Development and Quality Control of a Population Pharmacokinetic Model Library for Caspofungin.

BACKGROUND: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. OBJECTIVE: This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings. METHODS: We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections. RESULTS: A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level. CONCLUSION: At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients.

Knowledge, attitudes, and practices of primary healthcare practitioners regarding pharmacist clinics: a cross-sectional study in Shanghai.

BACKGROUND: Pharmacist clinics offer professional pharmaceutical services that can improve public health outcomes. However, primary healthcare staff in China face various barriers and challenges in implementing such clinics. To identify existing problems and provide recommendations for the implementation of pharmacist clinics, this study aims to assess the knowledge, attitudes, and practices of pharmacist clinics among primary healthcare providers. METHODS: A cross-sectional survey based on the Knowledge-Attitude-Practice (KAP) model, was conducted in community health centers (CHCs) and private hospitals in Shanghai, China in May, 2023. Descriptive analytics and the Pareto principle were used to multiple-answer questions. Chi-square test, Fisher's exact test, and binary logistic regression models were employed to identify factors associated with the knowledge, attitudes, and practices of pharmacist clinics. RESULTS: A total of 223 primary practitioners participated in the survey. Our study revealed that most of them had limited knowledge (60.1%, n = 134) but a positive attitude (82.9%, n = 185) towards pharmacist clinics, with only 17.0% (n = 38) having implemented them. The primary goal of pharmacist clinics was to provide comprehensive medication guidance (31.5%, n = 200), with medication education (26.3%, n = 202) being the primary service, and special populations (24.5%, n = 153) identified as key recipients. Logistic regression analysis revealed that education, age, occupation, position, work seniority, and institution significantly influenced their perceptions. Practitioners with bachelor's degrees, for instance, were more likely than those with less education to recognize the importance of pharmacist clinics in medication guidance (aOR: 7.130, 95%CI: 1.809-28.099, p-value = 0.005) and prescription reviews (aOR: 4.675, 95% CI: 1.548-14.112, p-value = 0.006). Additionally, practitioners expressed positive attitudes but low confidence, with only 33.3% (n = 74) feeling confident in implementation. The confidence levels of male practitioners surpassed those of female practitioners (p-value = 0.037), and practitioners from community health centers (CHCs) exhibited higher confidence compared to their counterparts in private hospitals (p-value = 0.008). Joint physician-pharmacist clinics (36.8%, n = 82) through collaboration with medical institutions (52.0%, n = 116) emerged as the favored modality. Daily sessions were preferred (38.5%, n = 86), and both registration and pharmacy service fees were considered appropriate for payment (42.2%, n = 94). The primary challenge identified was high outpatient workload (30.9%, n = 69). CONCLUSIONS: Although primary healthcare practitioners held positive attitudes towards pharmacist clinics, limited knowledge, low confidence, and high workload contributed to the scarcity of their implementation. Practitioners with diverse sociodemographic characteristics, such as education, age, and institution, showed varying perceptions and practices regarding pharmacist clinics.

Corrigendum: Synergistic effects of nab-PTX and anti-PD-1 antibody combination against lung cancer by regulating Pi3K/AKT pathway through the Serpinc1 gene.

[This corrects the article DOI: 10.3389/fonc.2022.933646.].

Cost-effectiveness analysis of once-daily oral semaglutide versus placebo and subcutaneous glucagon-like peptide-1 receptor agonists added to insulin in patients with type 2 diabetes in China.

Introduction: Oral semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that improves glycated hemoglobin levels and body weight in patients with type 2 diabetes (T2DM). We aim to evaluate the cost-effectiveness of once-daily oral semaglutide in comparison to placebo and injectable GLP-1 RAs in Chinese patients with T2DM inadequately controlled on basal insulin. Methods: The United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS OM2.1) was used to estimate the cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER). Baseline characteristics of the simulation cohort were obtained from the PIONEER 8 trial. Utility and safety inputs were derived from a network meta-analysis of 12 trials. Direct medical costs were retrieved from published literature and discounted at an annual rate of 5%. We used a willingness-to-pay (WTP) threshold of $36,528.3 per quality-adjusted life-year (QALY) gained. Scenario analysis, and one-way and probabilistic sensitivity analysis were performed. Results: The effectiveness of oral semaglutide was 10.39 QALYs with a total cost of $30,223.10, while placebo provided 10.13 QALYs at a lower total cost of $20,039.19. Oral semaglutide was not cost-effective at an ICER of $39,853.22 and $88,776.61 per QALY compared to placebo and exenatide at the WTP. However, at an annual price of $1,871.9, it was cost-effective compared with dulaglutide, liraglutide, and lixisenatide. The model was most sensitive to the discount rate and annual cost of oral semaglutide. The price of oral semaglutide needed to be reduced to $1,711.03 per year to be cost-effective compared to placebo and other injectable GLP-1 RAs except for exenatide and semaglutide injection. Conclusion: We found that once-daily oral semaglutide, at a comparable price of semaglutide injection, proves to be a cost-effective add-on therapy to insulin for Chinese patients with T2DM, especially when compared to subcutaneous GLP-1 RAs other than injectable semaglutide and exenatide. However, to achieve cost-effectiveness in comparison to placebo, further cost reduction of oral semaglutide is necessary. The estimated annual cost of $1,711.03 for oral semaglutide demonstrates a more cost-effective option than placebo, highlighting its potential value in the management of T2DM.

Prevalence of depression and association with all-cause and cardiovascular mortality among individuals with type 2 diabetes: a cohort study based on NHANES 2005-2018 data.

BACKGROUND: Individuals with diabetes have increased risk of depression, but there are limited nationally representative studies on this topic. We aimed to investigate the prevalence and predictors of depression, as well as its impact on all-cause and cardiovascular mortality in adults with type 2 diabetes (T2DM) using a prospective cohort study and a representative sample of the U.S. METHODS: We analyzed National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and linked it with the most recent publicly available National Death Index (NDI) data. Individuals aged 20 years or old who had depression measurements were included. Depression was defined as a Patient Health Questionnaire (PHQ-9) score ≥ 10, and categorized into moderate (10-14 points) and moderately severe to severe (≥ 15 points). Cox proportional hazard models were used to estimate the association between depression and mortality. RESULTS: Among 5695 participants with T2DM, 11.6% had depression. Depression was associated with female gender, younger age, overweight, lower education, being unmarried, smoking, and a history of coronary heart disease and stroke. During a mean follow-up period of 78.2 months, 1161 all-cause deaths occurred. Total depression and moderately severe to severe depression significantly increased all-cause mortality (adjusted hazard ratio [aHR] 1.36, 95% CI [1.09-1.70]; 1.67 [1.19-2.34]) and non-cardiovascular mortality (aHR 1.36, 95% CI [1.04-1.78]; 1.78, 95% CI [1.20-2.64]), but not cardiovascular mortality. Subgroup analysis showed a significant association between total depression and all-cause mortality in males (aHR 1.46, 95% CI [1.08-1.98]) and those aged 60 years or older (aHR 1.35, 95% CI [1.02-1.78]). Any severity of depression was not significantly associated with cardiovascular mortality in age- or gender- stratified subgroups. CONCLUSIONS: In a nationally representative sample of U.S. adults with T2DM, approximately 10% experienced depression. Depression did not significantly associate with cardiovascular mortality. However, comorbid depression in T2DM patients increased the risk of all-cause and non-cardiovascular mortality. The impact of depression on mortality varied across subgroups. Therefore, healthcare providers should consider incorporating depression screening and management into routine care, especially for subgroups with specific risk factors, due to the increased risk of all-cause mortality in T2DM patients with depression.

Population pharmacokinetics of buprenorphine and naloxone sublingual combination in Chinese healthy volunteers and patients with opioid use disorder: Model-based dose optimization.

The sublingual combination of buprenorphine (BUP) and naloxone (NLX) is a new treatment option for opioid use disorder (OUD) and is effective in preventing drug abuse. This study aimed to explore rational dosing regimen for OUD patients in China via a model-based dose optimization approach. BUP, norbuprenorphine (norBUP), and NLX plasma concentrations of 34 healthy volunteers and 12 OUD subjects after single or repeated dosing were included. A parent-metabolite population pharmacokinetics (popPK) model with transit compartments for absorption was implemented to describe the pharmacokinetic profile of BUP-norBUP. In addition, NLX concentrations were well captured by a one-compartment popPK model. Covariate analysis showed that every additional swallow after the administration within the observed range (0-12) resulted in a 3.5% reduction in BUP bioavailability. This provides a possible reason for the less-than-dose proportionality of BUP. There were no differences in the pharmacokinetic characteristics between BUP or NLX in healthy volunteers and OUD subjects. Ethnic sensitivity analysis demonstrated that the dose-normalized peak concentration and area-under-the-curve of BUP in Chinese were about half of Puerto Ricans, which was consistent with a higher clearance observed in Chinese (166 L / h vs. 270 L / h ). Furthermore, Monte Carlo simulations showed that an 8 mg three-times daily dose was the optimized regimen for Chinese OUD subjects. This regimen ensured that opioid receptor occupancy remained at a maximum (70%) in more than 95% of subjects, at the same time, with NLX plasma concentrations below the withdrawal reaction threshold (4.6  n g / m L ).

Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model.

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01−1.0 µg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.

Utilization of Physiologically Based Pharmacokinetic Modeling in Pharmacokinetic Study of Natural Medicine: An Overview.

Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional Chinese medicine and other natural plants, defining their chemical structure and pharmacological effects, and screening potential druggable candidates are also uprising directions in new drug research and development. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique that simulates the absorption, distribution, metabolism, and elimination of drugs in various tissues and organs in vivo based on physiological and anatomical characteristics and physicochemical properties. PBPK modeling in drug research and development has gradually been recognized by regulatory authorities in recent years, including the U.S. Food and Drug Administration. This review summarizes the general situation and shortcomings of the current research on the pharmacokinetics of natural medicine and introduces the concept and the advantages of the PBPK model in the study of pharmacokinetics of natural medicine. Finally, the pharmacokinetic studies of natural medicine using the PBPK models are summed up, followed by discussions on the applications of PBPK modeling to the enzyme-mediated pharmacokinetic changes, special populations, new drug research and development, and new indication adding for natural medicine. This paper aims to provide a novel strategy for the preclinical research and clinical use of natural medicine.

Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS.

Objective: We aimed to evaluate alirocumab- and evolocumab-related adverse events (AEs) in real-world compared with all other drugs, overall and by gender and age subgroups; we also aimed to compare their risks of cognitive impairment, musculoskeletal disorders and diabetes with various statins and ezetimibe. Methods: We retrospectively extracted AE reports from the FDA Adverse Event Reporting System (FAERS) database during July 2015-June 2021. Disproportionality analyses were performed using reporting odds ratios (RORs) to detect AE signals of alirocumab and evolocumab in the overall population and in different age and gender subgroups, respectively. Results: Compared with all other drugs, both alirocumab and evolocumab had a significant signal in "musculoskeletal and connective tissue disorders" (ROR1 = 2.626, 95% CI 2.552-2.702; ROR2 = 2.575, 95% CI 2.538-2.613). The highest ROR value of 2.311 (95% CI 2.272-2.351) was for "injury, poisoning and procedural complications" and was found in patients aged ≥65 years on evolocumab. The most frequent AEs were "general disorders and administration site conditions" and "musculoskeletal and connective tissue disorders" for all subpopulations. At the preferred term level, the most frequent AE signal was myalgia for alirocumab and injection site pain for evolocumab, overall and by subgroups. Compared with statins/ezetimibe, PCSK9 inhibitors exhibited lower ROR values for adverse events associated with SOC "nervous system disorders", "psychiatric disorders" and "metabolism and nutrition disorders" (all RORs < 1), but mixed results for musculoskeletal disorders. Compared with all other drugs, undocumented AEs, such as acute cardiac event (ROR = 30.0, 95% CI 9.4-95.3) and xanthoma (ROR = 9.3, 95% CI 3.4-25.5), were also reported. Conclusion: Real-world evidence showed that PCSK9 inhibitors were associated with an increased risk of musculoskeletal and connective tissue disorders and general disorders and administration site conditions, overall and by subgroups. Muscle toxicity, injection site reactions, and influenza-like illness were significant AE signals. Compared with various statins and ezetimibe, PCSK9 inhibitors have shown a favorable safety profile in muscle-related events, cognitive impairment and diabetes. Some undocumented AE signals were also reported. Due to the limitations of spontaneous reporting databases, further studies are still needed to establish causality and validate our results.

Applications of In Silico Models to Predict Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a major cause of the withdrawal of pre-marketed drugs, typically attributed to oxidative stress, mitochondrial damage, disrupted bile acid homeostasis, and innate immune-related inflammation. DILI can be divided into intrinsic and idiosyncratic DILI with cholestatic liver injury as an important manifestation. The diagnosis of DILI remains a challenge today and relies on clinical judgment and knowledge of the insulting agent. Early prediction of hepatotoxicity is an important but still unfulfilled component of drug development. In response, in silico modeling has shown good potential to fill the missing puzzle. Computer algorithms, with machine learning and artificial intelligence as a representative, can be established to initiate a reaction on the given condition to predict DILI. DILIsym is a mechanistic approach that integrates physiologically based pharmacokinetic modeling with the mechanisms of hepatoxicity and has gained increasing popularity for DILI prediction. This article reviews existing in silico approaches utilized to predict DILI risks in clinical medication and provides an overview of the underlying principles and related practical applications.

Changes in pharmaceutical retail market and regional inequality of community pharmacists accessibility in mainland China: a retrospective cross-sectional study.

OBJECTIVES: To describe the development of pharmaceutical retail market and community pharmacists in mainland China and identify challenges from both government and business perspectives. DESIGN: A retrospective cross-sectional study. SETTING: Community pharmacies providing primary care in mainland China. PARTICIPANTS: Community pharmacies and community pharmacists in all 31 provincial units in mainland China registered in the National Medical Products Administration during 2014-2020. Number of community pharmacies ranged from 433 529 (2014) to 553 892 (2020). Number of community pharmacists ranged from 129 895 (2014) to 541 264 (2020). PRIMARY AND SECONDARY OUTCOME MEASURES: Changes in pharmaceutical retail market and accessibility of community pharmacists over the study period. We also examined the qualification of pharmacists and regional differences. RESULTS: During 2014-2020, the total number of retail companies and pharmacies increased by 47.6% and 27.4%, respectively. The national retail chain rate boosted from 39.4% to 56.5%, and average number of stores per company increased from 40.2 to 49.7. The number of community pharmacists rose by 316.7%. Regarding accessibility, number of pharmacy stores per 10 000 inhabitants increased from 3.2 to 3.9; the average number of pharmacists per store and per 10 000 residents rose from 0.30 to 0.98 and from 0.95 to 3.83. However, the proportion holding a postgraduate or bachelor's degree dropped to one-third. Pharmacy resources were unevenly distributed across the country. Correlations were observed between economic indicators and number of pharmacy stores and pharmacists (p<0.05). CONCLUSIONS: In general, the accessibility and centralisation of retail pharmacies in China have shown a steady growth with a sign of regional disparities. The availability of community pharmacists has increased significantly, although with an unreasonable composition of academic qualifications and a shortage of personnel. Further efforts are necessary to provide sufficient pharmacy resources for community settings and resolve regional disparities.

Longitudinal trends in the prevalence and treatment of depression among adults with cardiovascular disease: An analysis of national health and nutrition examination survey 2009-2020.

Objectives: To assess the contemporary prevalence and decadal trends of depression and antidepressant use among adults with cardiovascular disease (CVD) in the United States, as well as their risk factors from 2009 to 2020. Materials and methods: We used the National Health and Nutrition Examination Survey data to calculate the weighted prevalence of depression and antidepressant use. Adults aged 20 years or older with CVD were included. Depression and CVD were assessed by the Patient Health Questionnaire (PHQ-9) and self-report, respectively. Results: A total of 3,073 eligible participants with CVD aged >20 years were included. The overall prevalence of depression defined by PHQ-9 score ≥10 was 15.7% (95% CI 13.8-17.5), with a steady trend during 2009-March 2020 (p = 0.777). Female gender (aOR 1.78, 95% CI 1.20-2.64) and sleep disorder (aOR 2.62, 95% CI 1.78-3.86) were independent risk factors for depression in CVD patients, while high education level, high income, longer sleep duration, and non-current smokers were considered protective factors. The weighted prevalence of antidepressant use among depressed patients with CVD was 38.6%, which also remained unchanged during the survey period (p = 0.699). Participants with normal sleep pattern and duration were significantly less likely to take antidepressants (p = 0.003). Conclusion: The longitudinal trends in the prevalence of depression among CVD patients in the United States have been stable over the past decade, despite being significantly higher in women, and those with sleep disorders. Overall, antidepressant use was fairly low. Aggressive screening and tailored treatment are recommended for specific vulnerable subpopulations to improve their clinical outcomes.

Synergistic effects of nab-PTX and anti-PD-1 antibody combination against lung cancer by regulating the Pi3K/AKT pathway through the Serpinc1 gene.

Lung cancer is a type of cancer with higher morbidity and mortality. In spite of the impressive response rates of nab-paclitaxel (nab-PTX) or programmed cell death-1 (PD-1) and its ligand inhibitors, the effective treatment remains limited. Currently, alternative strategies aim at drug combination of nab-PTX and PD-1/PD-L1 inhibitors. Even as the clinical impact of the combined agents continues to increase, basic research studies are still limited and the mechanisms underlying this synergy are not well studied. In this study, we evaluated the antitumor efficacy and the molecular mechanisms of action of nab-PTX in combination with anti-PD-1 antibody, using Lewis lung carcinoma (LLC) cell and subcutaneously transplanted tumor models. The combination of nab-PTX and anti-PD-1 antibody displayed stronger antitumor effects, manifested at tumor volume, proliferation and apoptosis through Ki67 and TUNEL staining. In-vivo experiments showed significant increases in CD4+ T cells, CD8+ T cells, IFN-γ, TNF-α, IL-2, PF, and Gzms-B, exerting antitumor effects with reductions in MDSCs and IL-10 after the treatments. Furthermore, transcriptomic analysis indicated 20 overlapped differentially expressed genes, and Serpin peptidase inhibitor clade C Member 1 (Serpinc1) was downregulated during treatment in vivo, whose expression level was markedly related to metastasis and overall survival of lung cancer patients. Functional enrichment analysis of the target gene revealed primary GO terms related to tumor, which warrants further investigation. We also found that Serpinc1 overexpression promoted cell proliferation, migration, and invasion and inhibited cell apoptosis of LLC cells in vitro, possibly regulating the associated factors via the Pi3K/AKT pathway. In summary, our results reveal the synergistic antitumor responses of nab-PTX combined with anti-PD-1 antibody, in which Serpinc1 may play an important role, providing a target gene for combination treatment strategy.

Case Report: Rhabdomyolysis secondary to vildagliptin overdose in a suicidal attempt: A case report and brief literature review.

Rhabdomyolysis is a life-threatening syndrome associated with direct or indirect muscle damage that is rarely reported with dipeptidyl peptidase (DPP)-4 inhibitors. Here we presented a case in which a 58-year-old female suffered from severe swelling and pain in bilateral lower limbs and oliguria after a suicidal vildagliptin overdose. Drug-induced rhabdomyolysis and drug-induced liver injury were diagnosed based on laboratory and radiological findings. The patient was treated with fluid resuscitation, insulin, electrolyte replacement, diuretics, urine alkalizing agents, anticoagulants, antioxidants, and 24-h bedside ECG monitoring and suicide prevention. After 20 days of hospitalization and close monitoring, the patient was discharged without sequelae. Risk factors, diagnostic criteria, disease mechanisms, and outcomes were also discussed. This case illustrated that overdose of oral anti-diabetic medications may result in clinically significant adverse events, such as rhabdomyolysis in this case with a DPP-4 inhibitor. Although the incidence is low, special attention should be paid to intentional or accidental exposure to anti-diabetic medications during suicide attempts, especially in depressed patients with diabetes.

Frailty in Community-Dwelling Adults Aged 40 Years and over with Type 2 Diabetes: Association with Self-Management Behaviors.

Background: Evidence is lacking on risk factors for frailty and prefrailty and their relationship with self-management behaviors in patients ≥40 years of age with type 2 diabetes. Methods: Participants were selected as a cross-sectional cohort at five communities in Shanghai, China during January−March 2021. The modified FRAIL scale and the Summary of Diabetes Self-Care Activities (SDSCA) measure were used. Results: Of the 558 participants, 10.2% were classified as frailty and 34.1% as prefrailty. The prevalence of frailty was higher in males than in females (p = 0.009), whereas females were associated with higher odds of prefrailty (aOR 1.67, 95% CI [1.08−2.60]). Multimorbidity, ≥3 chronic diseases, and hospitalization in the past year were considered risk factors for both frailty and prefrailty. Each point earned on SDSCA and physical activity were associated with lower odds of frailty (aOR 0.95, 95% CI [0.92−0.98]) and prefrailty (aOR 0.52, 95% CI [0.31−0.85]), respectively. Frail participants performed significantly worse self-care practice than prefrail and non-frail ones, especially on diet, physical activity, and medication adherence (p < 0.001). Conclusions: Frail patients ≥40 years of age with type 2 diabetes reported poorer self-care performance. Further interventional studies are warranted to clarify their causal relationship.

Application of Physiologically Based Pharmacokinetic Modeling in Preclinical Studies: A Feasible Strategy to Practice the Principles of 3Rs.

Pharmacokinetic characterization plays a vital role in drug discovery and development. Although involving numerous laboratory animals with error-prone, labor-intensive, and time-consuming procedures, pharmacokinetic profiling is still irreplaceable in preclinical studies. With physiologically based pharmacokinetic (PBPK) modeling, the in vivo profiles of drug absorption, distribution, metabolism, and excretion can be predicted. To evaluate the application of such an approach in preclinical investigations, the plasma pharmacokinetic profiles of seven commonly used probe substrates of microsomal enzymes, including phenacetin, tolbutamide, omeprazole, metoprolol, chlorzoxazone, nifedipine, and baicalein, were predicted in rats using bottom-up PBPK models built with in vitro data alone. The prediction's reliability was assessed by comparison with in vivo pharmacokinetic data reported in the literature. The overall predicted accuracy of PBPK models was good with most fold errors within 2, and the coefficient of determination (R2) between the predicted concentration data and the observed ones was more than 0.8. Moreover, most of the observation dots were within the prediction span of the sensitivity analysis. We conclude that PBPK modeling with acceptable accuracy may be incorporated into preclinical studies to refine in vivo investigations, and PBPK modeling is a feasible strategy to practice the principles of 3Rs.

Examination of the Impact of CYP3A4/5 on Drug-Drug Interaction between Schizandrol A/Schizandrol B and Tacrolimus (FK-506): A Physiologically Based Pharmacokinetic Modeling Approach.

Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug-drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes' inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.

Simultaneous Quantification of Propylthiouracil and Its N-ß-d Glucuronide by HPLC-MS/MS: Application to a Metabolic Study.

Propylthiouracil (PTU) is commonly prescribed for the management of hyperthyroidism and thyrotoxicosis. Although the exact mechanism of action is not fully understood, PTU is associated with hepatoxicity in pediatric population. Glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), which possess age-dependent expression, has been proposed as an important metabolic pathway of PTU. To further examine the metabolism of PTU, a reliable HPLC-MS/MS method for the simultaneous quantification of PTU and its N-ß-D glucuronide (PTU-GLU) was developed and validated. The chromatographic separation was achieved on a ZORBAX Extend-C18 column (2.1 × 50 mm, 1.8 µm) through gradient delivery of a mixture of formic acid, methanol and acetonitrile. The electrospray ionization (ESI) was operated in its negative ion mode while PTU and PTU-GLU were detected by multiple reaction monitoring (MRM). This analytical method displayed excellent linearity, sensitivity, accuracy, precision, recovery and stability while its matrix effect and carry-over were insignificant. Subsequently, the in vitro metabolism of PTU was assessed and UGT1A9 was identified as an important UGT isoform responsible for the glucuronidation of PTU. The information obtained from this study will facilitate future mechanistic investigation on the hepatoxicity of PTU and may optimize its clinical application.

Naloxone Protects against Lipopolysaccharide-Induced Neuroinflammation and Microglial Activation via Inhibiting ATP-Sensitive Potassium Channel.

AIM: The aim of this study was to evaluate the anti-inflammatory effects and underlying mechanism of naloxone on lipopolysaccharide- (LPS-) induced neuronal inflammation and microglial activation. METHODS: LPS-treated microglial BV-2 cells and mice were used to investigate the anti-inflammatory effects of naloxone. RESULTS: The results showed that naloxone dose-dependently promoted cell proliferation in LPS-induced BV-2 cells, downregulated the expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and proinflammatory enzymes iNOS and COX-2 as well as the expression of free radical molecule NO, and reduced the expression of Iba-1-positive microglia in LPS-stimulated BV-2 cells and mouse brain. Moreover, naloxone improved LPS-induced behavior degeneration in mice. Mechanically, naloxone inhibited LPS-induced activation in the ATP-sensitive potassium (KATP) channel. However, the presence of glibenclamide (Glib), an antagonist of KATP channel, ameliorated the suppressive effects of naloxone on inflammation and microglial activation. CONCLUSION: Naloxone prevented LPS-induced neuroinflammation and microglial activation partially through the KATP channel. These findings might highlight the potential of naloxone in neuroinflammation therapy.

A physiologically based pharmacokinetic/pharmacodynamic modeling approach for drug-drug interaction evaluation of warfarin enantiomers with sorafenib.

Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes. This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.