Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study.

OBJECTIVES: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. METHODS: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. RESULTS: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. CONCLUSION: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. TRIAL REGISTRATION: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.

A simple method to identify undiagnosed drug-induced liver injury (DILI) and its application in oncology pharmacy practice.

AIMS: To establish a simple method to identify chemotherapy-induced liver injury among oncological patients. To evaluate current clinical approach to elevated laboratory liver test results. METHODS: A total of 289 patients admitted to oncology department who had systemic chemotherapy episodes for cancer treatment from 1 January 2017 to 31 December 2017 were identified. With aid of healthcare information system, Hy's law was applied to laboratory liver test results to identify potential hepatocellular drug-induced liver injury cases. Medical record review was carried out among identified patients to exclude liver dysfunction of alternative causes. Current clinical approach to elevated laboratory liver tests was evaluated through medical record review. RESULTS: Of 289 patients who were treated by systemic chemotherapies, there were 123 patients with elevated laboratory liver tests, among which 8 patients were suspected as potential Hy's law cases. After medical record review, there were two patients determined with chemotherapy-associated liver injury, caused by 5-fluorouracil, leucovorin, irinotecan, and S-1 plus paclitaxel separately. Of eight potential Hy's law cases, seven (87.5%) patients were prescribed with ≥2 kinds of liver protectants and remained treated with traditional Chinese medicine for decoction. CONCLUSIONS: A reliable and simple method to identify undiagnosed drug-induced liver injury was successfully established. An annual incidence of 0.69% of chemotherapy-associated liver injury in oncology department of the setting was found.

Predicting drug-drug interactions with physiologically based pharmacokinetic/pharmacodynamic modelling and optimal dosing of apixaban and rivaroxaban with dronedarone co-administration.

BACKGROUND: The concurrent administration of dronedarone and oral anti-coagulants is common because both are used in managing atrial fibrillation (AF). Dronedarone is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein (P-gp). Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. This study aims to investigate the impact of exposure and bleeding risk of apixaban or rivaroxaban when co-administered with dronedarone using physiologically based pharmacokinetic/pharmacodynamic analysis. METHODS: Modeling and simulation were conducted using Simcyp® Simulator. The parameters required for dronedarone modeling were collected from the literature. The developed dronedarone physiologically based pharmacokinetic (PBPK) model was verified using reported drug-drug interactions (DDIs) between dronedarone and CYP3A4 and P-gp substrates. The model was applied to evaluate the DDI potential of dronedarone on the exposure of apixaban 5 mg every 12 h or rivaroxaban 20 mg every 24 h in geriatric and renally impaired populations. DDIs precipitating major bleeding risks were assessed using exposure-response analyses derived from literature. RESULTS: The model accurately described the pharmacokinetics of orally administered dronedarone in healthy subjects and accurately predicted DDIs between dronedarone and four CYP3A4 and P-gp substrates with fold errors <1.5. Dronedarone co-administration led to a 1.29 (90 % confidence interval (CI): 1.14-1.50) to 1.31 (90 % CI: 1.12-1.46)-fold increase in the area under concentration-time curve for rivaroxaban and 1.33 (90 % CI: 1.15-1.68) to 1.46 (90 % CI: 1.24-1.92)-fold increase for apixaban. The PD model indicated that dronedarone co-administration might potentiate the mean major bleeding risk of apixaban with a 1.45 to 1.95-fold increase. However, the mean major bleeding risk of rivaroxaban was increased by <1.5-fold in patients with normal or impaired renal function. CONCLUSIONS: Dronedarone co-administration increased the exposure of rivaroxaban and apixaban and might potentiate major bleeding risks. Reduced apixaban and rivaroxaban dosing regimens are recommended when dronedarone is co-administered to patients with AF.

Budget Impact Analysis of the Introduction of a Trastuzumab Biosimilar for HER2-Positive Breast Cancer in China.

BACKGROUND AND OBJECTIVE: Biosimilars provide the possibility to reduce the high expenditure on biologic drugs and expand access to effective but less expensive treatments. Biosimilars of trastuzumab showed significant cost savings from the payer's perspective in the USA and Europe. After 2020, with the first approval of a trastuzumab biosimilar in China, it became feasible for biosimilar switching for trastuzumab. However, the economic impact of switching to a trastuzumab biosimilar was not evaluated. A budget impact model was constructed from a payer's perspective of China to demonstrate the economic impact of the introduction of a biosimilar trastuzumab in the treatment of human epidermal growth factor receptor 2-positive breast cancer. METHODS: This budget impact model was based on disease incidence to estimate the net budget impact using epidemiological data from the literature, financial reports from manufacturers on the market shares of originator trastuzumab (Herceptin®) or the biosimilar, and localized direct costs. The budget impact was estimated for 5 years after the introduction of the first-approved trastuzumab biosimilar in China. Furthermore, two scenarios were simulated in this study to estimate the budget impact of biosimilars within: (1) real-world practice and (2) the policy of volume-based procurement. RESULTS: Analyses of the base-case and scenario results implied that adoption of a trastuzumab biosimilar would lead to an expenditure decrease. The average total cost savings over 5 years was estimated to be US$46,651,348, with a range from $10,306,611 in year 1 to $60,821,822 in year 5. The cost savings could benefit an additional 654-3858 patients with breast cancer. If utilizing costs from real-world practice, the introduction of a trastuzumab biosimilar could help an additional 2237-13,203 patients get access to human epidermal growth factor receptor 2-positive targeted therapy. When volume-based procurement was carried out after year 4, $672,366,180 could be saved annually. CONCLUSIONS: This budget impact analysis emphasized the positive effects of adopting a trastuzumab biosimilar in the healthcare system of China. However, cost savings still have a large potential to decrease by regulating pricing and by the procurement policy of biosimilars.

Development of a Nomogram for Predicting Surgical Site Infection in Patients with Resected Lung Neoplasm Undergoing Minimally Invasive Surgery.

Background: Predictive models are necessary to target high-risk populations and provide precision interventions for patients with lung neoplasm who suffer from surgical site infections (SSI). Patients and Methods: This case control study included patients with lung neoplasm who underwent minimally invasive surgeries (MIS). Logistic regression was used to generate the prediction model of SSI, and a nomogram was created. A receiver operator characteristic (ROC) curve was used to examine the predictive value of the model. Results: A total of 151 patients with SSI were included, and 604 patients were randomly selected among the patients without SSI (ratio 4:1). Male gender (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.57-4.15; p < 0.001), age >60 years (OR, 2.10; 95% CI, 1.29-3.44, p = 0.003), operation time >60 minutes (all categories, p < 0.05), treatments for diabetes mellitus (OR, 2.96; 95% CI, 1.75-4.98l; p < 0.001), and best forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC; OR, 0.96; 95% CI, 0.94-0.99; p = 0.008) were independently associated with SSI. The model based on these variables showed an area under the curve (AUC) of 0.813 for predicting SSI. Conclusions: A nomogram predictive model was successfully established for predicting SSI in patients receiving MIS, with good predictive value.

Population pharmacokinetics and model-informed precision dosing of lamivudine in Chinese HIV-infected patients with mild and moderate impaired renal function.

BACKGROUND: Lamivudine is a first-line medication used for human immunodeficiency virus (HIV) treatment. To date, the population pharmacokinetics of lamivudine in Chinese HIV-infected adults have not been assessed. This study aimed to develop a population pharmacokinetic model for oral lamivudine in Chinese HIV-infected adults and to determine the optimal lamivudine dosage regimens. RESEARCH DESIGN AND METHODS: A total of 1113 samples, from 828 Chinese HIV-infected patients treated with lamivudine 300 mg every 24 hours, were pooled from two open-label, prospective clinical trials. A population pharmacokinetics analysis was performed using a nonlinear mixed-effects modeling method. A Monte Carlo simulation was conducted to optimize lamivudine dosing. RESULTS: A two-compartment model adequately described the population pharmacokinetics of lamivudine. The typical population estimate for apparent clearance was 28.3 L/h. Creatinine clearance was identified as a significant factor influencing apparent clearance. According to the Monte Carlo simulation, patients with creatinine clearance between 50 and 70 mL/min should receive lamivudine 200 mg every 24 h or 300 mg every 36 h, to achieve optimal lamivudine exposure. CONCLUSIONS: No obvious ethnic differences were observed in lamivudine pharmacokinetics between Chinese and Caucasian populations. Additionally, a model-informed dosage regimen is recommended for patients with impaired renal function.

Precision Cardio-Oncology: Use of Mechanistic Pharmacokinetic and Pharmacodynamic Modeling to Predict Cardiotoxicities of Anti-Cancer Drugs.

The cardiotoxicity of anti-cancer drugs presents as a challenge to both clinicians and patients. Significant advances in cancer treatments have improved patient survival rates, but have also led to the chronic effects of anti-cancer therapies becoming more prominent. Additionally, it is difficult to clinically predict the occurrence of cardiovascular toxicities given that they can be transient or irreversible, with large between-subject variabilities. Further, cardiotoxicities present a range of different symptoms and pathophysiological mechanisms. These notwithstanding, mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling offers an important approach to predict cardiotoxicities and offering precise cardio-oncological care. Efforts have been made to integrate the structures of physiological and pharmacological networks into PK-PD modeling to the end of predicting cardiotoxicities based on clinical evaluation as well as individual variabilities, such as protein expression, and physiological changes under different disease states. Thus, this review aims to report recent progress in the use of PK-PD modeling to predict cardiovascular toxicities, as well as its application in anti-cancer therapies.

Population pharmacokinetic modeling of pyrotinib in patients with HER2-positive advanced or metastatic breast cancer.

OBJECTIVE: Pyrotinib, a new oral irreversible pan-ErbB tyrosine kinase inhibitor (TKI), has been approved in China for the treatment of HER2-positive advanced or metastatic breast cancer. This study aimed to conduct a population pharmacokinetics (PK) analysis of pyrotinib and to evaluate the impact of patient characteristics on pyrotinib's PK. METHOD: A total of 1152 samples, provided by 59 adult female patients from two phase I clinical trials, were analyzed by nonlinear mixed-effects modeling. Monte Carlo simulation was conducted to assess impact of covariates on the exposure to pyrotinib. RESULTS: The PK of pyrotinib was adequately described by a one-compartment model with first-order absorption and elimination. Patient's age and total protein levels could affect pyrotinib's apparent volume of distribution, and concomitant use of montmorillonite could decrease the bioavailability of pyrotinib by 50.3%. No PK interactions were observed between capecitabine and pyrotinib. CONCLUSION: In this study, a population PK model of pyrotinib was developed to determine the influence of patient characteristics on the PK of pyrotinib. While patient age and total protein levels can significantly affect the apparent distribution volume of pyrotinib, the magnitude of the impact was limited, thus no dosage adjustment was recommended. Furthermore, concomitant use of montmorillonite for diarrhea needs to be taken with precaution.

Relationship Between Leaflets and Root in Normal Aortic Valve Based on Computed Tomography Imaging: Implication for Aortic Valve Repair.

Objective: By assessing the normal dimensions and the relationship between the aortic root and leaflets in Chinese population, the objective of this three-dimensional computed tomography (3DCT)-based study was to establish a matching reference for leaflets and aortic root for aortic valve (AV) repair. Method: Electrocardiogram-gated multi-detector CT was performed on 168 Chinese participants with a normal aortic valve. Measurements of the aortic annuli and leaflets were obtained. The correlations between and the ratios of the specific root and leaflet measurements were analyzed. The references for the leaflet and root dimensions were suggested based on geometric height (gH) using a linear regression equation. The utility of the ratios was tested with CT images of 15 patients who underwent aortic valve repair. Result: The mean annulus diameter (AD), sino-tubular junction (STJ) diameter, geometric height (gH), effective height (eH), free margin length (FML), commissural height (ComH), inter-commissural distance (ICD), and coaptation height (CH) were 22.4 ± 1.7 mm, 27.3 ± 2, 0.4 mm, 15.5 ± 1.7 mm, 8.9 ± 1.2 mm, 32.0 ± 3.4 mm, 17.9 ± 1.9 mm, 23.1 ± 2.3 mm, and 3.1 ± 0.6 mm, respectively. The gH/AD, FML/ICD, and eH/ComH ratios were 0.69 ± 0.07, 1.38 ± 0.08, and 0.50 ± 0.07, respectively. The gH correlated with all other leaflet and root measurements (P < 0.01), whereas the FML demonstrated a better correlation with ICD compared with gH (R2 = 0.75, and R2 = 0.37, respectively). The FML/ICD and eH/ComH ratios might be used to assess leaflet-root mismatch and post-repair leaflet billowing. Conclusion: The normal aortic valve measurements based on 3DCT revealed a specific relationship between the root and leaflets; and this will guide the development of an objective method of aortic valve repair.

External Evaluation of Vancomycin Population Pharmacokinetic Models at Two Clinical Centers.

Background: Numerous vancomycin population pharmacokinetic models in neonates have been published; however, their predictive performances remain unknown. This study aims to evaluate their external predictability and explore the factors that might affect model performance. Methods: Published population pharmacokinetic models in neonates were identified from the literature and evaluated using datasets from two clinical centers, including 171 neonates with a total of 319 measurements of vancomycin levels. Predictive performance was assessed by prediction- and simulation-based diagnostics and Bayesian forecasting. Furthermore, the effect of model structure and a number of identified covariates was also investigated. Results: Eighteen published pharmacokinetic models of vancomycin were identified after a systematic literature search. Using prediction-based diagnostics, no model had a median prediction error of ≤ ± 15%, a median absolute prediction error of ≤30%, and a percentage of prediction error that fell within ±30% of >50%. A simulation-based visual predictive check of most models showed there were large deviations between observations and simulations. After Bayesian forecasting with one or two prior observations, the predicted performance improved significantly. Weight, age, and serum creatinine were identified as the most important covariates. Moreover, employing a maturation model based on weight and age as well as nonlinear model to incorporate serum creatinine level significantly improved predictive performance. Conclusion: The predictability of the pharmacokinetic models for vancomycin is closely related to the approach used for modeling covariates. Bayesian forecasting can significantly improve the predictive performance of models.

Probable Drug Interaction Between Etanercept and Cyclosporine Resulting in Clinically Unexpected Low Trough Concentrations: First Case Report.

Preclinical studies have shown that anti-cytokine therapies could alter drug dispositions through affecting cytochrome P450 synthesis; however, evidence and case reports evaluating clinical relevance of this interaction are scarce. This is the first reported case of interaction between cyclosporine (CsA) and etanercept in a 42-year-old male patient with ankylosing spondylitis and immunoglobulin A nephropathy in whom cytokine levels were monitored both before and after CsA initiation. The initiation of etanercept led to at least 2.5-folds increase in total clearance of CsA. After comprehensive assessment and stepwise exclusion of alternative causes, it was considered that inflammation resolution with etanercept administration has highly induced clearance of CsA, probably mediated by interleukin-2. The case has shown that co-administration of CsA and anti-cytokine therapies such as etanercept needs close monitoring of trough levels. Physicians and pharmacists should be aware of similar interactions especially when the biological therapy is initiated or discontinued and for patients undergoing acute inflammation phase. Monitoring cytokine levels should be considered when drug-cytokine interaction is suspected.