Pharmacokinetic evaluation and relative bioavailability pilot study of fidaxomicin in healthy Chinese subjects: An open, randomized, single-dose, cross-over study.

OBJECTIVE: To compare the pharmacokinetic (PK) characteristics, investigate relative bioavailability, and provide data for potential additional bioequivalence trials between generic fidaxomicin (test (T) formulation) and the original brand (reference (R) formulation) in healthy Chinese subjects. MATERIALS AND METHODS: An open, randomized, single-dose, cross-over study was conducted in 18 healthy Chinese subjects. The subjects randomly received T or R formulations and the alternative formulations were received after a 14-day wash-out period. Blood and fecal samples were collected and tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using a non-compartmental model. Relative bioavailability considering commonly established bioequivalence criteria was assessed. RESULTS: Cmax were 3.58 ± 2.74 ng/mL and 6.01 ± 3.93 ng/mL, and AUC0-∞ were 35.71 ± 18.68 h×ng/mL and 52.15 ± 31.31 h×ng/mL for the T and R formulations, respectively. The tmax of both formulations was 5.00 hours. The cumulative fecal excretion rate (Fe0-96h/F) of fidaxomicin and its main active metabolite OP-1118 were similar for both formulations. The geometric mean ratios and 90% confidence intervals (CI) of AUC0-t, AUC0-∞, and Cmax were not completely within the range of 80.00 - 125.00%. Significant within-subject and inter-subject coefficients of variation (> 30%) were found. CONCLUSION: Despite the differences in exposure, PK characteristics and fecal recovery of the two formulations were similar, suggesting that an effective concentration of the generic fidaxomicin could be achieved locally in the gastrointestinal tract. Fidaxomicin was a highly viable drug, thus providing reference for future clinical study design.

Pharmacokinetics and Safety of Single-Dose Amphotericin B Colloidal Dispersion in Healthy Chinese Subjects and Population Pharmacokinetic/Pharmacodynamic Analysis to Inform Clinical Efficacy in Invasive Infections Caused by Candida albicans.

PURPOSE: Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. METHODS: PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0-24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. FINDINGS: The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. IMPLICATIONS: PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.

Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human.

PURPOSES: To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. METHODS: Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. RESULTS: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·µg/mL and 51.09 ± 4.70 h·µg/mL, and the AUC0-inf of colistin were 15.39 ± 2.63 h·µg/mL and 12.36 ± 2.10 h·µg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted Css,avg (95% CI) were 0.92 (0.85, 0.99) µg/mL and 0.74 (0.69, 0.79) µg/mL for CTTQ and Parkedale, respectively. CONCLUSION: The difference in component content in the two CMS formulas had a significant (P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.

Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses.

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations (Cmax) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life (t1/2) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly (RAUC = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections.

Conjugated polymer nanomaterials for theranostics.

Conjugated polymer nanomaterials (CPNs), as optically and electronically active materials, hold promise for biomedical imaging and drug delivery applications. This review highlights the recent advances in the utilization of CPNs in theranostics. Specifically, CPN-based in vivo imaging techniques, including near-infrared (NIR) imaging, two-photon (TP) imaging, photoacoustic (PA) imaging, and multimodal (MM) imaging, are introduced. Then, CPN-based photodynamic therapy (PDT) and photothermal therapy (PTT) are surveyed. A variety of stimuli-responsive CPN systems for drug delivery are also summarized, and the promising trends and translational challenges are discussed.

Conjugated Polymer Nanoparticles for Fluorescence Imaging and Sensing of Neurotransmitter Dopamine in Living Cells and the Brains of Zebrafish Larvae.

Nanoscale materials are now attracting a great deal of attention for biomedical applications. Conjugated polymer nanoparticles have remarkable photophysical properties that make them highly advantageous for biological fluorescence imaging. We report on conjugated polymer nanoparticles with phenylboronic acid tags on the surface for fluorescence detection of neurotransmitter dopamine in both living PC12 cells and brain of zebrafish larvae. The selective enrichment of dopamine and fluorescence signal amplification characteristics of the nanoparticles show rapid and high-sensitive probing such neurotransmitter with the detection limit of 38.8 nM, and minimum interference from other endogenous molecules. It demonstrates the potential of nanomaterials as a multifunctional nanoplatform for targeting, diagnosis, and therapy of dopamine-relative disease.

Cationic fluorescent polymer core-shell nanoparticles for encapsulation, delivery, and non-invasively tracking the intracellular release of siRNA.

A multifunctional nanocarrier for encapsulation and delivery of short interfering RNA (siRNA) has been realized using cationic fluorescent polymer core-shell nanoparticles. The nanocarrier has good biocompatibility and high transfection efficiency over the most popular transfection reagent, Lipofectamine 2000. Fluorescence resonance energy transfer within the nanocarrier provides a non-invasive and label-free method to track the intracellular release of siRNA.

Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 µg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 µg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 µg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 µg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

Safety, tolerability, and pharmacokinetics of intravenous nemonoxacin in healthy chinese volunteers.

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 µg/ml, 7.152 µg/ml, and 11.029 µg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0-72 h) were 17.05 µg · h/ml, 39.30 µg · h/ml, and 61.98 µg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0-72 h and AUC0-∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

pH-Responsive and near-infrared-emissive polymer nanoparticles for simultaneous delivery, release, and fluorescence tracking of doxorubicin in vivo.

Dextran modified with pendant acetals is used to load doxorubicin (DOX) and a near-infrared-emissive conjugated polymer (BTTPF), and this aims to provide selective drug release at therapeutic targets including tumors. The BTTPF is applicable to tracking the anticancer drug release through the change of Förster resonance energy transfer efficiency between doxorubicin and BTTPF during degradation of the nanoparticles in vivo.

A fluorescence-Raman dual-imaging platform based on complexes of conjugated polymers and carbon nanotubes.

The present study describes a flexible nanoplatform based on electrostatic assembly of conjugated polyelectrolytes (CPEs) and carboxylated multi-walled carbon nanotubes (cMWNTs). It is demonstrated that the obtained nanocomposites inherit intrinsic optical properties of CPEs and characteristic Raman vibration modes of MWNTs, providing a fluorescence-Raman dual-imaging method for intracellular tracking and locating of MWNTs. We suggest that the cellular internalization of the CPE-cMWNT nanocomposites is a surface charge-dependent process. The strengths of this nanoplatform include satisfying biocompatibility, enhanced protein-repellent property, and ease of implementation, making it available for both in vitro and in vivo applications.

Establishment of norvancomycin fluorescence polarization immunoassay for therapeutic drug monitoring.

To establish a rapid and simple fluorescence polarization immunoassay method for determination of norvancomycin serum concentration, we collected 300 serum samples from the patients receiving norvancomycin in the hospitals localized in Shanghai, China. The drug concentrations were measured by the established HPLC method and FPIA with vancomycin kit. A FPIA algorithm for the determination of norvancomycin concentration was established according to the correlation between the FPIA and HPLC results. The methods and algorithm were validated in another 70 clinical samples. HPLC determination showed a good linear correlation within the range of 0.5-100 mg l(-1) of norvancomycin concentrations. The method was validated via extraction recovery, intra- and inter-day methodological recovery and stability of norvancomycin in serum. Correlation analysis between the measurements of HPLC and FPIA in 300 serum samples gave the linear regression equation: (concentration by HPLC)=0.760 × (concentration by FPIA)-0.577 (P<0.001, R(2)=0.982). An algorithm was derived from this correlation for measuring the serum norvancomycin concentrations with FPIA. When it was validated in additional 70 serum samples from patients, 'FPIA algorithm' showed good accuracy versus HPLC: 'FPIA algorithm'=0.93 (HPLC)+0.63, R(2)=0.962, and 94.3% of the results from FPIA algorithm fell within the range of -20%/+20% of HPLC. This algorithm developed in this study can be easily used for determination of norvancomycin using TDx analyzer with vancomycin kit indirectly. It may also be useful for norvancomycin therapeutic drug monitoring.

Permeability and concentration of levofloxacin in epithelial lining fluid in patients with lower respiratory tract infections.

The purpose of the study was to assess the bactericidal effects of a single oral dose of levofloxacin (LVFX) by examining the concentration of LVFX in alveolar epithelial lining fluid (ELF) from patients with lower respiratory tract infections (LRTI). Forty patients with LRTI took 500 mg of LVFX and then received a fiberoptic bronchoscopic procedure randomly 1, 4, 8, 12, or 24 hours following dosing. Bronchoalveolar lavage fluid and blood were collected at the time of the bronchopulmonary procedure, and the LVFX concentration was determined. The mean peak concentrations of LVFX in plasma and ELF were achieved at 1.5 hours (4.07 mg/L) and 1 hour (3.44 mg/L), respectively. The AUC(24h) samples were 50.12 mg . h/L and 34.51 mg . h/L, respectively. The permeability of LVFX, which was estimated based on the ratio of LVFX concentration in tissue fluids to that in plasma, was 0.78 on average across all time points. After a single dose of LVFX in patients with LRTI, the drug rapidly distributed into bronchopulmonary tissue, thereby suggesting this dose is capable of achieving the concentration in target organs required for bactericidal efficacy.

Selective method for the determination of cefdinir in human plasma using liquid chromatography electrospray ionization tandam mass spectrometry.

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of cefdinir in human plasma. After a simple protein precipitation using trichloracetic acid, the post-treatment samples were applied to a prepacked RP18 Waters SymmetryShield column interfaced with a triple quadrupole tandem mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase consisted of methanol-water-formic acid (25:75:0.075, v/v/v). The analyte and I.S. cefaclor were both detected by the use of selected reaction monitoring mode. The method was linear in the concentration range of 5-2,000 ng/ml. The lower limit of quantification was 5 ng/ml. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 4.3%. The accuracy determined at three concentrations (36, 360 and 1,800 ng/ml for cefdinir) ranged from 99.6 to 106.7% in terms of recovery. The chromatographic run time for each plasma sample was less than 3 min. The method herein described was successfully applied for the evaluation of pharmacokinetic profiles of cefdinir capsule in 12 healthy volunteers.

[Study of pharmacokinetics/pharmacodynamics of levofloxacin].

OBJECTIVE: To evaluate the dosing regimens of levofloxacin. METHODS: The drug concentrations in serum and urine were assayed by HPLC method and the pharmacokinetic parameters were calculated after intravenous infusion of a single dose of 200 mg, 300 mg and 500 mg levofloxacin to healthy volunteers. The in vitro activity MIC of levofloxacin against 823 clinical isolates were determined and compared with other antimicrobial agents. Based on the above results, the PK/PD parameters C(max)/MIC and AUC/MIC were calculated and the dosing regimens of levofloxacin were proposed for infections caused by different pathogens. RESULTS: The results of clinical pharmacokinetic study showed that the C(max) of levofloxacin was 3.4 mg/L +/- 0.8 mg/L, 4.8 mg/L +/- 1.4 mg/L and 7.6 mg/L +/- 1.1 mg/L respectively, AUC(0-infinity) was 14.4 mg.h/L +/- 2.5 mg.h/L, 21.9 mg.h/L +/- 4.5 mg.h/L and 38.3 mg.h/L +/- 4.9 mg.h/L respectively, T(1)/2 beta was 6.2 h +/- 0.4 h, 6.4 h +/- 0.9 h and 6.5 h +/- 0.6 h respectively, and 69% +/- 5%, 69% +/- 6%, and 65% +/- 4% of the doses were excreted in urine within 24 h after intravenous infusion of a single dose of levofloxacin 200 mg, 300 mg and 500 mg. The in vitro pharmacodynamic study showed that levofloxacin was highly active against Hemolytic streptococcus and Moraxella catarrhalis. It was active against Streptococcus pneumoniae (including penicillin nonsusceptible strains), Hemophilus influenzae, methicillin-sensitive Staphylococcus aureus (MSSA), Klebsiella pneumoniae and Stenotrophomonas maltophilia. Levofloxacin also had good activity against Pseudomonas aeruginosa and K.pneumoniae. However, most of isolates of enterococcal spp. were resistant to levofloxacin. Above 50% of Escherichia coli isolates were resistant to levofloxacin. Based on the results of PK/PD parameters, the adequate dosing regimens of levofloxacin should be once daily 200 mg once daily of levofloxacin was expected to be effective for the treatment of infections caused by M. catarrhalis. The regimen of 300 mg once daily could be effective for the treatment of infections caused by Hemolytic streptococcus. 500 mg once daily of levofloxacin was expected to be effective for the treatment of respiratory tract infections caused by S. pneumoniae or H. influenzae. For treatment of respiratory tract infections and urinary tract infections caused by levofloxacin-susceptible organisms including K. pneumoniae, E. coli, P. aeruginosa, and S.maltophilia, 500 mg once daily of levofloxacin was needed to obtain good clinical efficacy. But PK/PD parameters predicted that 500 mg daily of levofloxacin was not effective for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci. CONCLUSION: The proposed dosing regimens of levofloxacin based on PK/PD concepts are expected to provide good efficacy in clinical practice.