Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells.

Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite a persistently high rate of mitotic errors that cause aneuploidy, or chromosome imbalances. Consequently, to maintain genome stability, aneuploidy must inhibit hPSC proliferation, but the mechanisms are unknown. Here, we surprisingly find that homogeneous aneuploid populations of hPSCs proliferate unlike aneuploid non-transformed somatic cells. Instead, in mosaic populations, cell non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells. Aneuploid hPSCs with lower Myc or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain a selective advantage when Myc and p53 relative abundance switches. Thus, although hPSCs frequently missegregate chromosomes and inherently tolerate aneuploidy, Myc- and p53-driven cell competition preserves their genome integrity. These findings have important implications for the use of hPSCs in regenerative medicine and for how diploid human embryos are established despite the prevalence of aneuploidy during early development.

Population Pharmacokinetics of CMAB008 (an Infliximab Biosimilar) and Remicade® in Healthy Subjects and Patients with Moderately to Severely Active Rheumatoid Arthritis.

INTRODUCTION: CMAB008 is a monoclonal antibody developed as a biosimilar to infliximab (Remicade®, Janssen). The pharmacokinetic characteristics of CMAB008 and Remicade® in healthy subjects and patients with moderately to severely active rheumatoid arthritis (RA) were investigated using a population modeling approach, and the pharmacokinetic similarity of CMAB008 to Remicade® was assessed. METHODS: The population pharmacokinetic model was developed on the basis of intensive pharmacokinetic data from a phase 1 study in healthy male subjects and combined intensive and sparse pharmacokinetic data from a phase 3 study in patients with RA. RESULTS: A two-compartment model with first-order elimination adequately described CMAB008 and Remicade® concentration data in healthy subjects and patients with RA. The analysis of covariates identified anti-drug antibody (ADA), neutralizing antibody (NAB), real-time body weight (BWT), and real-time albumin (ALB) as significant covariates on clearance, and BWT was also a significant covariate for the central volume of distribution. The treatment type (CMAB008 versus Remicade®) and the study population (healthy subjects versus patients with RA) were not identified as significant covariates on the pharmacokinetics of infliximab, demonstrating pharmacokinetic similarity between CMAB008 and Remicade® in both study populations. The effect of BWT and ALB changes on exposures to infliximab was within the acceptable range, suggesting that the 3 mg/kg regimen is appropriate in clinical practice for patients with RA and BTW and ALB distribution within the range evaluated in the current analysis. CONCLUSIONS: The pharmacokinetic characteristics were similar between CMAB008 and Remicade® in healthy subjects and patients with RA. CMAB008 can be considered bioequivalent to Remicade®. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT04779892, NCT03478111.

A pluripotent developmental state confers a low fidelity of chromosome segregation.

During in vitro propagation, human pluripotent stem cells (hPSCs) frequently become aneuploid with incorrect chromosome numbers due to mitotic chromosome segregation errors. Yet, it is not understood why hPSCs exhibit a low mitotic fidelity. Here, we investigate the mechanisms responsible for mitotic errors in hPSCs and show that the primary cause is lagging chromosomes in anaphase with improper merotelic microtubule attachments. Accordingly, short-term treatment (<24 h) with small molecules that prolong mitotic duration or destabilize chromosome microtubule attachments reduces merotelic errors and lagging chromosome rates, although hPSCs adapt and lagging chromosome rates rebound upon long-term (>24 h) microtubule destabilization. Strikingly, we also demonstrate that mitotic error rates correlate with developmental potential decreasing or increasing upon loss or gain of pluripotency, respectively. Thus, a low mitotic fidelity is an inherent and conserved phenotype of hPSCs. Moreover, chromosome segregation fidelity depends on developmental state in normal human cells.

Effect of Ultrasound Image-Guided Nerve Block on the Postoperative Recovery Quality of Patients with Tibial Fractures Using the Concept of Enhanced Recovery after Surgery.

This study was aimed at investigating the clinical effect of ultrasound-guided nerve block based on the concept of enhanced recovery after surgery (ERAS) for postoperative anesthesia in patients with tibial fractures. The noise-reduction processing was introduced in ultrasound images to adjust the ultrasound clarity of the patient. A total of 177 patients with tibial fractures in our hospital were retrospectively analyzed and divided into OG group (general anesthesia combined with nerve block, 78 cases), C1 group (simple general anesthesia, 27 cases), C2 group (ultrasound-guided nerve block combined with general anesthesia, 10 cases), and C3 group (62 cases of spinal-epidural anesthesia). The effect of anesthesia and postoperative recovery time of patients in each group were analyzed. The wake-up time of the OG group was significantly shorter than that of the other three groups (P < 0.05). The doses of propofol and remifentanil in the OG group were much lower than those in the other groups (P < 0.05). After the ultrasound image was processed with noise reduction, the image showed the lesion more clearly. The excellent and good rates of OG group, C1 group, C2 group, and C3 group were 89.86%, 62.73%, 75.37%, and 61.07%, respectively. The Ramsay sedation score and anesthesia satisfaction in the OG group were obviously higher than those in the other groups, but there was no significant difference (P > 0.05). The visual analogue scale (VAS) scores of the OG group at 12 h, 24 h, and 36 h after the surgery were 4.52 ± 0.41, 4.72 ± 0.24, and 4.81 ± 0.74, respectively, which were significantly higher than those of the other three groups (P < 0.05). On the basis of ERAS, ultrasound-guided nerve block combined with general anesthesia can improve the perioperative pain in patients with tibial fractures and significantly shorten the time for the wake-up time. In addition, it was safe and reliable, so it was worthy of clinical promotion.

Population pharmacokinetics of omeprazole in obese and normal-weight adults.

BACKGROUND: Obesity is related to many pathophysiological changes that may result in altered drug disposition. Omeprazole is the most common option utilized for acid-related disorders ; however, the pharmacokinetic (PK) and dosing recommendations for the obese patient population are lacking. METHODS: Data from 40 healthy subjects with normal weights and data from 61 obese subjects were included. The subjects all received a single dose of 20 mg of omeprazole. Nonlinear mixed effects modeling were performed to characterize the effect of obesity on omeprazole PK. RESULTS: A one-compartment model with twelve transit absorption compartments and linear elimination described the data best. A lower clearance was observed in the obese patient population than in the normal-weight subjects. Moreover, the CYP2C19 genotype was identified as a significant covariate for clearance. CONCLUSION: Given the potential adverse events related to high exposure to proton pump inhibitors over time, obese patients may require a lower dose of omeprazole for long-term treatment. Further studies in obese individuals into other drugs metabolized by CYP2C19 are warranted, especially those with a narrow therapeutic window. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn identifier is ChiCTR2100046578; www.chinadrugtrials.org.cn identifier is CTR20190175.

Fixed dosing of kukoamine B in sepsis patients: Results from population pharmacokinetic modelling and simulation.

AIMS: To assess the appropriateness of the body weight or fixed dosing regimen, a population pharmacokinetic (PopPK) model of kukoamine B has been built in sepsis patients. METHODS: Plasma concentrations of kukoamine B and the covariates information were taken from 30 sepsis patients assigned into 0.06 mg/kg, 0.12 mg/kg and 0.24 mg/kg groups in a Phase IIa clinical trial. The PopPK model was built using a nonlinear mixed-effect (NLME) modelling approach. Based on the final model, PK profiles were respectively simulated 500 times applying the body weight and renal function information of 12 sepsis patients from the 0.24 mg/kg group on the body weight or the fixed dosing regimen. For each dosing regimen, PK profiles of 6000 virtual patients were obtained. Statistical analyses for Cmax and Cmin were performed. If the biases of Cmax and Cmin can all meet the criteria of ±15%, the fixed dosing regimen can substitute for the body weight dosing regimen. RESULTS: The PopPK model was successfully developed using the NLME approach. A bi-compartmental model was selected as the basic model. Renal function was identified as a statistically significant covariate of systemic clearance with the objective function value (OFV) decreasing 8.6, resulting in a 5.2% decrease in inter-individual variability (IIV) of systemic clearance. Body weight was not identified as a statistically significant covariate. Simulation results demonstrated two methods had a bias of 8.1% for Cmax , and 8.6% for Cmin . Furthermore, PK variability was lower on the fixed dosing regimen than the body weight regimen. CONCLUSIONS: Based on the simulation results, a fixed dosing regimen was recommended in the subsequent clinical trials.

Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis.

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (Ka ; 9.85 h-1 ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.

U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors.

PURPOSE: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib. PATIENTS AND METHODS: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity. RESULTS: A total of 46 patients were enrolled. Steady-state peak concentration (C max) and exposure (AUC0-8) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1+ NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation. CONCLUSIONS: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.

Violence against health care workers in China, 2013-2016: evidence from the national judgment documents.

BACKGROUND: Incidents of patient-initiated workplace violence against health care workers have been a subject of substantial public attention in China. Patient-initiated violence not only represents a risk of harm to health care providers but is also indicative of general tensions between doctors and patients which pose a challenge to improving health system access and quality. This study aims to provide a systematic, national-level characterization of serious workplace violence against health care workers in China. METHODS: This study extracted data from the China Judgment Online System, a comprehensive database of judgment documents. Three key phrases, "criminal case," "health care institution," and "health care worker" were used to search the China Judgment Online System for relevant cases between January 1, 2013, and December 31, 2016. Data extracted from identified cases was used to document the occurrence, the degree of risk, and the factors associated with serious workplace violence. RESULTS: In total, 459 criminal cases involving patient-initiated workplace violence against health care workers in China were reported and processed. The analysis revealed geographic heterogeneity in the occurrence of serious workplace violence, with lower incidence in western provinces compared to central and eastern provinces. Primary hospitals experienced the highest rates of serious workplace violence and emergency departments and doctors were at higher risk compared with other departments and health workers. Perpetrators were primarily male farmers aged 18 to 44 with low levels of education. The most frequently reported reasons of serious patient-initiated workplace violence included perceived medical malpractice by the perpetrator after the death of a patient, death of a patient with no other reason given, failures of the compensation negotiations after the death of a patient, and dissatisfaction with the treatment outcomes. CONCLUSIONS: Serious workplace violence against providers varies across regions and types of health care institutions in China. Perception of low-quality care is the most reported reason for violence. Efforts should be made to improve quality of care in the low-level health institutions and strengthen the doctor-patient communication during the whole course of service.

Hospital competition and the expenses for treatments of acute and non-acute common diseases: evidence from China.

BACKGROUND: Because there is heterogeneity in disease types, competition among hospitals could be influenced in various ways by service provision for diseases with different characteristics. Limited studies have focused on this matter. This study aims to evaluate and compare the relationships between hospital competition and the expenses of prostatectomies (elective surgery, representing treatments of non-acute common diseases) and appendectomies (emergency surgery, representing treatments of acute common diseases). METHODS: Multivariable log-linear models were constructed to determine the association between hospital competition and the expenses of prostatectomies and appendectomies. The fixed-radius Herfindahl-Hirschman Index was employed to measure hospital competition. RESULTS: We collected data on 13,958 inpatients from the hospital discharge data of Sichuan Province in China from September to December 2016. The data included 3578 prostatectomy patients and 10,380 appendectomy patients. The results showed that greater competition was associated with a lower total hospital charge for prostatectomy (p = 0.006) but a higher charge for appendectomy (p <  0.001). The subcategory analysis showed that greater competition was consistently associated with lower out-of-pocket (OOP) and higher reimbursement for both surgeries. CONCLUSIONS: Greater competition was significantly associated with lower total hospital charges for prostatectomies, while the opposite was true for appendectomies. Furthermore, greater competition was consistently associated with lower OOP but higher reimbursement for both surgeries. This study provides new evidence concerning the heterogeneous roles of competition in service provision for non-acute and acute common diseases. The findings of this study indicate that the pro-competition policy is a viable option for the Chinese government to relieve patients' financial burden (OOP). Our findings also provide references and insights for other countries facing similar challenges.

Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis
.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This analysis characterized the pharmacokinetics (PK) of tofacitinib in adult patients with active PsA and evaluated the impact of covariates (baseline characteristics) on the disposition of tofacitinib. MATERIALS AND METHODS: Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439)). This analysis included 650 tofacitinib-treated patients with 3,252 tofacitinib plasma concentration measurements. Tofacitinib PK was described using a one-compartment disposition model parameterized in terms of apparent oral clearance (CL/F) and apparent volume of distribution (V/F) with first-order absorption rate (Ka) and a lag time. Covariates evaluated were baseline age, baseline body weight, sex, race, ethnicity, baseline creatinine clearance (BCCL), and baseline C-reactive protein. RESULTS: The estimates (95% confidence interval) of PK model parameters of a reference patient were CL/F: 20.4 (18.6, 21.8) L/h; V/F: 110 (108, 113) L; and Ka: 13.8 (12.1, 16.6)/h. Among the covariates, only BCCL led to clinically relevant changes in exposure; however, this was consistent with the known contribution of renal excretion to the total clearance of tofacitinib (~ 30%). CONCLUSION: Tofacitinib did not require dose modification or restrictions for age, body weight, sex, race, ethnicity, or baseline disease severity in patients with active PsA based on the magnitude of exposure relative to a reference patient. Dosing adjustments for renal impairment were derived from a separate phase 1 study.

Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study.

Objective: Tofacitinib is an oral Janus kinase inhibitor for treatment of RA. We compared tofacitinib modified-release (MR) 11 mg once daily (QD) with tofacitinib immediate-release (IR) 5 mg twice daily (BID) in Japanese patients with RA and inadequate response to MTX. Methods: Phase III, randomized, double-blind, double-dummy, 12-week study. Patients were randomized to tofacitinib MR 11 mg QD (n = 104) or IR 5 mg BID (n = 105), with stable MTX. Compliance was based on returned pill counts. The primary objective was to demonstrate non-inferiority of MR 11 mg QD to IR 5 mg BID. Non-inferiority was declared if the upper bound of the two-sided 95% CI for the difference in change from baseline in DAS28-4(CRP) at week 12 was <0.6. Results: At week 12, with tofacitinib MR 11 mg QD and IR 5 mg BID, respectively, the change from baseline in least squares mean DAS28-4(CRP) was -2.43 and -2.85; the mean difference was 0.43 (95% CI 0.17, 0.69). Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met. Improvement of DAS28-4(CRP) ⩾1.2 was observed in 89 and 85% of patients, respectively, corresponding to a clinically important, significant change in both groups. The frequency of adverse events (52.9 and 51.4%, respectively) and serious adverse events (4.8 and 3.8%, respectively) was generally similar between treatments. No deaths were reported. Conclusion: Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met in this study. However, clinically meaningful improvements in RA were observed with both tofacitinib formulations in Japanese patients. The safety profile was similar with both formulations. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02281552.

Channel likelihood correction for photon-counting array receivers in the presence of dead time and jitters.

This paper presents a modified channel likelihood model for optical communication systems with a photon-counting array receiver where photon-counting events are impaired by undesirable dead time and jitters. After the photon-counting detector detects a photon, the detector will go into a period of dead time under which it cannot detect any incident photons. In this context, the channel will have memory. We derive the channel likelihood in the presence of the detector dead time and the random jitter of the photon arrival. The impact of dead time and jitters on the performance of a pulse-position-modulated (PPM) optical communication system is also investigated. The simulation results indicate that the modified channel likelihood expressions can obtain a more obvious performance gain under the context of a stronger background noise, fewer detection elements, longer dead time and bigger jitter.

Private hospital expansion in China: a global perspective.

Objective: To assess the private hospital development in China during 2005-2016 from a global perspective. Methods: We searched the English and Chinese literature in PubMed, CNKI and Google Scholar databases with the keywords including "private hospitals in China", "hospital ownership", "public and private hospital", "private hospital development". Descriptive statistical analysis was used to assess the trend of the private hospital development in China and worldwide. Both the change of private hospitals in supply capacity and health care delivery were studied in this paper. The number of hospitals, number of hospital beds and the average number of hospital beds per hospital were employed to measure the supply capacity. The visit number, inpatients number, and bed occupancy rate (BOR) were used to measure the healthcare delivery. The data was collected from the China Health Statistical Yearbook and the "Organisation for Economic and Co-operation and Development (OECD) Statistics" website. Results: The private sector rapidly expanded in China's hospital market in recent years. The number of private hospitals exceeded the public in 2015. There has also been a significant rise for the indicators of both the supply capacity (including number of hospitals, number of hospital beds and the average number of hospital beds per hospital) and the health care delivery (inpatients number and BOR) of the private hospitals. However, the growth rates of them were relatively lower than the public. The expansion trend of China's private sector in the hospital market accorded with most the OECD countries around the world. In 2016, China was above the medium level of the share of the private hospitals' number with the OECD countries, but below the medium for the supply capacity, in terms of the hospital beds. Conclusion: As a result of the economic growth and supporting policy, the private sector has experienced a vast expansion in China's hospital market in the past decade. The rising gap in average size between private and publicly owned hospitals, and the inconsistent development between the private hospitals' supply capacity and their market share, have become the two main challenges. Meanwhile, the future policy in supporting the private sector should be carefully introduced to advance the whole healthcare delivery system development in China.

Approaches for modeling within subject variability in pharmacometric count data analysis: dynamic inter-occasion variability and stochastic differential equations.

Parameter variation in pharmacometric analysis studies can be characterized as within subject parameter variability (WSV) in pharmacometric models. WSV has previously been successfully modeled using inter-occasion variability (IOV), but also stochastic differential equations (SDEs). In this study, two approaches, dynamic inter-occasion variability (dIOV) and adapted stochastic differential equations, were proposed to investigate WSV in pharmacometric count data analysis. These approaches were applied to published count models for seizure counts and Likert pain scores. Both approaches improved the model fits significantly. In addition, stochastic simulation and estimation were used to explore further the capability of the two approaches to diagnose and improve models where existing WSV is not recognized. The results of simulations confirmed the gain in introducing WSV as dIOV and SDEs when parameters vary randomly over time. Further, the approaches were also informative as diagnostics of model misspecification, when parameters changed systematically over time but this was not recognized in the structural model. The proposed approaches in this study offer strategies to characterize WSV and are not restricted to count data.

Population pharmacokinetic-pharmacodynamic (PopPK/PD) modeling of risperidone and its active metabolite in Chinese schizophrenia patients.

PURPOSE: Risperidone is a second-generation antipsychotic agent commonly used in the treatment of ~ 31.1% of schizophrenia patients in China, it is the most commonly-prescribed antipsychotic agent. Despite the abundant use of risperidone, population pharmacokinetic-pharmacodynamic models of risperidone have not been performed in Chinese schizophrenia patients. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PopPK/PD) model to describe the PK behavior and efficacy of risperidone and 9-hydroxy-risperidone (active metabolite) in Chinese patients. METHODS: Plasma concentration data (702 measurements from 131 patients) and positive and negative syndrome scale (PANSS) scores (258 observations from 56 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCEI). The influence of potential covariates was evaluated. Model robustness was assessed using external validation, normalized prediction distribution error, nonparametric bootstrap, and visual predictive check approaches. RESULTS: Risperidone concentration data were well described by a one-compartmental model incorporating an additional compartment that refers to the concentration profiles of 9-hydroxy-risperidone. A complex absorption procedure was incorporated into the model to describe the metabolism of risperidone to 9-hydroxy-risperidone in the gastrointestinal (GI) tract. A binomial distribution in the estimated clearance (CL) of risperidone has been identified in our model. Decrease in PANSS score along with total AUC (AUCtotal) of risperidone and 9-hydroxy-risperidone was best characterized by an Emax model with 3 transit compartments describing the delay of drug effect. CONCLUSIONS: Considerable differences in PK behavior and drug effect of risperidone have been identified among Chinese extensive metabolizing (EM) and poor metabolizing (PM) patients. This PopPK/PD model may fulfill individualized treatment in clinical practice and may potentially be transferred to other antipsychotic therapies.

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model.

AIM: Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. METHODS: Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. RESULTS: The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC50 value of 1.80 µg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm(3)/week, which described the impact of pEGFR degradation on tumor growth. CONCLUSION: The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.

OBJECTIVE: Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. MATERIALS AND METHODS: Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). CONCLUSION: This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.

Initial dosage regimens of vancomycin for Chinese adult patients based on population pharmacokinetic analysis.

OBJECTIVE: To build a population pharmacokinetic model for Chinese adult patients and develop initial dosage regimens for patients with different degrees of renal function to achieve target steady-state trough concentrations in the range of 10 - 15 and 15 - 20 mg/l. METHOD: Data on serum vancomycin concentration was collected from a retrospective study including 72 Chinese adult patients. NONMEM was used to build the population pharmacokinetic model, and a one-compartment model was chosen to describe the vancomycin concentration-time profile. Internal evaluation by bootstrap and visual predictive check (VPC) was performed to evaluate the robustness and prediction of the final model. Monte Carlo simulations were conducted to develop initial dosage regimens to achieve target trough concentrations. RESULTS: A one-compartment model was built with creatinine clearance (CLcr) as the key covariate influencing drug clearance. The estimated drug clearance for patients with normal renal function (CLcr ≥ 80 ml/min) was 4.90 l/h, and 0.0654 × CLcr if CLcr was < 80 ml/min. The apparent volume of the central compartment was 47.76 l and no covariate was found to affect it. The results of bootstrap analysis were in agreement with the original parameters of the final model, and VPC of the final model demonstrated good predictability. Initial dosage regimens were developed based on the simulations of the population pharmacokinetic model. CONCLUSION: A one-compartment model fitted the retrospective data and CLcr had a significant effect on drug clearance. Initial dosage regimens for vancomycin were proposed to provide some help to individual therapy for Chinese adult patients with different renal functions.

Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China.

AIM: To describe the population pharmacokinetic profile of modafinil acid and to compare the extent of metabolism of modafinil into modafinil acid in 5 major ethnic groups (Han, Mongolian, Korean, Uygur, and Hui) of China. METHODS: In a multi-center, open-label, single dose clinical trial, 49 healthy volunteers from the 5 ethnic groups received 200 mg of modafinil orally. Blood samples for pharmacokinetic evaluation of modafinil and modafinil acid were drawn before and at different time after the administration. Systematic population pharmacokinetic (PopPK) modeling for modafinil acid was conducted, integrating with our previous PopPK model for modafinil. The influence of ethnicity, gender, height, body weight and body mass index (BMI) was estimated. The extent of metabolism of modafinil into modafinil acid, expressed as the relative conversion fraction, was estimated and compared among the 5 ethnic groups. RESULTS: When combined with the PopPK model of modafinil, the concentration of modafinil acid versus time profile was best described with a one-compartment model. The typical clearance and volume of distribution for modafinil acid were 4.94 (l/h) and 2.73 (l), respectively. The Korean group had 25% higher clearance, and the Uygur and Hui groups had 12% higher clearance than the Han group. The median for the relative conversion fraction was 0.53 for Koreans, and 0.24 for the other 4 ethnicities. CONCLUSION: Ethnicity has significant influence on the clearance of modafinil acid. When patients in the 5 ethnic groups are administered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.