Zhanjun Dong’s research while affiliated with State Key Laboratory of Medical Genetics of China and other places

Ondansetron is a highly selective 5-HT3 receptor antagonist that alleviates nausea and vomiting. Bioequivalence evaluation ensures that the efficacy of generic drugs is consistent with that of the original drug. The objective of this study was to evaluate the bioequivalence of ondansetron hydrochloride (HCl) tablets taken in single doses under fasting and postprandial conditions in healthy subjects. In this randomized, open-label, two-cycle, crossover phase I study, liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to determine the ondansetron concentration in dipotassium-ethylenediaminetetraacetate (K2-EDTA) plasma after the subjects received a single 8 mg of ondansetron and reference formulation. Twenty-six healthy subjects received one tablet of ondansetron under fasting conditions and 28 subjects received one under postprandial conditions. Bioequivalence was established if the 90% confidence interval (CI) was 80.00–125.00%. The pharmacokinetic parameters were calculated via WinNonLin 8.1 software and the bioequivalence data were evaluated via Phoenix WinNonlin 8.1 statistics software. The geometric mean ratio (GMR) of the maximum observed concentration (Cmax), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC0–t), and the AUC from time zero to infinity (AUC0–∞) from the test/reference formulation under fasting conditions were 90.50, 90.43, and 90.25, respectively. The 90% CIs were 83.75–97.79, 82.64–98.95, and 82.25–99.03, respectively. The GMRs of Cmax, AUC0–t, and AUC0–∞ after a high-fat meal were 96.85, 93.57, and 93.77, respectively; the 90% CIs were 88.43–106.07, 87.35–100.24, and 87.35–100.68, respectively. The test and reference formulations of ondansetron HCl have bioequivalence for healthy adult subjects under fasting and postprandial conditions.

Background In Chinese healthcare settings, drug selection decisions are predominantly influenced by the Pharmacy & Therapeutics Committee (PTC). This study evaluates two recently introduced potassium-competitive acid blockers, vonoprazan (VPZ) and tegoprazan (TPZ), utilizing the Evidence and Value: Impact on DEcisionMaking (EVIDEM) framework. Methods The study employed the 10th edition of EVIDEM, which includes a core model with five domains and 13 criteria. Two independent expert panels were involved: the PTC expert panel, tasked with assigning weights using a 5-point scale, defining scoring indicators, examining the evidence matrix, scoring, and decision-making; and the evidence matrix expert panel, responsible for conducting a systematic literature review, creating the evidence matrix, and evaluating the value contributions of VPZ and TPZ. Results The analysis estimated the value contributions of VPZ and TPZ to be 0.59 and 0.54, respectively. The domain of ‘economic consequences of intervention’ showed the most significant variation in value contribution between the two drugs, followed by ‘comparative outcomes of intervention’ and ‘type of benefit of intervention’. Conclusion Employing the EVIDEM framework, VPZ’s value contribution was found to be marginally superior to that of TPZ. The EVIDEM framework demonstrates potential for broader application in Chinese medical institutions.

Objective This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application. Methods A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (Cmax), the areas under the plasma concentration–time curve (AUC0-t, AUC0-∞), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated. Results Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09–103.44% for Cmax, 94.05–103.51% for AUC0-t, and 94.56–103.86% for AUC0-∞ under fasting conditions, and 99.18–112.48% for Cmax, 98.79–106.02% for AUC0-t, and 98.95–105.89% for AUC0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00–125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study. Conclusion The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated. Clinical Trial Registration chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023).

Donafenib(DONA) and lenvatinib(LEN) are small-molecule tyrosine kinase inhibitors(TKI) that are used to treat advanced hepatocellular carcinoma(HCC).Empagliflozin and henagliflozin are sodium-glucose cotransporter 2(T2DM) inhibitors that are used to treat type 2 diabetes(T2DM).Empagliflozin and henaglifiozin are uridine diphosphate glucuronosyltransferase(UGT)1A9, Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)Donafenib is metabolized by UGT1A9 and is an inhibitor of UGT1A9 and lenvatinib is a substrate for P-gp and BCRP.T2DM is one of the risk factors for HCC progression, so the two drugs may be used in combination in clinical practice, but there is a lack of clear information about drug interactions. Therefore, the present study aimed to reveal the extent of drug interactions between donafenib, lenvatinib and empagliflozin and henagliflozin in rats and explore the possible mechanisms.Rats were divided into fourteen groups (n = 6) that received empaglifiozin(1,2),henagliflozin(3,4,)donafenib(5), lenvatinib(6), empaglifiozin and donafenib (7), hennagliflozin and donafenib (8), empaglifiozin and lenvatinib(9) ,henagliflozin and lenvatinib (10),donafenib and empaglifiozin (11), donafenib and henagliflozin (12),lenvatinib and empaglifiozin(13),lenvatinib and henagliflozin(14). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple administration of empagliflozin reduced the area under the concentration-time curve (AUC0 − t and AUC0−∞) of donafenib by 33.46% and 32.7% respectively. The apparent clearance rate (CLz/F) and apparent volume of distribution (Vd/F) were reduced by 66.7% and 95.2%, respectively. The half-life (T1/2) was prolonged by 17.6%.Henagliflozin modest decreased donafenib AUC0 − t and AUC0−∞ by 27.8% and 26.9%. The CLz/F of donafenib was 2.6-fold compared to the control group.Multiple doses of donafenib caused empagliflozin to AUC0 − t and AUC0−∞ increased by 57.5%and58.5%. CLz/F were significantly decreased by 39.9% .The combination of multiple doses of donafenib increased the maximum plasma concentration (Cmax) of henagliflozin by 65.5%, AUC0 − t and AUC0−∞ by 177.0% and178.0%, respectively. CLz/F and Vz/F of hanagliflozin were decreased by 64.1% and 45.1%.Multiple administration of empagliflozin decreased the AUC0 − t and AUC0−∞ of lenvatinib by 18.7% and21.4%, respectively. CLz/F was accelerated by 30.0%. After multiple administration of constant gliflozin, the AUC0 − t and AUC0−∞ of lenvatinib decreased by 20.3% and 20.9%, respectively, and CLz/F increased by 1.30-flod.Multiple doses of lenvatinib had no significant effect on the pharmacokinetics of empagliflozin and henagliflozin.The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.

Background In Chinese healthcare settings, decisions regarding drug selection are predominantly guided by the Pharmacy & Therapeutics Committee (PTC). This study focuses on two recently introduced potassium-competitive acid blockers in China, vonoprazan (VPZ) and tegoprazan (TPZ). The objective was to assess these drugs using the Evidence and Value: Impact on DEcisionMaking (EVIDEM) framework. Methods This study utilized the 10th edition of EVIDEM, comprising a core model with five domains and 13 criteria. It involved two independent expert panels. The PTC expert panel was tasked with five responsibilities: assigning weights using a 5-point scale, defining scoring indicators, examining the evidence matrix, scoring, and decision-making. The evidence matrix expert panel had three duties: conducting a systematic literature review, creating the evidence matrix, and evaluating the value contributions of VPZ and TPZ. Results The analysis estimated the value contributions of VPZ and TPZ at 0.59 and 0.54, respectively. The 'economic consequences of intervention' domain exhibited the most significant variation in value contribution between the two drugs, followed by 'comparative outcomes of intervention' and 'type of benefit of intervention'. Conclusion Utilizing the EVIDEM framework, VPZ's value contribution appears marginally superior to that of TPZ. The EVIDEM framework shows promise for application in Chinese medical institutions.

Background The objective of this study was to evaluate the effect of a high-fat meal on the pharmacokinetics and safety of 80/5 mg valsartan/amlodipine tablets in healthy subjects. Subjects and Methods These results were derived from a bioequivalence trial where subjects were randomly assigned to take valsartan/amlodipine 80/5mg under fed conditions or after a high-fat meal contained 978.6 kilocalories (54.6% from fat). The blood samples were collected and plasma concentrations of valsartan/amlodipine were measured using high-performance liquid chromatography-mass spectrometry. The non-compartmental module of Phoenix WinNonlin Version 8.2 was used to calculate pharmacokinetic parameters. The BE module of WinNonLin was used to analyze the statistics of the maximum plasma concentration (Cmax), the area under the concentration-time curve from zero to the last quantifiable time point (AUC0-t), and the area under the concentration-time curve from zero to infinity(AUC0–∞) in plasma. 88 healthy subjects were enrolled and divided into in a fasted group and a fed group. Results The Cmax, AUC0–t, and AUC0–∞ of valsartan in plasma under fed conditions were 51%, 56%, and 57% lower, respectively, than those under fasted conditions, and the 90% confidence interval (90% CI) were outside the 80.00–125.00% range. All the pharmacokinetic parameters for amlodipine under fed conditions were similar to those observed under fasted conditions, and the 90% CIs were within the 80.00–125.00% range. The incidence of treatment emergent adverse events (TEAE) was similar between the fasted group and the fed group, while adverse drug reaction (ADR) was more frequent in the fasted group which may be related to the higher blood concentrations of valsartan, but all were mild. Conclusion The result indicated that the high-fat meal had a significant effect on the pharmacokinetics of valsartan, but no effect on amlodipine. All treatments were safe and well tolerated in healthy subjects under fed and fasted conditions.

Background: Almonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations. Rivaroxaban and apixaban are a selective, direct factor Xa inhibitor used to treat venous thromboembolism (VTE), which is a frequent complication of NSCLC. Rivaroxaban and apixaban are substrates of CYP3A4, P-gp and BCRP, whereas almonertinib is an inhibitor of P-gp and BCRP. Rivaroxaban or apixaban are often prescribed together with almonertinib in NSCLC patients, but clear information on pharmacokinetic drug interaction is lacking. Therefore, this study aimed to unravel the extent of interactions between almonertinib-rivaroxaban and almonertinib apixaban in rats, and whether the pharmacokinetic interaction can be mitigated by rivaroxaban and apixaban dose adjustment. Methods: Rats were divided into ten groups (n = 6) that received rivaroxaban (2 mg/kg) (group 1), apixaban (0.5 mg/kg) (group 2), almonertinib (15 mg/kg) (group 3, group 4), almonertinib with rivaroxaban (2 mg/kg) (group 5), almonertinib with rivaroxaban (1 mg/kg) (group 6), almonertinib with apixaban (0.5 mg/kg) (group 7), almonertinib with apixaban (0.25 mg/kg) (group 8), rivaroxaban (2 mg/kg) with almonertinib (group 9), apixaban (0.5 mg/kg) with almonertinib (group 10). The concentrations of drugs were determined by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The levels of messenger RNA were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Results and Discussion: The results indicate that almonertinib increased the Cmax and AUC0-t of 2 mg/kg rivaroxaban by 3.30 and 3.60-fold, 1 mg/kg rivaroxaban by 1.28 and 1.90-fold. Almonertinib increased the Cmax and AUC0-t of 0.5 mg/kg apixaban by 2.69 and 2.87-fold, 0.25 mg/kg apixaban by 2.19 and 2.06-fold. In addition, rivaroxaban also increased systemic exposure to almonertinib. The results of qRT-PCR showed that almonertinib reduced the expression of Cyp3a1 in liver and intestine, and Abcb1a, Abcg2 in intestine and kidney. The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.

Objective This study compared the pharmacokinetic and safety profiles of generic and original vortioxetine hydrobromide tablets under fasting and fed conditions, and evaluated the bioequivalence of two vortioxetine formulations to obtain sufficient evidence for abbreviated new drug application. Methods A randomized, open-label, two-formulation, single-dose, two-period crossover bioequivalence study was conducted under fasting and fed conditions (n = 32 per study). Eligible healthy Chinese subjects received a single 10-mg dose of the test or reference vortioxetine hydrobromide tablet, followed by a 28-day washout interval between periods. Serial blood samples were collected up to 72 h after administration in each period, and the plasma concentrations of vortioxetine were detected using a validated method. The primary pharmacokinetic (PK) parameters were calculated using the non-compartmental method. The geometric mean ratios for the PK parameters of the test drug to the reference drug and the corresponding 90% confidence intervals were acquired for bioequivalence analysis. A safety evaluation was performed throughout the study. Results Under fasting and fed conditions, the PK parameters of the test drug were similar to those of the reference drug. The 90% confidence intervals (CIs) of the geometric mean ratios of the test to reference formulations were 96.44–105.81% for peak concentration (Cmax), 97.94–105.05% for the area under the curve truncated at 72 hours (AUC0-72 h) under fasting conditions, 93.92–104.15% for Cmax, and 96.67–102.55% for AUC0-72 h under fed conditions, all of which were within the accepted bioequivalence range of 80.00–125.00%. Both the test and reference formulations were well-tolerated, and no serious adverse events related to the study drug were reported during the study. Conclusion The PK bioequivalence of the test and reference vortioxetine hydrobromide tablets in healthy Chinese subjects was established under fasting and fed conditions, which met the predetermined regulatory criteria. Both formulations were safe and well tolerated.