Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review.

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization.

AIMS: The aim of this study was to explore the influence and possible mechanisms of pharmacokinetics-related gene polymorphisms, especially CYP2C19 polymorphisms, and non-genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population. METHODS: Clinical studies were performed by collecting more than one VRC trough concentration and C-reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients. RESULTS: Results of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cmin ss/D in patients with no to mild inflammation (R2 = 0.12, P < .001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T-Bil) levels (R2 = 0.19, P < .001). In non-clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0-t) ) of VRC in the inflammatory group was significantly longer than that in the control group (P < .001), which may be due to down-regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3 pathway. CONCLUSIONS: Therefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T-Bil on VRC metabolism should not be disregarded.

Clinical Benefit, Price, and Uptake for Cancer Biosimilars vs Reference Drugs in China: A Systematic Review and Meta-Analysis.

Importance: The high cost of biologics used to treat cancer has been an increasing burden in the world. In China, the recent approval of cancer biosimilar drugs to resolve this problem is promising, but evidence of clinical benefits, price, and uptake for these drugs is still lacking. Objectives: To compare characteristics of pivotal clinical trials in China and other countries for biosimilars of bevacizumab, rituximab, and trastuzumab and investigate the efficacy or effectiveness, safety, and immunogenicity outcomes of cancer biosimilars compared with reference drugs by meta-analysis. Data Sources: For this systematic review and meta-analysis, PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched for published studies from database inception to February 1, 2023, using the search topics (cancers) AND (biosimilars). Study Selection: Randomized clinical trials and cohort studies that included patients with cancer were included. Data Extraction and Synthesis: Two authors independently extracted the outcome estimates and characteristics for each study. A random-effects meta-analysis was performed to summarize the relative estimates with 95% CIs. This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Main Outcomes and Measures: Clinical trial characteristics were collected for biosimilars of bevacizumab, rituximab, and trastuzumab. The relative estimates of efficacy or effectiveness (objective response rate, progression-free survival, and overall survival), safety, and immunogenicity outcomes were analyzed for biosimilars vs reference drugs. The weighted average price and uptake rate were evaluated for biosimilars relative to their reference drugs between 2015 and 2022. Results: A total of 39 RCTs (involving 18 791 patients) and 10 cohort studies (involving 1998 patients) were included. The biosimilars of bevacizumab (16 RCTs; risk ratio [RR], 0.97; 95% CI, 0.93-1.01; P = .17), rituximab (12 RCTs; RR, 1.03; 95% CI, 0.98-1.08; P = .70), and trastuzumab (9 RCTs: RR, 1.04; 95% CI, 0.97-1.12; P = .29) met equivalence with reference biologics in regard to the objective response rate. The results summarized from cohort studies were consistent with those from RCTs. In 2022, cancer biosimilars were priced at 69% to 90% of the costs for the reference drugs, and their uptake reached 54% to 83% in China. Conclusions and Relevance: This systematic review and meta-analysis indicated that cancer biosimilars provided comparable clinical benefits at lower prices compared with reference drugs. These findings suggest the potential feasibility of expediting the transition from reference drugs to biosimilars to benefit more patients with cancer.

Evidence of pre-approval clinical trial supporting the granted conditional approval for novel cancer drugs in China between 2015 and 2022.

Background: Accelerated approval (AA) of novel anticancer drugs based on surrogacy has attracted considerable concern globally. China National Medical Products Administration (NMPA) also established a similar conditional approval (CA) program to accelerate the approval of novel drugs to address unmet medical needs. This cross-sectional study aimed to evaluate the pre-approval clinical trial evidence and potential challenge of cancer drugs receiving CA in China from policy implementation to 2022. Methods: The cancer drugs (initial and supplemental indications) granted CA between January 1, 2015 and December 31, 2022 using the public database of the NMPA were analyzed. The characteristics of the cancer drugs received CA were described. Primary efficacy endpoints and safety derived from the pre-approval clinical trial, including response rates (RR), progression-free survival (PFS), overall survival (OS), treatment-related serious adverse events (SAE) and Grade ≥3 adverse events (AEs) were quantitatively estimated by meta-analysis. Besides, the correlation between the surrogate endpoints and OS was estimated by the reported trial-level correlation analysis. Findings: The NMPA approved 72 cancer indications (56 new molecular entities) with CA between 2015 and 2022. 34 indications (47%) were also approved by the FDA or EMA. 74% (53/72) of cancer indications were based on a single-arm trial design while 26% (19/72) for randomized controlled trials. The pooled RR was 0.50 (95% CI: 0.45-0.55, I2 = 96%) with significant differences across cancer types and targets while the pooled hazard risk was 0.39 (95% CI: 0.28-0.53, I2 = 89%) for PFS and 0.67 (95% CI: 0.61-0.73, I2 = 0%) for OS. The pooled treatment-related SAE and Grade ≥3 AEs from single-arm designs resulted in 15% and 25%, respectively. In randomized controlled trials, the pooled treatment-related SAE and Grade ≥3 AEs observed in CA drugs and the control groups were comparable. Surrogate endpoints were widely used as the primary efficacy endpoints in the pre-approval pivotal clinical trials with 75% (54/72) for RR, 10% (7/72) for PFS, and 4% (3/72) for others. Of these, 27% (17/63) of the surrogate endpoints reported a trial-level correlation with OS; three reported high correlation (r ≥ 0.85), two reported moderate correlation (0.70 ≤ r < 0.85) and 12 reported low correlation (r < 0.70). Interpretation: The majority of novel cancer drugs that received CA were based on RR designed for single-arm trials. The reported correlations of treatment effect between the surrogate endpoints and OS used for CA were limited. Our findings highlighted that the introduction of OS or quality of life based on RCT in confirmatory clinical trials as much as feasible was essential to ensure the clinical benefits for patients. Funding: This study was supported by postdoctoral fellowship from Tsinghua-Peking Joint Centers for Life Sciences (CLS).

Evaluation of clinical trial designs for novel anticancer drugs in China: A cohort study of drugs approved between 2015 and 2021.

China has greatly facilitated the approval of many novel anticancer drugs since the drug regulatory reform in 2015. Here, we review the clinical trial designs used in pivotal clinical trials for approved anticancer agents in China from 2015 to 2021. Overall, 79 new molecular entities (NMEs) with 140 anticancer indications were identified. Of these, adaptive randomized controlled trial (RCT) designs were used most frequently in pivotal clinical trials (n = 83, 49%), followed by single-arm design trials (n = 52, 30%) and traditional RCT design trials (n = 36, 21%). The single-arm trials and adaptive RCTs can significantly shorten clinical trial duration compared with traditional RCT designs. Our findings showed that novel clinical trial designs were widely used in China to accelerate the launch of anticancer drugs.

The price, efficacy, and safety of within-class targeted anticancer medicines between domestic and imported drugs in China: a comparative analysis.

Background: Affordability to novel anticancer drugs has become a major health issue in China. It is encouraging to note that China initiated its drug regulatory reform and national price negotiation policies since 2015. As a growing number of domestic within-class targeted anticancer drugs are approved in China, it is expected that this may reduce the price of novel anticancer drugs and improve the affordability of anticancer drugs. This study aimed to evaluate the price, efficacy, and safety of the within-class anticancer drugs between domestic and imported drugs approved in China from 2010 to 2022. Methods: The domestic and imported within-class targeted drugs for solid cancers approved in China between 2010 and 2022 were extracted. We classified it as a class of anticancer drugs based on the same indication and similar biological mechanism. The published literature derived from pivotal clinical trials of these domestic and imported drugs was identified based on the review report and the latest labels issued by the China National Medical Products Administration. We evaluated the monthly treatment price at launch and the latest (2022), primary efficacy endpoint and safety between domestic and imported anticancer drugs. Meta-analyses were further employed to evaluate the efficacy and safety of the domestic and imported anticancer drugs, including pooled hazard ratios (HR) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR) for solid cancers, and relative risk for serious adverse events (SAE) and Grade ≥3 adverse events (AEs). Findings: In our cohort study, 12 within-class anticancer drugs with 7 cancer diseases were analyzed, including 18 domestic (21 indications; 21 pivotal trials) and 18 imported (21 indications; 27 pivotal trials) novel anticancer drugs, respectively. The median monthly treatment price of domestic and imported drugs from the years of launch to 2022 had significantly decreased by 71% and 62%, respectively. Moreover, the median monthly treatment price of domestic targeted anticancer drugs on the market at launch ($3786 vs. $5393, P = 0.007) and the latest ($1222 vs. $2077, P = 0.011) was significantly lower than that of imported drugs. No significant differences in median PFS gains (9.0 vs. 11.0 months; P = 0.24), OS gains (9.3 vs 10.6 months; P = 0.66), and ORR (57% vs 62%, P = 0.77) of targeted anticancer drugs in their pivotal trials were observed between the domestic and imported drugs. Additionally, there was no significant difference between domestic and imported drugs in the incidence of SAE (23% vs. 24%; P = 0.41) and Grade ≥3 AEs (59% vs. 57%; P = 0.45). These findings were also further confirmed in the meta-analyses for primary efficacy endpoints and safety outcomes. Interpretation: The prices of both domestic and imported anticancer drugs significantly decreased after market entry mainly due to the role of national price negotiations. The median monthly treatment price of domestic within-class targeted anticancer drugs was significantly lower than that of imported drugs. Furthermore, the efficacy and safety of domestic anticancer drugs were comparable to that of imported drugs. This evidence implicated that the development of within-class anticancer drugs with national price negotiations in China significantly improved the affordability for patients. Funding: This study was supported by postdoctoral fellowship from Tsinghua-Peking Joint Centers for Life Sciences (CLS).

Assessment of the Delay in Novel Anticancer Drugs between China and the United States: A Comparative Study of Drugs Approved between 2010 and 2021.

Access to anticancer drugs has been a critical health issue in China for many years. We retrospectively analyzed the novel anticancer drugs approved in the United States (US) between 2010 and 2021 to assess the evolving landscape of the drug lags in China by taking Japan and the European Union (EU) as comparisons. The absolute and relative lags of drug initial approval (DIA) and indication approval were calculated between China (or Japan/European Union) and the US based on the US approval date of novel agents, the duration was divided into 2010-2015 and 2016-2021. Overall, 123 (244 indications) new molecular entities (NMEs) approved in the United States were included, of which 58 (94 indications), 72 (128 indications), and 99 (170 indications) NMEs were also approved in China, Japan, and the European Union, respectively. The absolute lags of DIA and indications for approval in China improved dramatically in 2016-2021 compared with 2010-2015. Similarly, the relative DIA and indication approval lags in China decreased significantly in 2016-2021. The median review lags for DIA of China in 2016-2021 were comparable to Japan but dramatically lower than that of the European Union. Nevertheless, China had significantly longer median submission lags for DIA (28 months) in 2016-2021 than that of Japan (6 months) and the European Union (1 month). Although the absolute and relative lags of anticancer drugs in China had been initially addressed, 53% of NMEs and 61% of indications were still not approved for cancers in China compared with the United States. Therefore, China should adopt steps to further reduce drug lags.

Assessment of the breakthrough-therapy-designated drugs granted in China: A pooled analysis 2020-2022.

The implementation of China's breakthrough therapy designation (BTD) program in 2020 to accelerate drug development for serious or life-threatening diseases has attracted widespread attention. Here, we review the characteristics of BTD and its implementation in China. Overall, 78 drugs with 82 BTDs were collected from the program's inception to April 2022. The time to obtain BTD for imported new drugs was significantly faster than for domestic ones. The BTDs granted for domestic new drugs were highly concentrated in oncology. The BTD drugs can reduce clinical trial and review times compared with non-BTD drugs. The implementation of BTD is expected to expedite the development of new drugs to address unmet clinical needs in China.

Analysis of Patent and Regulatory Exclusivity for Novel Agents in China and the United States: A Cohort Study of Drugs Approved Between 2018 and 2021.

Patent and regulatory exclusivity shall constitute incentives for pharmaceutical companies to develop new drugs. This study aims to investigate the differences in the patent term extension (PTE) and regulatory exclusivity between China and the United States, and to evaluate their potential impact on the market exclusivity period of novel drugs. Small-molecule novel drugs with their first indication approved in China and the United States between 2018 and 2021 were evaluated regarding their PTE and regulatory exclusivity. The PTE length of the China-approved drugs was calculated by simulation, whereas that of the US-approved drugs was extracted from the United States Patent and Trademark Office. Thirty-two and 107 novel drugs approved in China and the United States, respectively, were included in the study. The PTE length of the US-approved drugs calculated by the China-PTE method was significantly longer than that calculated by the US-PTE method. Patent extensions should be granted for 91% of new drugs in China and 82% in the United States. The simulated median PTE length of novel drugs approved in China was significantly higher than that of the United States (5.0 vs. 2.9 years, P < 0.05). It can be expected that the implementation of the PTE policy in China would significantly extend the period of market exclusivity for novel drugs similar to that of the United States. China should fully evaluate the potential impact of the PTE policy on the market exclusivity of novel drugs and provide better incentives to the development of novel drugs in addressing unmet clinical needs when developing its regulatory exclusivity policy.

Effectiveness and Economic Evaluation of Polyene Phosphatidyl Choline in Patients With Liver Diseases Based on Real-World Research.

Aims: Liver disease has high prevalence, number, and disease burden in China, and polyene phosphatidyl choline (PPC) is a widely used liver protective drug. We aim to explore the effectiveness and economy of PPC in patients with liver diseases based on real-world research and compare with other hepatoprotective drugs. Methods: This is a "three-phase" study from three medical centers, including descriptive study of patients using PPC injection, self-control case study of patients using PPC injection, and specific-disease cohort study of patients using PPC injection or control drugs. The major measurements of liver function for effectiveness analysis were the alanine transaminase (ALT) level changes and recovery rate. The main statistical methods were Wilcoxon signed rank test, χ 2 test, and Mann-Whitney U test. Propensity score matching was applied to reduce bias. Cost-effectiveness analysis, cost minimization analysis, and sensitivity analysis were used for economic evaluation. Results: PPC alone or in combination with glutathione and magnesium isoglycyrrhizinate shows less total hospitalization cost (p < 0.05) and smaller cost-effectiveness ratio and was effective in protecting liver function, especially in patients with liver transplantation or postoperation of nontumor liver disease (ALT decreased significantly after PPC treatment; p < 0.05). Glutathione and magnesium isoglycyrrhizinate combined with PPC could enhance the protective function of liver. Conclusion: PPC was an effective and economic liver protective drug in patients with specific liver diseases, and PPC could enhance the liver protective function of glutathione and magnesium isoglycyrrhizinate.

Therapeutic Drug Monitoring and Individualized Medicine of Dasatinib: Focus on Clinical Pharmacokinetics and Pharmacodynamics.

Dasatinib is an oral second-generation tyrosine kinase inhibitor known to be used widely in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). Notably, although a high pharmacokinetic variability in patients and an increased risk of pleural effusion are attendant, fixed dosing remains standard practice. Retrospective studies have suggested that dasatinib exposure may be associated with treatment response (efficacy/safety). Therapeutic drug monitoring (TDM) is gradually becoming a practical tool to achieve the goal of individualized medicine for patients receiving targeted drugs. With the help of TDM, these patients who maintain response while have minimum adverse events may achieve long-term survival. This review summaries current knowledge of the clinical pharmacokinetics variation, exposure-response relationships and analytical method for individualized dosing of dasatinib, in particular with respect to therapeutic drug monitoring. In addition, it highlights the emerging insights into several controversial issues in TDM of dasatinib, with the aim of presenting up-to-date evidence for clinical decision-making and insights for future studies.

The Comparison of Plasma and Cerebrospinal Fluid R(-)- and S(+)-Flurbiprofen Concentration After Intravenous Injection of Flurbiprofen Axetil in Human Subjects.

Background: Flurbiprofen axetil is a prodrug that releases the active substance through enzymatic removal of the ester moiety. It is formulated through encapsulation in a lipid microsphere carrier, and widely used to treat perioperative pain. Here, we studied the distribution of R (-)- and S (+)-flurbiprofen in human plasma and cerebrospinal fluid (CSF) after intravenous injection of flurbiprofen axetil. Methods: A total of 70 adult patients undergoing elective lower limb surgery under spinal anesthesia were given a single intravenous injection of 100-mg flurbiprofen axetil. The patients were randomly assigned to 10 groups for plasma and CSF sampling at 10 time points (5-50 min) after subarachnoid puncture and before actual spinal anesthesia. R (-)- and S (+)-flurbiprofen and CSF/plasma ratio were determined by liquid chromatography-tandem mass spectrometry. Results: R (-)-flurbiprofen concentration ranged from 2.01 to 10.9 µg/mL in plasma and 1.46-34.4 ng/mL in CSF. S (+)-flurbiprofen concentration ranged from 1.18 to 10.8 µg/mL in plasma and from 2.53 to 47 ng/mL in CSF. In comparison to S (+)-flurbiprofen, R (-)-flurbiprofen concentration was significantly higher in plasma at all time points (p < 0.05) except at 30 or 40 min, and lower in CSF at all time points (p < 0.05) except at 10, 15 and 40 min. Analysis after correcting drug concentration for body mass index also revealed higher plasma and lower CSF R (-)-flurbiprofen concentration. In comparison to S (+)-flurbiprofen, AUC0-50 for R (-)-flurbiprofen was larger in plasma and smaller in CSF (p < 0.05 for both), and accordingly smaller CSF/plasma AUC0-50 ratio (p < 0.05). There was a positive correlation between R (-)-flurbiprofen concentration and S (+)-flurbiprofen concentration in plasma (r = 0.725, p < 0.001) as well as in CSF (r = 0.718, p < 0.001), and a negative correlation between plasma and CSF concentration of S (+)-flurbiprofen (r = -0.250, p = 0.037), but not R (-)-flurbiprofen. Conclusion: Distribution of R (-)- and S (+)-flurbiprofen in plasma and CSF differed significantly. Penetration of R (-)-flurbiprofen into the CNS was lower than S (+)-flurbiprofen.

The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

BACKGROUND: Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. OBJECTIVES: The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. METHODS: Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. RESULTS: Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2  = 44%, p < .00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2  = 46%, p < .00001) had significantly higher voriconazole Cmin (µg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2  = 0%, p = .0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2  = 22%, p = .003). Similarly, the Cmin /D (µg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2  = 0%, p = .002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2  = 0%, p = .003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2  = 0%, p < .00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2  = 50%, p = .005). CONCLUSIONS: Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.

Differential effects of C-reactive protein levels on voriconazole metabolism at three age groups in allogeneic hematopoietic cell transplant recipients.

The aim of this study was to evaluate the impact of inflammation on voriconazole (VRCZ) metabolism at three age groups in the allogeneic hematopoietic cell transplant recipients of the Chinese population. The study was performed with collecting more than one VRCZ trough concentration and C-reactive protein (CRP) levels. Longitudinal analysis, correlation and comparative analysis were conducted to evaluate. A total of 104 patients with 386 VRCZ trough concentration and CRP level measured on the same day were collected. For children, CRP levels significantly associated with VRCZ pharmacokinetics in age 11-18 years but not in age 2-10 years. For adults, VRCZ concentrations were increased slightly by 0.006 mg/L when every 1 mg/L increased in CRP levels. Additionally, meropenem and inflammation might work together to cause a higher VRCZ concentration. Therefore, therapeutic drug monitoring of VRCZ should be warranted at age >10 years in allogeneic hematopoietic cell transplant recipients with elevated CRP level.

Differential Impacts of Azole Antifungal Drugs on the Pharmacokinetic Profiles of Dasatinib in Rats by LC-MS-MS.

BACKGROUND: Dasatinib, as an oral multi-targeted inhibitor of BCR-ABL and SRC family kinases, has been widely used for the treatment of Philadelphia Chromosome Positive Leukemias in imatinib-acquired resistance and intolerance. The study aimed to develop and validate a simple and robust assay with a small volume of plasma based on liquid chromatography coupled with tandem mass spectrometry to determine the concentration of dasatinib and to investigate the impact of the cytochrome 3A4 inhibitors, including ketoconazole, voriconazole, itraconazole and posaconazole, on the pharmacokinetics of dasatinib in rats. METHODS: Thirty rats were divided randomly into five groups, control group (0.5% carboxymethylcellulose sodium), ketoconazole (30 mg/kg) group, voriconazole group (30 mg/kg), itraconazole group (30 mg/kg) and posaconazole group (30 mg/kg). After 150 µL blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h and precipitated with acetonitrile, the plasma concentration of dasatinib was determined through Fluoro- Phenyl column (150 mm×2.1 mm, 3 µm) in a positive ionization mode. RESULTS: The results suggested that ketoconazole, voriconazole, and posaconazole could increase the AUC0-t of dasatinib to varying degrees while significantly reducing its clearance. However, there was no significant impact on the pharmacokinetics of dasatinib, co-administered with itraconazole except for the CL and MRT0-t of dasatinib. Additionally, voriconazole could significantly increase Cmax of dasatinib by approximately 4.12 fold. CONCLUSION: These data indicated that ketoconazole, posaconazole and voriconazole should be cautiously co-administered with dasatinib or close therapeutic drug monitoring of dasatinib concentration, which might cause the drug-drug interaction.

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation.

Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1-16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.

The impact of azole antifungal drugs on imatinib metabolism in human liver microsomes.

1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole. The relevant assay was also performed to screen mechanism-based inhibitors (MBI). 3. The inhibition ability of 1-OH midazolam formation from midazolam based on IC50 values was ketoconazole (0.09 µM)>itraconazole (0.31 µM)> posaconazole (0.68 µM)>voriconazole (2.10 µM) > fluconazole (8.90 µM). Similarly, the rank order of inhibitory effects on formation of N-desmethyl imatinib from imatinib was ketoconazole (4.58 µM)>itraconazole (17.45 µM)> posaconazole (31.02 µM)> voriconazole (367.9 µM) >fluconazole (1.11 mM). Posaconazole and itraconazole displayed evidence of MBI. Additionally, imatinib was also shown as a MBI of CYP3A with IC50 value of 5.40 µM against the midazolam. 4. The significant difference in IC50 values of midazolam and imatinib inhibited by azole antifungal agents was observed. The role of CYP2C8 in imatinib metabolism and imatinib autoinhibits CYP3A activity may explain this difference. Our findings suggest that the azole antifungal agents might have limited impacts on imatinib exposure by CYP3A activity.