Taniya Paiboonvong (1), Korbtham Sathirakul (1), Preecha Montakantikul (1)
(1) Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
Objectives: Alveolar epithelial lining fluid (ELF) has been suggested as an important site of lower respiratory tract infections caused by extracellular pathogens. Therefore, the drug concentrations in ELF has been demonstrated more relevant than the concentrations in plasma for predicting therapeutic efficacy. Most of the fluoroquinolones have been studied for determining the degree of lung penetration, and the overall results showed that they could achieve the higher ELF concentrations than in serum or plasma [1, 2]. However, there are still limited data of drug penetration in critically ill patients. Sitafloxacin, a new broad-spectrum fluoroquinolone antimicrobial agent, has been approved for oral formulation for treatment of pneumonia in Thailand since 2011. Oral sitafloxacin was rapidly absorbed and widely distributed into various tissues. Pharmacokinetics of sitafloxacin were demonstrated with linear plasma pharmacokinetics that maximum plasma concentration (Cmax) and area under concentration-time curve (AUC) were increased in dose proportion ranging from 25 mg to 500 mg [3-5]. The objective of this study was to develop physiologically based pharmacokinetic (PBPK) modeling approach to predict concentrations of sitafloxacin in ELF.
Methods: The PBPK model was constructed and evaluated using plasma and ELF concentrations obtained from 12 critically ill patients with pneumonia after oral sitafloxacin single dose 200 mg administration during 0.5-2, 3-4, 5-6, and 7-9 h. Sitafloxacin concentrations were determined using liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. The concentrations in ELF were calculated using plasma concentration * fraction unbound in plasma calculated from albumin level in each subject. The concentrations in ELF were assumed to be free drug. The plasma pharmacokinetic parameters described by one-compartment model with first-order absorption were used in conjunction with lung compartment for developing simple PBPK model using Stella software version 9.1.4. Tissue to plasma distribution coefficients (Kp) were determined from the ratio of ELF and plasma concentrations (Kp = CELF/CPlasma). The PBPK model was evaluated by root-mean-square error (RMSE) between concentrations predicted by the model and the concentrations actually observed in ELF. The different dosage regimens were simulated to create sitafloxacin concentration-time profiles in ELF.
Results: The concentrations in ELF had variation with different sampling times. The mean ± SD of Cmax was 1.07± 0.93 µg/mL. Accounting for physiology, the parameters included blood flow (Q), and volume of lung compartment were inputted into the model. The PBPK model can be used to predict the pharmacokinetic behavior of sitafloxacin in agreement with observed data (RMSE of 0.54). From the modelling and simulation, sitafloxacin penetrated into ELF and accumulated with the dose proportion at steady state. Stimulation with the dose of 200 mg, 300 mg, 400, mg, and 500 mg q 12 h, the Cmax of sitafloxacin in ELF at steady state were 0.8 µg/mL, 1.20 µg/mL, 1.61 µg/mL, and 2.01 µg/mL, respectively.
Conclusion: The PBPK modeling of sitafloxacin are acceptable to predict sitafloxacin concentrations in ELF in critically ill patients with pneumonia. This findings provided the useful information for further development of population PK/PD modelling to predict the optimal dosage regimen of sitafloxacin.
References:
[1] Rodvold KA, George JM, Yoo L. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agent. Clin Pharmacokinet. 2011; 50(10):637-64.
[2] Jamal JA, Abdul-Aziz MH, Lipman, J, Roberts JA. Defining antibiotic dosing in lung infections. Clin Pulmo Med. 2013;20(3):121-8.
[3] Keating GM. Sitafloxacin: in bacterial infections. Drugs. 2011;71(6):731–44.
[4] Nakashima M, Uematsu T, Kosuge K, Umemura K, Hakusui H, Tanaka M. 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.
[5] O’Grady J, Briggs A, Atarashi S, Kobayashi H, Smith R, Ward J, et al. Pharmacokinetics and absolute bioavailability of sitafloxacin, a new fluoroquinolone antibiotic, in healthy male and female Caucasian subjects. Xenobiotica. 2001;31(11):811-22.
Reference: PAGE 28 (2019) Abstr 8816 [www.page-meeting.org/?abstract=8816]
Poster: Drug/Disease Modelling - Infection