Chika Ogami (1), Yasuhiro Tsuji (1), Nick Holford (2), Hidefumi Kasai (1), Hideto To (1), Yoshihiro Yamamoto (3)
(1) Department of medical pharmaceutics, University of Toyama. (2) Department of pharmacology and clinical pharmacology, University of Auckland. (3) Department of clinical infectious diseases, University of Toyama
Objectives: Daptomycin is a lipopeptide antimicrobial agent that exhibits bactericidal activity against a broad range of Gram-positive bacteria, including multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus. The clinical benefit of daptomycin is dependent on adequate drug concentrations however the risk of inducing creatine phosphokinase elevation is increased in patients with blood concentrations greater than 20 mg/L [1, 2]. Daptomycin is primarily excreted renally and dose adjustments are recommended in patients with renal impairment [3]. In this study, we evaluated the pharmacokinetics of unbound daptomycin based on population pharmacokinetic approaches.
Methods: Routine clinical data including daptomycin concentrations were collected from 52 patients with Gram-positive infections. The pharmacokinetics of daptomycin were described with a zero-order input, two compartment distribution and first-order elimination model. Pharmacokinetic parameters were estimated based on observed daptomycin unbound concentrations (n = 339) and fraction unbound in plasma was estimated from total (n = 329) and unbound concentrations. Normal fat mass (NFM) was used as the body size index and pharmacokinetic parameters were standardized to total body weight of 70 kg height of 1.76 m [4]. Renal function (RF) was described by the ratio of observed creatinine clearance standardized to total body wright of 70kg to standard creatinine clearance of 6 L/h/70kg.
Results: The pharmacokinetic parameters for unbound daptomycin CL, VC, VP, Q and Fu (fraction of unbound) were:
CL (L/h) = (2.94 × 0.544^HD + 6.00 × RF) × (NFMCLobs/NFMCLstd)^3/4
VC (L) = 167 × 0.643^HD × (NFMVobs/NFMVstd)
Q (L/h) = 0.879 × (NFMCLobs/NFMCLstd)^3/4
VP (L) = 65.2 × (NFMVobs/NFMVstd)
Fu = 0.0946 × 1.27^HD
HD represents hemodialysis with a value of 1 in patients who received hemodialysis and 0 in those who did not. The elimination half-life for unbound daptomycin calculated from the estimated population mean of clearance and volume of central and peripheral compartment was 18.0 h. Clearance of daptomycin was estimated to be about 60% dependent on renal function. The influence of hemodialysis was incorporated into non-renal clearance and unbound volume of distribution. Both these pharmacokinetic parameters were decreased in patients with hemodialysis. The fractions of unbound daptomycin was estimated to be 0.0946 and increased by 1.27-fold in patients receiving hemodialysis. Ffat included in NFM as the factor describing the influence of fat mass on clearance was not significantly different from 1 and Ffat for volume of distribution was not significantly different from 0. This indicates that total body weight is the best predictor of allometric size for clearance and fat free mass is the best predictor for volume of distribution [4].
Conclusions: We have described the influence of renal function, body size and composition and hemodialysis on the pharmacokinetics of unbound daptomycin. This model can be applied to wide range of patients including elderly, obesity, and renal insufficiency. These factors should be considered for dosing regimens in individual patients with Gram-positive infections.
References:
[1]. Safdar N, Andes D, Craig WA. In Vivo Pharmacodynamic Activity of Daptomycin. Antimicrobial Agents and Chemotherapy. 2003;48(1):63-8.
[2]. Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis. 2010;50(12):1568-74.
[3]. Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother. 2008;62 Suppl 3:iii7-14.
[4]. Holford NHG, Anderson BJ. Allometric size: The scientific theory and extension to normal fat mass. Eur J Pharm Sci. 2017;109(Supplement):S59-S64.
Reference: PAGE 27 (2018) Abstr 8568 [www.page-meeting.org/?abstract=8568]
Poster: Drug/Disease Modelling - Infection