Taniya Paiboonvong (1), Baralee Punyawudho (2), Preecha Montakantikul (1) Noppaket Singkham (3) Navarat Panjasawatwong (1)
(1) Faculty of Pharmacy, Mahidol University, Bangkok, Thailand (2) Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand (3) School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
Objectives: Severe pneumonia is one of the most infections among critically ill patients, associated with a high mortality rate. Sitafloxacin is a new fluoroquinolone antimicrobial agent with broad-spectrum activity, including multidrug-resistant organisms. Additionally, sitafloxacin showed a potent in vitro activity against nosocomial respiratory tract pathogens (e.g., Pseudomonas aeruginosa and Acinetobacter baumannii) which are major causes of infection in intensive care unit (ICU) [1, 2]. Sitafloxacin has been approved for oral formulation and used in Thailand for treatment of urinary tract infections and lower respiratory tract infections since 2011. Oral sitafloxacin was rapidly absorbed and has a high bioavailability, including widely distributed into various tissues [3]. According to a population pharmacokinetic (PK) analysis of sitafloxacin in Japanese subjects, changes in covariates could effect on the PK parameters [4]. Thus, physiological changes in critically ill patients may alter the PK of sitafloxacin. The aim of this study was to develop a population PK model for sitafloxacin in Thai critically ill patients with pneumonia.
Methods: Plasma samples were obtained from 12 critically ill patients admitted to ICU, Ramathibodi Hospital, Thailand. Sitafloxacin was given as a 200 mg single dose on fasting stage. Serial blood samples (seven time points) were collected in each patient prior to the first dose of sitafloxacin and at 0.5-2, 3-4, 5-6, and 7-9 hours post dose. Plasma concentrations of sitafloxacin were determined using liquid chromatography–tandem mass spectrometry (LC/MS/MS) assay. The data were analyzed using the nonlinear mixed-effect modelling software (NONMEM) with FOCEI method. One- and two-compartment model were tested to characterize pharmacokinetics and the covariates were screened for their significant impact on the PK parameters. Age, sex, body weight, creatinine clearance (CLCr) estimated by Cockcroft and Gault equation, and acute physiology and chronic health evaluation (APACHE) II score were evaluated as covariates using a stepwise forward selection (α=0.05) and backward elimination (α=0.01). The final PK model was validated using bootstrap analysis.
Results: The median age and weight of the patients were 57 [range 26-75] years and 52 [range 38.5-74.5] kg. Plasma concentrations of sitafloxacin were best described by one-compartment model with first-order absorption. Clearance (CL), volume of distribution (V) and absorption rate constant (Ka) were estimated to be 7.06 L/h, 119 L, and 0.486 h-1, with the interindividual variability (IIV) of 82.2%, 48.3%, and 121.5%, respectively. Age was only a statistically significant covariate on volume of distribution (V = 119 x (age/57)-1.91). Increase in age will lead to a smaller volume of distribution.
Conclusions: The PK profiles of sitafloxacin in Thai critically ill patients were best described by one-compartment model. Volume of distribution of sitafloxacin was influenced by age. The model can be useful to determine an appropriate dosage regimen.
References:
[1] Thamlikitkul V, Tiengrim S. In vitro susceptibility test of sitafloxacin against resistant gram-negative bacilli isolated from Thai patients by disk diffusion method. J Med Assoc Thai 2014;97(Suppl 3):S7-12.
[2] Tiengrim S, Phiboonbanakit D, Thunyaharn S, Tantisiriwat W, Santiwatanakul S, Susaengrat W, et al. Comparative in vitro activity of sitafloxacin against bacteria isolated from Thai patients with urinary tract infections and lower respiratory tract infections. J Med Assoc Thai 2012;95(Suppl 2):S6-17.
[3] Nakashima M, Uematsu T, Kosuge K, et al. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers. Antimicrob Agents Chemother 1995;39:170-4.
[4] Tanigawara Y, Kaku M, Totsuka K, Tsuge H, Saito A. Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections. Journal of Infection and Chemotherapy 2013;19(5):858-66.
Reference: PAGE 27 (2018) Abstr 8532 [www.page-meeting.org/?abstract=8532]
Poster: Drug/Disease Modelling - Infection