While zanubrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, is known for its improved target selectivity, a systematic integration of its clinical pharmacology with efficacy and safety across diverse B-cell lymphomas - particularly highlighting its distinct pharmacokinetic and pharmacodynamic profile relative to other BTK inhibitors - is lacking. This review comprehensively summarizes zanubrutinib’s pharmacological characteristics, clinical trial and real-world outcomes, and adverse event management strategies, aiming to provide a clinically actionable resource for optimized and individualized therapy. We conducted a structured literature search in PubMed, Embase, Cochrane Library, and Web of Science using keywords including “zanubrutinib,” “BGB-3111,” “BTK inhibitor,” and “B-cell lymphoma.” Relevant publications were critically reviewed to synthesize evidence on zanubrutinib’s pharmacokinetics, pharmacodynamics, clinical efficacy across indications, and management of adverse events, with an emphasis on mechanistic insights and practical clinical guidance. Zanubrutinib demonstrates a favorable efficacy and safety profile supported by its distinct pharmacological characteristics. Its favorable pharmacokinetics include high central nervous system penetration and well-characterized metabolic pathways. Clinically, it induces deep and durable responses across multiple B-cell malignancies, supported by sustained BTK occupancy and a superior free-drug trough concentration relative to its half-inhibitory concentration (IC50). The safety profile is characterized by lower incidences of certain off-target toxicities (e.g., atrial fibrillation) compared to ibrutinib, though infections, bleeding, and cytopenias require vigilant management. Analysis of resistance mechanisms underscores the central role of BTK mutations (e.g., C481S, L528W), informing future therapeutic sequencing. This review underscores the value of a pharmacology-guided approach to maximizing zanubrutinib’s benefits, encompassing rational dosing, proactive toxicity management, and strategic positioning within the BTK inhibitor landscape. Future directions should prioritize combinatorial strategies to overcome resistance and therapeutic drug monitoring for precision dosing.

Venetoclax, a selective BCL-2 inhibitor, demonstrates efficacy in acute leukemia (AL) but variable pharmacokinetics. Therapeutic drug monitoring (TDM) may provide valuable pharmacologic insights for optimizing venetoclax therapy. This study explored the factors influencing plasma venetoclax concentrations and their correlation with febrile neutropenia (FN), aiming to establish predictive thresholds. AL patients receiving venetoclax between August 2023 and March 2025 were retrospectively analyzed. Plasma concentration, baseline characteristics, pharmacogenomics, and clinical parameters were collected. Univariate and multivariate linear regression analyses were performed to identify determinants of venetoclax concentrations and factors associated with FN incidence. Receiver operating characteristic (ROC) curves were used to define FN-predictive thresholds. The cohort comprised 123 patients, with FN developing in 35 cases (28.5

Objectives To explore the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of ADC189 in vivo. Methods In this study, which used a single-center, open, nonrandomized, single-dose trial design. Results [14C] ADC189 is rapidly absorbed in humans and undergoes O-dealkylation to form [14C] ADC189-I07 (M485b). The metabolite M485b has been reported to exhibit Tmax was 3.51 h, Cmax was 57.5 ng/mL, and AUC0-∞ was 2647 h·ng/mL. In plasma and blood, the mean Cmax values for radioactivity were 152 and 119 ng eq./mL, respectively, the mean AUC0-∞ values were 7,373 and 1,011 ng eq./mL·h, respectively, the mean Tmax values were 3,373 and 1,011 ng eq./mL·h, respectively, the mean Tmax values were 3.03 and 3.15 h, and the mean t1/2 values were 40.4 and 11.6 h, respectively. Based on the results of the metabolite profile, and metabolite structure analyses of the urine and fecal samples, it was hypothesized that the main clearance pathways of ADC189 in the human body after a single dose of the drug are as follows: the prodrug ADC189 is metabolized and excreted via several pathways: it can be O-dealkylated to form M485b (excreted in feces and urine), glucuronidated to form M661 (excreted in urine), oxidized to form M501a/b (excreted in feces and urine), or deoxygenated to form M457 (excreted in feces). Conclusion The results of this study collectively indicate that [14C]ADC189 does not significantly bind to blood cells, and its primary excretion route is fecal excretion, while urinary excretion is a secondary route.

OBJECTIVE:This study evaluated and compared the safety, pharmacokinetics, and pharmacodynamics of regadenoson injection (test) and regadenoson original injection (Lexiscan, reference) in healthy Chinese subjects. MATERIALS AND METHODS:In a randomized, positive-control, single-center, single-dose study, 24 healthy Chinese subjects were divided into test and reference groups (12 subjects each). Subjects in the test group received a single bolus of test drug (0.4 mg/5 mL), while the reference group received the same dose of reference drug. Blood and urine samples were collected before and after drug administration, and regadenoson concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS:No serious adverse events (AEs) occurred. There was no significant difference in the incidence of adverse reactions between the two preparations. The pharmacokinetic parameters, including maximum concentration (Cmax), the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t), and the area under the concentration-time curve from time 0 to infinity (AUC0-∞), were assessed to compare the pharmacokinetic of two regadenoson preparations. The test/reference geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ were 102.84, 99.16, and 99.77%, respectively. The 90% confidence intervals (CIs) of AUC0-t and AUC0-∞ fell within 0.8 - 1.25, but the 90% CIs of Cmax did not. Blood pressure (BP) and heart rate (HR) were measured to compare the pharmacodynamics of the two preparations. The test and reference drugs had similar HR responses (63.22 ± 38.45% vs. 37.50 ± 16.96%), systolic BP response (4.81 ± 13.73% vs. -3.83 ± 12.29%), and diastolic BP response (-7.75 ± 12.84% vs. -16.13 ± 9.85%), p > 0.05. After adjusting the weight of males and females, there were significant differences in Cmax, AUC0-t, AUC0-∞, T1/2, Vss, λz, Ae%, p < 0.05. CONCLUSION:The test drug demonstrated similar pharmacokinetic and pharmacodynamic characteristics as the reference drug. Additionally, it was well-tolerated and safe in healthy Chinese participants. Sex may influence regadenoson pharmacokinetics.

BACKGROUND:Although therapeutic drug monitoring is crucial for the comprehensive management of gastrointestinal stromal tumors (GISTs), the relationship between plasma concentration of ripretinib and its therapeutic efficacy is unknown. This study aimed to explore the relationship between ripretinib plasma trough concentration (R-Ctrough) and clinical efficacy and between ripretinib concentration and the incidence of adverse reactions among Chinese patients with advanced GIST. METHODS:The authors analyzed patients with GIST treated continuously for ≥1 month with a consistent daily dose ripretinib in a real-life setting. Peripheral venous blood samples were collected 24 h after the previous dose to measure R-Ctrough and 4 h after the current dose to identify the maximum concentration (R-C4). The plasma concentrations of ripretinib and its metabolites were quantified using liquid chromatography-tandem mass spectrometry. RESULTS:Between June 2021 and October 2024, 102 patients receiving ripretinib were evaluated. Ripretinib treatment resulted in higher mean R-Ctrough values in the nonprogression group than in the progression group (p < .05). Patients exhibiting an R-Ctrough above the threshold (R-Cmin, 475 ng/mL) demonstrated a significant improvement in median progression-free survival from 12.8 to 22.6 months (p < .05). A correlation was observed between ripretinib blood concentration and the occurrence of alopecia, fatigue, hand-foot syndrome, and rashes (p < .05). Moreover, variability in blood-drug concentrations was observed among patients with different KIT genotypes. CONCLUSIONS:Ripretinib and its metabolites maintained consistent plasma concentrations in Chinese patients with advanced GIST. Furthermore, a trough ripretinib concentration >475 ng/mL was associated with extended survival.

Imatinib is the first-line therapy for gastrointestinal stromal tumor (GIST), significantly enhancing patient prognosis. However, its clinical efficacy and safety are highly dependent on plasma concentration, which exhibits considerable interindividual variability. The purpose of this study is to determine the optimal monitoring time for imatinib concentration in postoperative patients with GIST, analyze single nucleotide polymorphisms affecting plasma concentration, and investigate their correlation with efficacy and adverse drug reactions (ADRs), offering valuable insights for personalized therapy. This study was conducted on 116 postoperative patients with GIST treated with imatinib in China between 2014 and 2018. Imatinib peak and trough concentrations (Cmax and Cmin) were measured in 608 samples using liquid chromatography-tandem mass spectrometry to determine the optimal monitoring time for steady-state concentration. DNA was extracted from 60 patients’ peripheral blood to Genotype 22 single nucleotide polymorphisms in genes such as CYP3A4, CYP3A5, ABCB1, SLC22A1, and SLC22A5 (OCTN2). Therapeutic efficacy was evaluated based on recurrence-free survival (RFS), and ADRs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Statistical analyses were performed using SPSS 26.0, with p < 0.05 considered statistically significant. The Cmax and Cmin of imatinib and its metabolite N-desmethyl imatinib reached their highest levels within the first month of treatment, and were stabilized by the third month. Genetic polymorphisms in ABCG2 (rs2231137), SLC22A1 (rs628031, rs3605065), and SLC22A5 (OCTN2) (rs2631372) were significantly associated with variations in imatinib Cmin. Genetic polymorphisms in CYP3A5 (rs776746), ABCG2 (rs2231137), and SLC22A1 (rs755828176) influenced imatinib Cmax. Patients carrying the CG and CC genotypes of SLC22A5 (OCTN2) (rs2631372) exhibited longer RFS and lower disease progression risk compared to those with the GG genotype (p < 0.05). Additionally, there was no significant correlation between the occurrence of ADRs and the studied genetic polymorphisms. Imatinib plasma concentration was stabilized by the third month in postoperative patients with GIST. Genetic polymorphisms in ABCG2, SLC22A1, and SLC22A5 (OCTN2) were associated with imatinib plasma concentration, while SLC22A5 (OCTN2) also influenced recurrence rates. These results provide a reference for personalized therapy and concentration monitoring.

Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.

BackgroundRAY1216 is an alpha-ketoamide-based peptide inhibitor of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) major protease (Mpro). This study evaluated the absorption, distribution, metabolism and excretion of [14C]-labelled RAY1216 by oral administration.Research design and methodsThis phase Ι study was designed to assess the pharmacokinetics, mass balance and metabolic pathways in 6 healthy Chinese adult men after a single fasting oral administration of 240 mL (containing 400 mg/100 μCi) [14C] RAY1216.ResultsRAY1216 absorbed rapidly in the plasma, with a Cmax of 1796.83 ng/mL, tmax of 1.42 h and t1/2 of 5.97 h. RAY1216 is mainly excreted through feces and a small amount through urine, indicating that the excretion of RAY1216 occurs through the fecal route, within 96 h after administration, the majority (>90%) of the radioactive substances were excreted 104.17% of the metabolites were identified in urine and fecal samples. The radioactive transformation pathways suggest that RAY1216 has multiple metabolic pathways, including Oxidation-dealkylation, Mono-oxidation, Hydrolysis, and Urea binding. There were no reports of death, serious adverse events (SAEs), or withdrawals related to SAEs.ConclusionThe overall recovery rate data of radioactive substances in the excreta of all 6 subjects indicate that favourable mass balance recovery. The overall safety profile is favourable, and it demonstrates promising potential in mitigating both the duration and severity of COVID-19, and the comprehensive clinical safety and therapeutic effect are significantly superior to those of similar COVID-19 treatment drugs. RAY1216 can be referred to and further verified for the Phase II and Phase III clinical trials for the treatment of COVID-19.

Background RAY1216 is an alpha-ketoamide-based peptide inhibitor of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) major protease (M pro ). This study evaluated the absorption, distribution, metabolism and excretion of [ 14 C]-labelled RAY1216 by oral administration. Research design and methods This phase Ι study was designed to assess the pharmacokinetics, mass balance and metabolic pathways in 6 healthy Chinese adult men after a single fasting oral administration of 240 mL (containing 400 mg/100 μCi) [ 14 C] RAY1216. Results RAY1216 absorbed rapidly in the plasma, with a C max of 1796.83 ng/mL, t max of 1.42 h and t 1/2 of 5.97 h. RAY1216 is mainly excreted through feces and a small amount through urine, indicating that the excretion of RAY1216 occurs through the fecal route, within 96 h after administration, the majority (>90%) of the radioactive substances were excreted 104.17% of the metabolites were identified in urine and fecal samples. The radioactive transformation pathways suggest that RAY1216 has multiple metabolic pathways, including Oxidation-dealkylation, Mono-oxidation, Hydrolysis, and Urea binding. There were no reports of death, serious adverse events (SAEs), or withdrawals related to SAEs. Conclusion The overall recovery rate data of radioactive substances in the excreta of all 6 subjects indicate that favourable mass balance recovery. The overall safety profile is favourable, and it demonstrates promising potential in mitigating both the duration and severity of COVID-19, and the comprehensive clinical safety and therapeutic effect are significantly superior to those of similar COVID-19 treatment drugs. RAY1216 can be referred to and further verified for the Phase II and Phase III clinical trials for the treatment of COVID-19.

Background: Ibrutinib and zanubrutinib are Bruton tyrosine kinase inhibitors used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Dihydroxydiol ibrutinib (DHI) is an active metabolite of the drug. A liquid chromatography–tandem mass spectrometry method was developed to detect ibrutinib, DHI, and zanubrutinib in human plasma. Methods: The method involved a protein precipitation step, followed by chromatographic separation using a gradient of 10 mM ammonium acetate (containing 0.1% formic acid)–acetonitrile. Ibrutinib-d5 was used as an internal standard. Analytes were separated within 6.5 minutes. The optimized multiple reaction monitoring transitions of m/z 441.1 → 304.2, 475.2 → 304.2, 472.2 → 455.2, and 446.2 → 309.2 were selected to inspect ibrutinib, DHI, zanubrutinib, and the internal standards in positive ion mode. Results: The validated curve ranges included 0.200–800, 0.500–500, and 1.00–1000 ng/mL for ibrutinib, DHI, and zanubrutinib, respectively. The precisions of the lower limit of quantification of samples were below 15.5%, the precisions of the other level samples were below 11.4%, and the accuracies were between −8.6% and 8.4%. The matrix effect and extraction recovery of all compounds ranged between 97.6%–109.0% and 93.9%–105.2%, respectively. The selectivity, accuracy, precision, matrix effect, and extraction recovery results were acceptable according to international method validation guidelines. Conclusions: A simple and rapid method was developed and validated in this study. This method was used to analyze plasma concentrations of ibrutinib and zanubrutinib in patients with mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, or diffuse large B-cell lymphoma. The selected patients were aged between 44 and 74 years.

Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.

Aims: Youkenafil is a novel selective phosphodiesterase type 5 inhibitor to treat erectile dysfunction. Since it was mainly metabolized through cytochrome P450 3A4/5 (CYP3A4/5) in vitro, the effects of itraconazole and rifampicin (potent CYP3A4/5 inhibitor and inducer, respectively) on the pharmacokinetics of youkenafil and its main metabolite (M1) were investigated in two clinical studies. Methods: Each study enrolled thirty healthy male subjects. In study 1, subjects were given a single dose of youkenafil (50 mg on Days 1 and 13) and multiple doses of itraconazole (200 mg once daily from Days 6 to 14). In study 2, subjects were given a single dose of youkenafil (100 mg on Days 1 and 20) and multiple doses of rifampicin (600 mg once daily from Days 6 to 20). Results: Itraconazole significantly increased the systemic exposure to youkenafil and M1. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for the AUC0-t, AUC0-∞ and Cmax of youkenafil were 1198.58% (900.33%–1595.63%), 1162.54% (874.69%–1545.11%) and 632.17% (500.40%–798.64%), respectively. Conversely, rifampicin significantly decreased the systemic exposure to youkenafil but had a slight effect on M1. The GMRs (90% CI) for the AUC0-t, AUC0-∞ and Cmax of youkenafil were 1.72% (1.27%–2.33%), 1.80% (1.33%–2.43%) and 1.77% (1.27%–2.47%), respectively. All subjects tolerated well in both studies. Conclusion: Itraconazole increased youkenafil AUC and Cmax by 12- and 6-fold, respectively. Rifampicin decreased youkenafil AUC and Cmax both by about 98%. Therefore, combined administration of youkenafil with potent inhibitors or inducers of CYP3A4/5 should be avoided or carefully monitored.

Background: Ripretinib, a recently developed tyrosine kinase inhibitor with switch-control abilities, can inhibit both primary and secondary activation of KIT (KIT proto-oncogene receptor tyrosine kinase) and platelet-derived growth factor receptor alpha (PDGFRA) mutants, which contribute to gastrointestinal stromal tumor progression. Methods: In this study, a high-performance liquid chromatography–tandem mass spectrometry method to measure the concentrations of ripretinib and its active desmethyl metabolite DP-5439 in human plasma was developed and validated. Plasma samples were extracted and recovered by precipitation with acetonitrile containing the internal standard and diluted with acetonitrile before analysis. Ripretinib and DP-5439 were separated using chromatography on a Waters ACQUITY UPLC HSS T3 column (2.1 mm × 50 mm, 1.8 μm) with gradient elution using 0.1% formic acid and 5 mM ammonium formate in water as mobile phase A and acetonitrile as mobile phase B. The mobile phase was set to a flow rate of 0.5 mL/min. Results: The calibration curves were linear across the following concentration range: 7.5 to 3000 ng/mL for ripretinib and 10 to 4000 ng/mL for DP-5439. The intraday and interday precisions were approximately 15% for all analytes in the quality control samples. The relative matrix effects in extracted plasma samples (90.3%–108.8% at different levels) were considered acceptable. Conclusions: This method will be a useful tool in oncology to facilitate the further clinical development of ripretinib.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Objective A simple,specific and rapid LC-MS/MS method was established to determine flumatinib and its two major metabolites in human plasma for clinical therapeutic drug monitoring.Methods The determination was performed on an ACQUITY UPLC HSS T3 column(2.1 mm×50 mm,1.8 μm)with mobile phases consisting of acetonitrile and 10 mmol·L-1 ammonium formate(containing 0.1%formic acid)with gradient elution at the flow rate of 0.5 mL·min-1.The elution time was 6 min.The temperature of the column was 38℃.The ion source was electrospray ion source and the scanning mode was multiple reaction monitoring scanning in positive ion mode.Results The mass concentrations of flumatinib and its metabolites(flumatinib M1 and flumatinib M3)have a good linear relationship within the concentration range investigated.The precision and stability of the method are good.The precision is less than 15%,and the relative deviation is within±15%.The extraction recoveries of flumatinib and its metabolites approach nearly 100%.Conclusion The method is simple and sensitive,and can accurately determine the plasma concentration of flumatinib and its metabolites,providing a basis for clinical rational drug use.

Background: Orelabrutinib is a second-generation Bruton tyrosine kinase inhibitor that improves the management of B-cell malignancies. The objective of this study was to develop and validate an LC-MS/MS method for quantifying orelabrutinib in human plasma. Methods: Plasma samples were processed using acetonitrile to precipitate proteins. Ibrutinib-d5 was used as the internal standard. The mobile phase comprised 10 mM ammonium formate containing 0.1% formic acid and acetonitrile (62:38, vol/vol). The multiple reaction monitoring transitions at m/z = 428.1 → 411.2 and 446.2 → 309.2 were selected for orelabrutinib and ibrutinib-d5, respectively, after ionization in the positive mode. Results: Total runtime was 4.5 minutes. The validated curve ranges were 1.00–500 ng/mL. This method exhibited acceptable selectivity, dilution integrity, matrix effects, and recovery. Interrun and intrarun accuracy ranged from −3.4% to 6.5%, and interrun and intrarun precision was between 2.8% and 12.8%. Stability was studied under different conditions. The incurred sample reanalysis demonstrated good reproducibility. Conclusions: The LC-MS/MS method provided a simple, specific, and rapid quantification of orelabrutinib in the plasma of patients with mantle cell lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. The results indicated that orelabrutinib exhibits large variability between individuals and should be prudently used in combination with CYP3A4 inhibitors.

Ibrutinib, orelabrutinib, and zanubrutinib are all Bruton’s tyrosine kinase inhibitors, which have greatly improved the treatment of B-cell malignancies. In this study, an LC-MS/MS method was developed and validated for the determination of orelabrutinib, zanubrutinib, ibrutinib, and its active metabolite dihydrodiol ibrutinib in human plasma. The Ibrutinib-d5 was used as the internal standard. Pretreatment was performed using a simple protein precipitation step using acetonitrile. The ACQUITY UPLC HSS T3 column (2.1×50 mm, 1.8 μm) was used to separate the analytes, and the run time was 6.5 min. The mobile phase consisted of acetonitrile and 10 mM of ammonium formate, which contained 0.1% formic acid. The multiple reactions’ monitoring transitions were selected at m/z 428.1→411.2, 472.2→455.2, 441.1→304.2, 475.2→304.2 and 446.2→309.2 respectively for orelabrutinib, zanubrutinib, ibrutinib, dihydrodiol ibrutinib and ibrutinib-d5 using positive ion electrospray ionization. The standard curves were linear, from 0.400 to 200 ng/mL for ibrutinib and dihydrodiol ibrutinib, 1.00–500 ng/mL for orelabrutinib, and 2.00–1000 ng/mL for zanubrutinib. Selectivity, the lower limit of quantitation, precision, accuracy, matrix effect, recovery, stability, and dilution integrity all met the acceptance criteria of FDA guidance. This method was used to quantify the plasma levels of orelabrutinib, zanubrutinib, ibrutinib, and dihydrodiol ibrutinib in clinical patients.

The feasibility of taking the ratio of 6β-hydroxycortisol (6β-OHCOR) to cortisol (COR) in plasma as a biomarker to reflect CYP3A4 activity needs to be verified, but the low concentration of 6β-OHCOR which is an endogenous substance in plasma presents a challenge for determination. In this study, a Liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was established to simultaneously quantify the COR and 6β-OHCOR in plasma with COR-d4 and 6β-OHCOR-d4 as internal standards (ISs). Plasma samples were treated by protein precipitation using acetonitrile. Separation with a gradient elution within 5 min was achieved on C18+ column utilizing 5 mM ammonium formate and methanol. An API 4,000 MS in multiple reaction monitoring mode with transitions of 407.1 → 361.1 and 423.1 → 347.1 was utilized. Albumin solution was used as a surrogate matrix, with good linearities over the concentration of 1.20-300 ng/mL for COR and 0.0400-10.0 ng/mL for 6β-OHCOR. The precisions for intrarun and interrun were < 6.8%, and the accuracy was fell in the interval of -5.2 to 3.5%. Matrix effect was not found. Recovery was close to 100.0%. Stability was confirmed under the storage and processing conditions. The validated method was applied to evaluate the inhibitory effect of voriconazole to CYP3A by the ratio of 6β-OHCOR to COR.

目的 建立同时测定尿液中咖啡因及3种代谢产物茶碱、副黄嘌呤和可可碱浓度的方法并应用于临床.方法 以咖啡因-13C3-d3为内标,尿液样本经乙腈沉淀蛋白后,采用高效液相色谱-串联质谱(HPLC-MS/MS)技术测定咖啡因及3种代谢产物的浓度.以Waters ACQUITY UPLC? BEH HILIC为色谱柱,60 mmol/L乙酸铵溶液(A)-乙腈(B)为流动相进行梯度洗脱,流速为0.5 mL/min,柱温为38℃,进样量为2 μL.采用电喷雾离子源,以多反应监测模式进行正离子扫描,用于定量分析的离子对分别为m/z 195.1→110.0(咖啡因)、m/z 181.1→124.0(茶碱)、m/z 181.1→124.0(副黄嘌呤)、m/z 181.1→138.0(可可碱)、m/z 198.1→140.1(内标).采用上述方法测定19例早产儿呼吸暂停(AOP)患儿尿液中咖啡因及3种代谢产物的浓度.结果 咖啡因、茶碱、副黄嘌呤、可可碱检测质量浓度的线性范围分别为0.200～200、0.050～50.0、0.050～50.0、0.100～100 μg/mL(r均大于0.990),定量下限分别为0.200、0.050、0.050、0.100 μg/mL;日内、日间精密度的RSD均不高于10.37%,基质因子为85.68%～109.90%,提取回收率为93.53%～109.40%(RSD均小于15%),稳定性试验的RSD均小于15%.19例AOP患儿尿液中咖啡因及3种代谢产物的质量浓度分别为(27.346±7.951)、(0.351±0.223)、(0.428±0.395)、(0.472±0.374)μg/mL.结论 所建HPLC-MS/MS法操作简单、灵敏度高,可用于AOP患儿尿液中咖啡因及3种代谢产物浓度的测定.