy volunteers

In healthy volunteers, when considering total concentrations, daptomycin has a volume of distribution of 0.1 L/kg (7 L), a systemic clearance of 8-10 mL/h/kg (0.56-0.70 L/h=9.3-11.7 mL/min), a fraction of dose excreted unchanged in urine of 54%, a protein binding of 92%, a half-life (t 1/2 ) of 8-9 h. [START_REF] Benvenuto | Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers[END_REF][START_REF] Dvorchik | Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects[END_REF] Daptomycin PK is almost linear in the 4 to 12 mg/kg dose range, regarding AUC, peak concentration (Cmax) and Cmin levels. [START_REF] Benvenuto | Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers[END_REF][START_REF] Dvorchik | Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects[END_REF][START_REF] Chakraborty | Comparison of the pharmacokinetics, safety and tolerability of daptomycin in healthy adult volunteers following intravenous administration by 30 min infusion or 2 min injection[END_REF] After daptomycin administration as a bolus (10 s or 2 min), the AUC and the Cmin were equivalent to those obtained after administration as a 30 min infusion. [START_REF] Chakraborty | Comparison of the pharmacokinetics, safety and tolerability of daptomycin in healthy adult volunteers following intravenous administration by 30 min infusion or 2 min injection[END_REF][START_REF] Aoki | Evaluation of the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin in healthy Japanese subjects[END_REF] However, after the bolus, the Cmax was higher than after the 30-minute infusion

PK in special populations

It should be noted that, due to the difficulty of measuring free concentrations, most studies in special populations have been conducted using total concentrations, making interpretation more difficult.

Renal impairment. Clearance and therefore AUC decrease while and t 1/2 increases with decreasing renal function. [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Dvorchik | Population pharmacokinetics of daptomycin[END_REF][START_REF] Goutelle | Pharmacokinetic Variability of Daptomycin during Prolonged Therapy for Bone and Joint Infections[END_REF][START_REF] Paolo | Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections[END_REF] Compared with critically ill patients with normal renal function (creatinine clearance, CLcr=120 mL/min), urinary excretion dropped from 61% to 21% while AUC jumped by 2-folds in critically ill patients with severe renal insufficiency (CLcr=20 mL/min). [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF] This illustrates that neither total clearance nor renal excretion clearance is proportional to glomerular filtration rate because elimination is only partially renal and renal impairment may alter the free fraction and tubular reabsorption. Also, t 1/2 was 19 h in pati nts with cr≤40 mL/min vs 8 h in pati nts with cr≥80 mL/min. [START_REF] Dvorchik | Population pharmacokinetics of daptomycin[END_REF] In order to take into account this effect of renal impairment on daptomycin PK, it is recommended to administer daptomycin once every 48 h instead of once every 24 h for patients with CLcr lower than 30 mL/min. [START_REF]Cubicin: Summary of product characteristics[END_REF] PK in patients with haemodialysis. PK of daptomycin in patients undergoing continuous renal replacement therapy (CRRT) have been described by several groups. [START_REF] Xu | Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy[END_REF][START_REF] Corti | Pharmacokinetics of daily daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF][START_REF] Vilay | Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis[END_REF][START_REF] Wenisch | Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration[END_REF][START_REF] Xie | Population pharmacokinetics and dosing considerations of daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF] Daptomycin is excreted during CRRT, mean total clearances estimated during continuous veno-venous haemodialysis (CVVHD) varied between 0.68 and 1.03 L/h (corresponding to 11 and 17 mL/min). [START_REF] Xu | Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy[END_REF][START_REF] Vilay | Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis[END_REF][START_REF] Burkhardt | Elimination of daptomycin in a patient with acute renal failure undergoing extended daily dialysis[END_REF][START_REF] Kielstein | Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis--a pharmacokinetic study[END_REF][START_REF] Falcone | Daptomycin serum levels in critical patients undergoing continuous renal replacement[END_REF][START_REF] Khadzhynov | Plasma pharmacokinetics of daptomycin in critically ill patients with renal failure and undergoing CVVHD[END_REF] Mean total clearances estimated during continuous venovenous haemodiafiltration (CVVHDF) varied between 0.36 and 0.61 L/h. [START_REF] Xu | Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy[END_REF][START_REF] Corti | Pharmacokinetics of daily daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF][START_REF] Wenisch | Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration[END_REF][START_REF] Xie | Population pharmacokinetics and dosing considerations of daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF] These values are quite close to the clearance values observed in healthy volunteers (0.56-0.70 L/h). Based on these results, the authors performed simulations to determine the most appropriate dosing regimens to achieve the efficacy targets and to avoid muscle toxicity. It is important to note that the unbound fraction of daptomycin was twice higher in haemodialyzed critically ill patients compared with values reported in non-haemodialyzed patients (16-18% vs 9%). [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Vilay | Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis[END_REF][START_REF] Wenisch | Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration[END_REF] Accordingly, as simulations performed in these studies were performed from total concentrations, actual unbound concentrations should have been underestimated as well as PTA to reach efficacy and toxicity targets. Dosing recommendations for patients undergoing CRRT are still a matter of debate. Thus, the dosages recommended by the various authors range from 6 mg/kg q48h to 8 mg/kg q24h. [START_REF] Xu | Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy[END_REF][START_REF] Corti | Pharmacokinetics of daily daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF][START_REF] Vilay | Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis[END_REF][START_REF] Wenisch | Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration[END_REF][START_REF] Xie | Population pharmacokinetics and dosing considerations of daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF][START_REF] Burkhardt | Elimination of daptomycin in a patient with acute renal failure undergoing extended daily dialysis[END_REF][START_REF] Kielstein | Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis--a pharmacokinetic study[END_REF][START_REF] Falcone | Daptomycin serum levels in critical patients undergoing continuous renal replacement[END_REF][START_REF] Khadzhynov | Plasma pharmacokinetics of daptomycin in critically ill patients with renal failure and undergoing CVVHD[END_REF] Clearance of daptomycin in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) was reported to be 0.31 L/h. [START_REF] Cardone | Pharmacokinetics and pharmacodynamics of intravenous daptomycin during continuous ambulatory peritoneal dialysis[END_REF] In that case, an IV administration of daptomycin 4 to 6 mg/kg q48h appears to be adequate to achieve effective plasma concentrations. [START_REF] Cardone | Pharmacokinetics and pharmacodynamics of intravenous daptomycin during continuous ambulatory peritoneal dialysis[END_REF] Hepatic impairment.

Results from an open label, single dose study (6 mg/kg) showed that moderate hepatic impairment (Child-Pugh B) did not affect daptomycin PK. [START_REF]Cubicin: Scientific discussion[END_REF] No data are available for severe hepatic impairment, therefore daptomycin should be used with caution for these patients. In addition, hepatic failure may be accompanied by hypoalbuminemia which may alter protein binding of daptomycin.

Obese. Regulatory agencies approved daptomycin dosing proportional to actual body weight (4 or 6 mg/kg/day depending on indication). When considering non-weight-normalized parameters, the volume of distribution [START_REF] Dvorchik | Population pharmacokinetics of daptomycin[END_REF][START_REF] Cojutti | Population pharmacokinetics and dosing considerations for the use of daptomycin in adult patients with haematological malignancies[END_REF][START_REF] Dvorchik | The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects[END_REF] and the elimination clearance [START_REF] Xie | Population pharmacokinetics and dosing considerations of daptomycin in critically ill patients undergoing continuous renal replacement therapy[END_REF][START_REF] Dvorchik | The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects[END_REF] of daptomycin have been shown to increase with body weight. However, after administration of a weight-proportional dose of daptomycin, exposure (AUC, Cmax, Cmin) was 25% to 93% higher in obese subjects compared to non-obese subjects. [START_REF] Dvorchik | The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects[END_REF][START_REF] Pai | Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin[END_REF][START_REF] Butterfield-Cowper | A Fixed versus Weight-Based Dosing Strategy of Daptomycin May Improve Safety in Obese Adults[END_REF] Moreover, complicated obese patients who received daptomycin dosed on actual body weight have increased rates of CPK elevations. [START_REF] Bookstaver | Safety and effectiveness of daptomycin across a hospitalized obese population: results of a multicenter investigation in the southeastern United States[END_REF] Thus, dosing regimens, either fixed (500 mg/day), based on ideal body weight or based on adjusted body weight (calculated according to a function depending on actual and ideal body weights), have been proposed. [START_REF] Butterfield-Cowper | A Fixed versus Weight-Based Dosing Strategy of Daptomycin May Improve Safety in Obese Adults[END_REF][START_REF] Fox | Daptomycin dosing in obese patients: analysis of the use of adjusted body weight versus actual body weight. Therapeutic advances in infectious disease[END_REF][START_REF] Lorenzo | Evaluation of Fixed-Dose Daptomycin in Obese Patients With Bloodstream Infections Caused by Staphylococcus aureus[END_REF][100]] Although it appears that the administration of fixed doses is most likely to lead to comparable exposures between obese and non-obese patients, this approach needs to be better evaluated and the determination of fixed doses to achieve effective exposure in obese patients remains to be done. [START_REF] Butterfield-Cowper | A Fixed versus Weight-Based Dosing Strategy of Daptomycin May Improve Safety in Obese Adults[END_REF] Furthermore, in order to make dose recommendations in obese patients, it seems important to measure the free fraction in this population.

Gender. In two studies, clearance has been shown to be 20-44% lower for female subjects than for male subjects. [START_REF] Bricca | Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing daptomycin pharmacokinetics: a population analysis in patients with bone and joint infection[END_REF][START_REF] Dvorchik | Population pharmacokinetics of daptomycin[END_REF][START_REF] Goutelle | Pharmacokinetic Variability of Daptomycin during Prolonged Therapy for Bone and Joint Infections[END_REF] However, in some other studies, difference of clearance between genders was not significant. [START_REF] Paolo | Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections[END_REF]101] It may be hypothesized that gender could be a better descriptor of the influence of body size on the clearance of daptomycin, but this requires further investigation. [START_REF] Bricca | Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing daptomycin pharmacokinetics: a population analysis in patients with bone and joint infection[END_REF]. However, it is known that protein binding of drugs may be decreased in children, and should therefore be evaluated for daptomycin in order to correctly interpret these results obtained for total concentrations. [110]

Paediatrics

Elderly. An open-label, single-dose (4 mg/kg) Phase I study showed that total exposure (AUC 0-∞ ) of daptomycin was 58% higher in geriatric subjects 75 years old compared with younger subjects between 18 and 30 years old.

[111] The 35% lower clearance explaining this difference in exposure was in fact not due to the difference in age but to the difference in renal function. No statistical differences in Cmax and volume of distribution were observed between geriatric and younger subjects.

PK in critically ill patients.

Intensive care unit (ICU) patients with infections often have other co-morbidities, such as renal failure, hypoalbuminemia, or obesity. In addition, the presence of sepsis may lead to acute renal failure and require haemodialysis. Therefore, they are at risk of having altered pharmacokinetics of daptomycin. As a matter of fact, pharmacokinetics of daptomycin is highly variable between ICU patients, but also highly variable for the same patient over time. [START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF] Compared to healthy volunteers, one of the main differences observed in ICU patients is an increase by two folds on average of the volume of distribution, on average about twice as much (0.2 L/kg vs 0.1 L/kg). [START_REF] Falcone | Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia[END_REF][START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF]112] Reported clearances values are dependent on the renal function of patients included in the various clinical trials.

[ [START_REF] Falcone | Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia[END_REF][START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF]112] In order to reach PK/PD targets for efficacy, it is generally recommended to give high, and off-label, doses of daptomycin (10 mg/kg/day or 560-840 mg/day) to ICU patients, except for those with reduced renal function, and to perform therapeutic drug monitoring. [START_REF] Falcone | Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia[END_REF][START_REF] Gregoire | Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment[END_REF][START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF]112] The pathophysiological state of ICU patients is rarely stable over time and this can affect the PK of daptomycin. For example, augmented renal clearance or the presence of sepsis may induce a decrease in daptomycin concentrations. [START_REF] Falcone | Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia[END_REF]113] The fact that the septic state of patients tends to improve over time has led some authors to propose that the dosage of daptomycin should be adapted to the evolution of the pathology, in particular with high doses during the first days (10 mg/kg/day or 750 mg/day) then lower doses.

[113] Overall, the unstable nature of the PK of daptomycin in ICU patients seems to be a strong argument for clinicians to use therapeutic drug monitoring for this patient population.

10 Therapeutic drug monitoring (TDM)

TDM of daptomycin is currently not widespread, but it could benefit some patients. [114,115] Thus, some patients are at risk of having disturbed pharmacokinetics, such as ICU patients with sepsis, patients with renal or hepatic insufficiency, patients with augmented renal clearance, patients undergoing renal replacement therapy, obese patients, paediatric or geriatric patients, or patients with severe burns. In addition, in order to monitor the risk of toxicity, there is an interest in monitoring daptomycin concentrations for patients receiving high doses. [116] Few (one to our knowledge) commercial kits are available for the determination of daptomycin, but HPLC-UV and LC-MS/MS assay methods have been published (see bioanalytical section). Some targets for efficacy and toxicity have been published. A target of AUC/MIC>666 may be selected for clinical efficacy, even if this value needs to be confirmed in larger patient cohorts. [START_REF] Falcone | Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? Journal of infection and chemotherapy : official journal of the[END_REF] In addition, protein binding, and thus possible hypoalbuminemia, should be taken into account when interpreting and comparing daptomycin assay results with this target value (cf protein binding section). A Cmin greater than 3.2 mg/L was also proposed as an efficacy target. [START_REF] Galar | Current use of daptomycin and systematic therapeutic drug monitoring: Clinical experience in a tertiary care institution[END_REF] The target value for Cmin not to be exceeded in order to limit the risk of undesirable muscular effects is 24.3 mg/L. [START_REF] Tally | Daptomycin: a novel agent for Gram-positive infections[END_REF][START_REF] Tally | Development of daptomycin for gram-positive infections[END_REF][START_REF] Bhavnani | Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis[END_REF][START_REF] Oleson | Once-daily dosing in dogs optimizes daptomycin safety[END_REF] Ideally, TDM of daptomycin should be based on free concentrations, which is technically difficult at the moment. It is therefore based on total concentrations. Monitoring for muscle toxicity is fairly simple, since it is sufficient to measure Cmin just before next administration.

On the other hand, monitoring of efficacy and estimation of AUC is more problematic and requires either the use of Bayesian approaches, or the use of simplified equations requiring measurements of one concentration approximately two hours after the start of the infusion and of Cmin.

[117] As alternative approaches, some authors have proposed that Cmin should exceed 3.2 mg/L [START_REF] Galar | Current use of daptomycin and systematic therapeutic drug monitoring: Clinical experience in a tertiary care institution[END_REF] or that Cmax at the end of the infusion should exceed 100 mg/L. [START_REF] Vilay | Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis[END_REF]118] 11 Conclusion

Due to a low level of resistance, daptomycin has an important place in the treatment of Grampositive infections. Its pharmacokinetics is characterized by predominantly renal elimination and high protein binding (90%). Due to high inter-individual variability, therapeutic monitoring of daptomycin concentrations may be of interest for certain patients such as ICU patients, patients with renal or hepatic insufficiency, dialysis patients, obese patients or children.

Compliance with Ethical Standards

Funding. No support was received for the preparation of this manuscript.

Conflicts of interest. Nicolas Grégoire, Alexia Chauzy, Sandrine Marchand and William

Couet declare that they have no conflicts of interest.