A crosscorrelation methodology for in vivo pharmacokinetic study by the trans-scale fluorescent system

Conventional single-organ-isolation-based pharmacokinetics study is short of time-course information and exists considerable inaccuracy due to the inter-individual differences and characteristic imparities between in vivo and ex vivo tissues/cells. The in vivo time-course and multi-organs study of model drugs in living subjects could afford precise spatio-temporal correlation. Herein, a revolutionized trans-dimensional fluorescence system was home built, with the macro-level detection part for simultaneous pharmacokinetic study in different organs, and one confocal imaging needle for micro-level visualizing cellular uptake of drugs with super-high resolution (0.472 μm). Correlating these simultaneous acquired trans-scale data, an innovative physiologically-based pharmacokinetics (PBPK) model was firstly created for predicting drug disposition in other species. Its accuracy and reliability was firmly supported by the high consistent predicted-data with the real-measured data in mice and in human, respectively. This study provides an innovative methodology and revolutionized instrument for in vivo real-time advancing assessment of druggability.

LC-MS/MS Method for Determination of Hydroxychloroquine and Metabolites: Application in a Pharmacokinetic Study

Hydroxychloroquine (HCQ) was originally used as an antimalarial and immunomodulation drug. We developed and validated a simple and sensitive ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous quantitation of HCQ and its three metabolites in rat blood, and reported their pharmacokinetic parameters. The chromatographic separation and detection of analytes were achieved within 4 min on ZORBAX SB-C8 (3.5 μm, 2.1 × 150 mm) column with gradient elution, and the flow rate was 0.25 mL/min. Simple protein precipitation was successfully applied for sample pretreatment. The HCQ displays a good linearity in the range of 2.0–5000.0 ng/mL, and the three metabolites also show good linearity ranging from 1.0 to 2500.0 ng/mL, with all correlation coefficients (R2) better than 0.98. In conclusion, this rapid, sensitive method was successfully developed, validated, and then applied to a pharmacokinetic study of HCQ in rat model in high dose. The results of the pharmacokinetic study presented an average half-life time 21.14 ± 10.31 h (mean ± SD) of HCQ, which is much shorter in human compared to that in mice. For the three metabolites, longer half-life times (approximately 100 h) were shown in rat.

Comparative pharmacokinetic study of bicalutamide administration alone and in combination with vitamin D in rats

Bicalutamide (BCL) has been approved for treatment of advanced prostate cancer (Pca), and vitamin D is inevitably used in combination with BCL in Pca patients for skeletal or anti-tumor strategies. Therefore, it is necessary to study the effect of vitamin D application on the pharmacokinetics of BCL. We developed and validated a specific, sensitive and rapid UHPLC–MS/MS method to investigate the pharmacokinetic behaviours of BCL in rat plasma with and without the combined use of vitamin D. Plasma samples were extracted by protein precipitation with ether/dichloromethane (2:1 v/v), and the analytes were separated by a Kinetex Biphenyl 100A column (2.1 × 100 mm, 2.6 μm) with a mobile phase composed of 0.5 mM ammonium acetate (PH 6.5) in water (A) and acetonitrile (B) in a ratio of A:B = 35:65 (v/v). Analysis of the ions was run in the multiple reactions monitoring (MRM) mode. The linear range of BCL was 5–2000 ng mL−1. The intra- and inter-day precision were less than 14%, and the accuracy was in the range of 94.4–107.1%. The mean extraction recoveries, matrix effects and stabilities were acceptable for this method. The validated method was successfully applied to evaluate the pharmacokinetic behaviours of BCL in rat plasma. The results demonstrated that the pharmacokinetic property of BCL is significantly affected by combined use of vitamin D, which might help provide useful evidence for the clinical therapy and further pharmacokinetic study.

Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.