Ji Jiang

Objective: This phase Ia study was designed to assess the pharmacokinetic (PK) characters of free vincristine (F-VCR, refer to as non-liposomal VCR and VCR released from liposome) and total vincristine (T-VCR, the sum of both liposomal VCR and F-VCR), urinary excretion and safety of intravenous administration of vincristine sulfate liposomes injection (VSLI) in Chinese patients with malignant lymphoma and compare the results with those for conventional vincristine sulfate injection (VSI). Methods: In the phase Ia, randomized, open-label, two sequence cross-over study, patients from one group were exposed to treatment 1 including cytoxan (cyclophosphamide power injection), hydroxyrubicin (adriamycin power injection), oncovin (VSI), and prednisone tablets (standard CHOP scheme) before crossed over to treatment 2 (modified CHOP scheme in which VSI was replaced with VSLI). Patients from another group received treatments in reverse order. Results: In this phase Ia study, a total of eight subjects participated. VCR elimination from the circulation after injection of VSLI was characterized by a significantly increased maximum concentration (C_max, 86.6 ng/mL) and plasma area under the plasma concentration-time curve from zero to infinity (AUC_0-Inf, 222.1 ng/mL h), markedly decreased distribution volume (V_z, 224.1 L) and plasma clearance (CL, 8.9 L/h) compared to lower C_max (26.6 ng/mL) and AUC_0-Inf (95.1 ng/mL h), larger V_z (688.8 L) and CL (22.1 L/h) for VSI. The small proportion of F-VCR following infusion of VSLI in circulation was reflected by very low C_max (1.8 ng/mL) and AUC_0-Inf (50.5 ng/mL h). Less than 3% of the administered dose of VSLI was excreted in urine and the extent was similar to that for VSI. The elimination percentage of 40–21–14% for VSI changed to 6.2–24–39% for VSLI at intervals of 0–5, 5–13 and 13–25 h, respectively. Significant difference of toxicity between VSLI and VSI was not observed. Conclusion: VSLI exhibits higher AUC_0-Inf of T-VCR, lower CL and V_z compared with VSI. VSLI was well tolerated, maybe due to the markedly decreasing AUC_0-Inf of F-VCR. The majority of VCR was enveloped in liposome and VCR was released gradually from liposome following injection of VSLI. Liposomal encapsulation of VCR does not alter the route and extent of VCR excretion in urine.

Aim: Hemay005 is a novel small-molecule inhibitor of phosphodiesterase-4 developed for the treatment of psoriasis. Measurement of Hemay005 in biological samples is critical for evaluation of its pharmacokinetics in clinical studies. Methodology & results: Plasma and urine samples were extracted and then chromatographed on an Acquity UPLC HSS T3 column with a gradient elution. Detection was performed on a Xevo TQ-S tandem mass spectrometer using negative ESI. Conclusion: For the first time, a sensitive and robust ultra-high performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was established and validated for the quantitative determination of Hemay005 in human plasma and urine, and it was successfully applied to evaluate the pharmacokinetics of Hemay005 in healthy subjects in a first-in-human study.

Vincristine sulfate liposome injection (VSLI) is a liposomal formulation of vincristine (VCR) sulfate, being developed for the systemic treatment of cancer. In this paper, we have developed and validated a method to quantify VCR in human urine to obtain the urinary excretion of VCR after intravenous administration of VSLI. The analyte was extracted from urine samples using liquid–liquid extraction after addition of vinblastine (VBL, used as internal standard) and chromatographed on an Acquity UPLC HSS T3 column with a gradient mobile phase at a flow rate of 0.4 mL/min. The multiple reactions monitoring transitions of m/z 413.2 → 353.2 and m/z 406.2 → 271.6 were used to quantify VCR and VBL, respectively. The lower limit of quantification was 0.5 ng/mL with a precision (RSD%) of 5.7% and an accuracy (RE%) of 6.7%. The calibration curve was linear up to 100.0 ng/mL. Intraday precision and accuracy ranged from 0.8 to 11.0% and from −12.4 to 11.3%, respectively. Interassay precision and accuracy ranged from 8.0 to 10.1% and from −7.7 to 3.6%, respectively. No significant matrix effect was observed for VCR. The method was successfully applied for pharmacokinetic study of VSLI to investigate the route and extent of VCR urinary excretion in Chinese subjects with lymphoma.

A specific, sensitive and rapid method based on high performance liquid chromatography coupled to tandem mass spectrometry (HPLC‐MS/MS) was developed for the determination of pseudo‐ginsenoside GQ in human plasma. Liquid–liquid extraction was used to isolate the analyte from biological matrix followed by injection of the extracts onto a C₈ column with isocratic elution. Detection was carried out on a triple quadrupole tandem mass spectrometer (API‐4000 system) in multiple reaction monitoring mode using negative electrospray ionization. The mobile phase consisted of methanol–10 mm ammonium acetate (90:10, v/v) and the flow rate was 0.3 mL/min. The method was validated over the concentration range of 5.0–5000.0 ng/mL for plasma. Inter‐ and intra‐day precisions (relative standard deviation) were all within 15% and the accuracy (relative error) was ≤9.4%. The lower limit of quantitation was 5.0 ng/mL. The pseudo‐ginsenoside GQ was stable after 8 h at room temperature, 24 h at autosampler and three freeze–thaw cycles (from −30 to 25 °C). The method was successfully applied to the pharmacokinetic study of pseudo‐ginsenoside GQ in healthy Chinese volunteers. Copyright © 2013 John Wiley & Sons, Ltd.

Calcium L-threonate is a novel drug that was developed for the treatment of osteoporosis and as a calcium supplement. However, calcium bioavailability of this drug is unknown due to lack of effective evaluation methods. In this study, we sought to measure the bioavailability of calcium L-threonate with a double-label stable isotope method. Fourteen healthy Chinese subjects were enrolled in the clinical study and were given 300 mg calcium L-threonate tablets containing 40 mg ⁴⁴Ca after an intravenous injection of 4 mg ⁴²Ca solution (as calcium chloride). Fractional urine samples were collected at the following time intervals: 0–3, 3–6, 6–9, 9–13, 13–24, 24–36 and 36–48 h. The abundance ratios of ⁴⁴Ca/⁴⁰Ca and ⁴²Ca/⁴⁰Ca in the urine were determined with thermal-ionization mass spectrometry (TI-MS). The calcium bioavailability was estimated by calculating the true fractional calcium absorption (TFCA) using the abundance ratios of ⁴⁴Ca/⁴⁰Ca and ⁴²Ca/⁴⁰Ca. The bioavailability of calcium L-threonate in 14 healthy Chinese subjects was 26.49 ± 9.39 %. There was good agreement between TFCA from the 24 to 36 h and the 36 to 48 h urine pool, indicating that calcium balance was achieved at 24 h after dosing. The TFCA of the subjects did not statistically correlate with total urinary calcium excretion (0–48 h). There were no serious adverse events in this study. The bioavailability of calcium L-threonate in humans was successfully determined by estimating TFCA with the double-label stable isotope method, thus providing a useful approach for the evaluation of bioavailability of calcium formulations.

To evaluate the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy Chinese volunteers. This was an open-label, single- and multiple-dose study. The subjects were assigned to receive a single dose, 675, 2025, or 4050 mg, of calcium L-threonate (n=12) or repeated doses of 2025 mg twice daily for 4 d (n=12). Serial plasma and urine samples were analyzed with HPLC-MS/MS. Pharmacokinetic parameters of L-threonate were calculated using non-compartmental analysis with WinNonlin software. In the single dose group, C_max reached at 2.0 h and the mean t_1/2 was approximately 2.5 h. Area under curve (AUC) and C_max increased with dose escalation, but dose proportionality was not observed over the range of 675 to 4050 mg. AUC and C_max in the fasted subjects were lower compared with those in the non-fasted subjects. Cumulative urinary excretion of L-threonate over 24 h represented 5.9% of the administered dose with a mean Cl/r of 0.8 L/h. In the multiple-dose study, no accumulation appeared upon repeated doses of 2025 mg twice daily for 4 d. There were no serious adverse events that occurred during this study. Calcium L-threonate was well tolerated in healthy Chinese subjects, with no pattern of dose-related adverse events. Plasma exposure increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. L-threonate was absorbed rapidly, and its absorption was enhanced by food intake. No systemic accumulation appeared after repeated administrations.