A Rapid and Sensitive UHPLC-MS/MS Method for Determination of 2, 3, 8-Trimethylellagic, a Potent Active Compound from Sanguisorba officinalis L., and Its Application in the Pharmacokinetic Study within Thrombocytopenia Rats

To investigate the pharmacokinetics of 2, 3, 8-trimethylellagic (TMEA) in rats in vivo and determine the possible effects of the pathological conditions and compatibility, a rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantitative determination was developed. TMEA and Artemetin (internal standard, IS) were separated on an Acquity Shim-pack GIST column with a total running time of 7 min using gradient elution at a flow rate of 0.3 mL/min. The intraday and interday relative standard deviations were <9.50%, and the relative error of accuracy was between −5.70% and 2.96%. The calibration curve of TMEA demonstrated good linearity with r2 = 0.9996, with the average recovery changing from 94.77% to 102.47% and the matrix effect from 93.16% to 100.15%. Compared with the normal group, the area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration (AUC(0 − t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0 − ∞)), and the maximum concentration (Cmax) of TMEA increased, whereas the time of maximum concentration (Tmax) and apparent clearance (CL/F) remarkably decreased in the TMEA group. With significantly reduced CL/F, AUC(0 − t), AUC(0 − ∞), and Cmax for TMEA were increased approximately one time after combining with 3, 7-Di-O-methylducheside A (DOMA). AUC(0 − t) and Cmax for TMEA in the 2, 3, 8-trimethylellagic-3, 8-dimethoxyellagic acid-2-oxyglucoside (TMEA-DMAG) group were significantly lower than that in the TMEA group with clearly prolonged Tmax and increased CL/F. These findings indicate that the changes in the pharmacokinetic parameters of TMEA may be caused by pathological and combination conditions.

Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer

We evaluated the area under the plasma concentration–time curve (AUC) of afatinib required to avoid the onset of grade 2 or higher diarrhea. The C0 and AUC0–24 of afatinib were significant higher in patients with grade 2 diarrhea than in those with grade 0–1 diarrhea. The areas under the receiver operator curves were 0.795 with the highest sensitivity (89%) and specificity (74%) at an AUC0–24 threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C0 threshold of 28.5 ng/mL. In Kaplan–Meier analysis based on these cut-off AUC0–24 and C0 values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC0–24 of afatinib from the single point of C6 showed the highest correlation with the measured AUC0–24 (r2 = 0.840); however, a significant correlation between the AUC0–24 and C0 was also observed (r2 = 0.761). C0 could be used as a marker of therapeutic drug monitoring because afatinib C0 was related to AUC0–24. Therefore, afatinib C0 should be monitored on day 8 after beginning therapy, and the daily dose of afatinib should be adjusted as an index with a cut-off value of 28.5 ng/mL.

Pharmacokinetic/Pharmacodynamic Modeling of Spiramycin against Mycoplasma synoviae in Chickens

This research aimed to assess the pharmacokinetics/pharmacodynamics (PK/PD) and tissue residues of spiramycin in chickens. The PK of spiramycin were determined in 12 chickens using a parallel study design in which each group of chickens (n = 6) received a single dose of spiramycin at 17 mg/kg intravenously (IV) or orally. Plasma samples were collected at assigned times for up to 48 h to measure spiramycin concentrations. Additionally, a tissue depletion study was performed in 42 chickens receiving spiramycin at 17 mg/kg/day orally for 7 days. The area under the plasma concentration–time curve values were 29.94 ± 4.74 and 23.11 ± 1.83 µg*h/mL after IV and oral administrations, respectively. The oral bioavailability was 77.18%. The computed withdrawal periods of spiramycin were 11, 10, and 7 days for liver, muscle, and skin and fat, respectively. The minimum inhibitory concentration for spiramycin against Mycoplasma synoviae (M. synoviae) strain 1853 was 0.0625 µg/mL. Using the PK/PD integration, the appropriate oral dose of spiramycin against M. synoviae was estimated to be 15.6 mg/kg. Thus, we recommend an oral dose of 15.6 mg spiramycin/kg against M. synoviae in chickens and a withdrawal period of 11 days following oral treatment with 17 mg spiramycin/kg/day for 7 days.

Pharmacokinetics of Tildipirosin in Healthy and Mycoplasma gallisepticum Infected Chickens

The pharmacokinetic features of tildipirosin were explored following a single dose of 4 mg/kg in healthy and Mycoplasma gallisepticum (M. gallisepticum) infected chickens. Eighteen healthy chickens (400-500g) were allocated into 3 groups (n=6); group I and II were received tildipirosin by intravenous (IV) and intramuscular (IM) routes, respectively. Group III was experimentally infected with M. gallisepticum and injected IM with tildipirosin after confirming the infection (9-10 days after inoculation of M. gallisepticum). Plasma samples were harvested at different time points until 14 days after tildipirosin injection to measure its concentrations using HPLC. After IM administration of tildipirosin in healthy chickens, the maximum concentration in plasma (Cmax), time to achieve Cmax (Tmax), area under the plasma concentration time curve from 0 to last time (AUC0-last), clearance (Cl-F-obs) and the absolute bioavailability were recorded to be 403.76ng/ml, 0.25 hr, 6.82 µg.hr/ml, 0.56L/hr/kg, and 103.50% respectively. Cmax and AUC0-last, were significantly lower in infected than healthy chickens, while Cl-F-obs was significantly higher in infected than healthy chickens. Therefore, M. gallispeticum infection produced significant changes in some of the pharmacokinetic parameters of tildipirosin in chickens. Further studies are warranted to assess pharmacokinetic/ pharmacodynamic profile of tildipirosin against M. gallisepticum in chickens and to gain deeper insight into its safety utilization in chickens.

Pharmacokinetics of toltrazuril and its metabolites toltrazuril sulphoxide and toltrazuril sulphone in pregnant and non-pregnant goats

The pharmacokinetic characteristics of toltrazuril (TZR) and its metabolites toltrazuril sulphoxide (TZR.SO) and toltrazuril sulphone (TZR.SO2) were assessed in non-pregnant and pregnant goats. Ten healthy Baladi female goats were allocated into two groups (n = 5 per group): non-pregnant goats (group 1) and pregnant goats at 2–3 months of gestation (group 2). Toltrazuril was administered once orally to all goats at 20 mg/kg. Plasma samples were collected at 0 (before TZR administration), 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 h and 5, 7, 9, 12, 16, 20, 24, 27, 30, and 35 days post therapy to measure the concentrations of TZR and its metabolites. In pregnant goats, the maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and the area under the plasma concentration-time curve from time zero to the last sample (AUC0-last) of TZR were significantly higher (P < 0.05) compared to the non-pregnant ones, whereas the volume of distribution (Vz_F_obs) and clearance (Cl_F_obs) were significantly lower (P < 0.05) in pregnant goats. No significant differences were observed in the elimination half-life (T1/2λz), and mean residence time (MRT) between the two groups. In non-pregnant goats, TZR.SO and TZR.SO2 could be detected in plasma until 12 and 30 days, respectively; whereas in pregnant goats, they were quantified up to 16 and 35 days, respectively. Conclusively, TZR was well absorbed and rapidly metabolized to TZR.SO and TZR.SO2, after oral dosing in goats. Pregnancy caused significant alterations in some of the pharmacokinetic indicators of TZR and its metabolites in goats.

Pharmacokinetics and Bioequivalence Study of Two Ciprofloxacin Hydrochloride Tablets in Chinese Healthy Volunteers Under Fasting and Fed Conditions: A Randomized, Open-Label, Two-Formulation, Two-Sequence, Two-Period, Single-Dose Crossover Study.

BackgroundCiprofloxacin is a broad-spectrum fluoroquinolone antibiotic which is active against a wide range of Gram-positive and Gram-negative bacteria. The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under the fasting and fed conditions.MethodsThe study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg of ciprofloxacin hydrochloride. Blood samples were collected from an hour before dosing to 36 h after administration with 16 time points in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including maximum concentration (Cmax), area under the plasma concentration–time curve from time 0 to time t (AUC0-t), area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞). Two formulations are considered bioequivalent if the 90% confidence intervals (CIs) for the test/reference geometric mean ratios (GMRs) for the ln-transformed pharmacokinetic parameters fall within the standard acceptance range of 80% – 125%. ResultsIn total of 48 subjects were enrolled in the fasting and fed studies, and one of the subjects was excluded before the administration. In the fasting study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0–t, and AUC0–∞ were 85.41% to 100.97%, 95.40% to 100.27%, and 95.48% to 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0–t, and AUC0–∞ were 90.15% to 113.75%, 99.10% to 103.77% and 99.11% to 103.80%, respectively. A total of 8 of 47 subjects experienced AEs in the fasting and fed studies.ConclusionsIn the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after a single oral dose administration under the fasting and fed conditions. Both two brands of ciprofloxacin tablets were safe and well tolerated.Trial registrationThe clinical trial was registered at Center for the Drug Evaluation of the National Medical Products Administration (registration number: CTR20171152; date of registration：September 25, 2017; http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml).

Interpretation of Drug Interaction Using Systemic and Local Tissue Exposure Changes

Systemic exposure of a drug is generally associated with its pharmacodynamic (PD) effect (e.g., efficacy and toxicity). In this regard, the change in area under the plasma concentration-time curve (AUC) of a drug, representing its systemic exposure, has been mainly considered in evaluation of drug-drug interactions (DDIs). Besides the systemic exposure, the drug concentration in the tissues has emerged as a factor to alter the PD effects. In this review, the status of systemic exposure, and/or tissue exposure changes in DDIs, were discussed based on the recent reports dealing with transporters and/or metabolic enzymes mediating DDIs. Particularly, the tissue concentration in the intestine, liver and kidney were referred to as important factors of PK-based DDIs.

Comparative bioavailability study of phenytoin in healthy Nepalese volunteers

Our study aimed to assess and compare the bioavailability of Eptoin 100 mg and Epileptin 100mg tablets in Nepalese healthy volunteers. A randomized, two-treatment cross-over study with two weeks’ wash-out period was conducted in 12 healthy non-smoker and non-alcoholic Nepalese male volunteers over a period of 6 months in the department of Clinical Pharmacology and Therapeutic at B. P. Koirala Institute of Health Sciences, Dharan, Nepal after approval from the Institutional Review Committee. The participants were randomized using sealed envelope system and received a single 100 mg oral tablet of either of the formulations with a two week washout period. Blood samples were collected predose and at regular intervals postdose upto 72 hours. Plasma phenytoin levels were estimated by reverse phase high performance liquid chromatography. The analytical method was validated prior to the start of study. Cmax (Peak Plasma Concentration), Tmax (Time to achieve maximum Plasma Concentration), AUC0-72 (Area under plasma concentration time curve 0 to 72 hours), AUC0-∞ (Area under plasma concentration time curve 0 to ∞) and T½ (Elimination half-life) and Kel (Elimination rate constant) were calculated and 80-120% margin (90% confidence interval) was used to assess bioequivalence. ANOVA test was used to analyze the data at P-value of 0.05. All volunteers completed the study. The log-transformed values of Cmax, Tmax, AUC0-t, and AUC0-∞ of the both formulations were within the specified limits and were bioequivalent according to the regulatory definition of bioequivalence based on the rate and extent of absorption. Both products can be considered equally effective in medical practice. Keywords: Bioavailability, Bioequivalence, healthy volunteer, Nepal, phenytoin sodium.

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects

ABSTRACTMeropenem-vaborbactam is a fixed combination of the novel β-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.)