The JCOG1113, a multicenter, randomized phase III trial in patients with advanced/recurrent biliary tract cancer showed the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin. Although liver cirrhosis (LC) is a known risk factor for intrahepatic cholangiocarcinoma (ICC), few reports focus on the efficacy and safety of chemotherapy in ICC patients with LC.

We performed a subgroup analysis of ICC patients enrolled in the JCOG1113. The presence or absence of LC was evaluated based on clinical factors such as radiographic findings, medical history, laboratory data, and physical examination at enrollment. We evaluated differences in the safety and efficacy of chemotherapy according to the presence or absence of clinically diagnosed LC.

Of the 94 eligible patients with ICC, 10 were clinically diagnosed with LC. In the non-LC/clinically diagnosed LC group, grade 3 or 4 neutropenia, anemia, decreased platelet count, and non-hematological adverse events were observed in 51.2%/60%, 15.5%/0%, 11.9%/40%, and 38.1%/30% patients. The median overall survival was 13.7 months in the non-LC group and 19.0 months in the clinically diagnosed LC group (hazard ratio [HR]: 0.969, 95% confidence interval [CI]: 0.482-1.948). The median progression-free survival was 5.9 months in the non-LC group and 7.1 months in the clinically diagnosed LC group (HR, 0.995; 95% CI, 0.513-1.929).

The results of this study indicated that eligible ICC patients with clinically diagnosed LC, as determined by clinical and CT imaging findings, did not exhibit any apparent safety or efficacy disadvantage compared to those without LC.

Drug-induced liver injury (DILI) has increasingly become a major concern in Western countries since the late 1960s, with an estimated annual incidence of 13.9-19.1 cases per 100,000 people. DILI is a significant cause of acute liver failure, exhibiting a high mortality rate of 10-50 %. Its etiology includes medications, herbal products, and dietary supplements, exacerbated by pre-existing liver conditions, sonorities, pregnancy, and nutritional deficiencies. It is categorized into intrinsic and idiosyncratic reactions. Intrinsic DILI, dose-dependent and predictable, is primarily caused by substances like paracetamol, which leads to liver toxicity through direct metabolic pathways. In contrast, idiosyncratic DILI is less common, unpredictable, and affects susceptible individuals, with non-steroidal anti-inflammatory drugs, antibiotics, and cardiovascular agents frequently implicated in hospitals. Oxidative stress, mitochondrial dysfunction, bile salt export inhibition, and stress on the endoplasmic reticulum are some DILI-related pathophysiology. Diagnosis relies on biochemical tests, serological markers, radiological investigations, and liver biopsy. Management strategies emphasize the identification and cessation of the offending drugs, supportive care, and specific treatment options targeted to the culprit drugs. Management depends on the severity and nature of the injury.

Rivaroxaban is an anticoagulant medication that targets a key stage in the blood clotting process, preventing the formation and growth of clots. It is commonly used to prevent thrombosis or inhibit the enlargement of existing clots. Rivaroxaban functions as a Factor Xa inhibitor and is indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, treating deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as reducing the risk of recurrent DVT and PE, and prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

A robust, precise, and selective reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for analyzing Rivaroxaban in raw materials. Isocratic elution at a flow rate of 1 mL/min was performed using a Thermo ODS Hypersil C18 column (4.6 × 250 mm, 5 µm) at ambient temperature. The mobile phase consisted of monobasic potassium phosphate at pH 2.9 and acetonitrile in a 70:30 (v/v) ratio, with UV detection at 249 nm.

Linearity was established in the concentration range of 50-1,000 ppm (R2 = 0.999), and the retention time for Rivaroxaban was approximately 12 min. The percentage relative standard deviation (RSD) for precision and accuracy was consistently below 2.0%, ensuring method reliability. Solution stability studies confirmed the stability of Rivaroxaban over the analysis period, as no peak loss, degradation, or additional peaks were observed between the first and last injections. Furthermore, forced degradation studies were conducted under various stress conditions, including acid and base hydrolysis, as well as hydrogen peroxide oxidation. The method successfully resolved Rivaroxaban from its degradation products, demonstrating its stability-indicating capability.

Rivaroxaban is a novel oral anticoagulant that selectively and directly inhibits factor Xa. A method has been developed and validated for its analysis, adhering to guidelines from the International Conference on Harmonisation (ICH) and the U.S. Pharmacopeia (USP). The validation process assessed parameters such as specificity, robustness, linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ). The LOD for impurities and degradants was determined to be 0.3 ppm, while the LOQ was 1 ppm. This stability-indicating method is highly suitable for routine quality control and analytical applications in both raw materials and finished drug products, owing to its simplicity, efficiency, and robustness.

Severe fever with thrombocytopenia syndrome (SFTS) is a novel emerging acute infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV), characterized by high fever and thrombocytopenia. It has been proved that traditional Chinese medicine (TCM) has displayed definite therapeutic effects on viral hemorrhagic fever, indicating its potential to treat SFTS. In this study, SFTS-relative key targets were predicted via gene ontology (GO) analysis and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Molecular docking was then used to select stable binders. Molecules matched TCMs were identified, and a new prescription, Qingqi Guxue decoction (QQGX), was formulated to clear heat and nourish blood, with a resulting drug composition network. We explored the optimal drug proportion for QQGX. Through an in-depth study of molecular mechanisms, we found that QQGX induces S phase arrest by promoting the degradation of cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2), thereby inhibiting SFTSV replication. Finally, we verified the effectiveness and safety of QQGX based on the mouse liver bile duct organoid model infected with SFTSV. In summary, our study prepared a TCM decoction using the method of network pharmacology. This decoction has a significant inhibitory effect on the replication of SFTSV and provides a new treatment strategy for hemorrhagic fever with TCM.

Special populations are not enrolled in randomized clinical trials, and their safety and efficacy of anticancer therapy are not well described. We aimed to assess the safety and efficacy of anticancer therapy in breast cancer (BC) patients with cirrhosis.

We performed a retrospective case-control study (1:5) to assess the adverse events (AEs) morbidity and mortality of anticancer therapy in BC patients with cirrhosis based on a review of patients' medical records.

We included 26 BC patients with cirrhosis and 130 matched BC patients without cirrhosis. Postoperative morbidity was higher in the group with cirrhosis (26.9% vs 6.9%, P = 0.007) when postoperative mortality was not significance (3.8% vs 0%, P = 0.167). Liver toxicity (73.1% vs 26.9%, P < 0.001) was more frequent in the group with cirrhosis. The incidence of disruption and mortality during chemotherapy was higher in the group with cirrhosis (46.2% vs 3.1%, P < 0.001 and 15.4% vs 0%, P = 0.001, respectively). The 2-year recurrence rate and 2-year metastasis rate were higher in the group with cirrhosis (19.0% vs 3.8%, P = 0.022 and 23.8% vs 6.9%, P = 0.028). Cirrhosis was the risk factor for liver metastasis (OR: 17.326, 95% CI: 2.164-138.707, P=0.007).

It is safe for BC patients with compensated cirrhosis to accept surgery. But they are vulnerable to AEs, disruptions and death during chemotherapy and have poor prognosis. Multidisciplinary cooperation before therapy and closely monitoring AEs during therapy are critical. Attention should be given to optimize the prognosis of special BC patients.

Patients with liver disease express multiple pathophysiological variations that alter the pharmacokinetics of numerous drugs. At this time, there is insufficient evidence about the proper dosing of vancomycin in patients with liver disease. This study aimed to assess the risk of acute kidney injury (AKI) during vancomycin therapy and identify predictors of AKI and all-cause mortality among patients with varying degrees of liver dysfunction.

A retrospective cohort study was conducted including patients with chronic liver disease who used vancomycin during hospitalization from January 2016 to January 2024 in two Saudi hospitals. Patients were grouped by the severity of the liver disease (mild liver disease [MLD] or moderate-to-severe liver disease [MSLD] based on the Child-Pugh score). The incidence of AKI, vancomycin mean trough level, and all-cause mortality were compared between the two groups. A multivariable logistic regression model was employed to identify predictors of AKI and mortality.

A total of 110 patients treated with vancomycin were included in this study (28 had MLD and 82 had MSLD). A higher incidence of AKI in patients with MSLD than those with MLD was observed (28% vs. 14.3%, respectively; p = 0.1440), but the difference was statistically insignificant. The vancomycin mean trough levels (12.9 ± 5.2 μmol/L vs. 10.2 ± 4.7 μmol/L, p = 0.0143) and the percentage of patients with vancomycin trough level > 13.8 μmol/L (35.4% vs. 10.7%, p = 0.0131) were significantly higher in the MSLD group compared to the MLD group. Having a Creatinine Clearance (CrCl) between 15.1-29.9 ml/min (adjusted Odds ratio [aOR]: 45.5; 95% Confidence interval [CI] 4.99-414.8), and a vancomycin mean trough level > 13.8 μmol/L (aOR: 7.67; 95%CI 2.49-23.63) were associated with a higher risk of AKI development. Similarly, mortality was significantly higher in the MSLD group than in the MLD (23.2% vs. 3.6%, respectively; p = 0.0203). The risk of mortality was associated with having a body mass index (BMI) between 25-29.9 kg/m2 (sOR 6.69; 95%CI 1.73-25.8), an albumin level < 25 g/L (aOR: 4.33; 95%CI 1.36-13.8), and a vancomycin mean trough level > 13.8 μmol/L (aOR: 6.13; 95%CI 1.82-20.6).

Patients who had MSLD had a higher trough vancomycin levels and mortality than patients who had MLD; and this risk increases as liver disease progresses. Thus, the existence of chronic liver disease should be considered when monitoring toxicity from vancomycin to minimize the risk of adverse outcomes and mortality. Larger studies are needed to closely quantify the risk of vancomycin toxicity among patients with chronic liver disease.

Valsartan (VAL) is commonly prescribed for patients with cardiovascular disease (CVD) to lower blood pressure, reduce heart failure risk, and prevent heart attacks or strokes by blocking the effects of angiotensin II. Many patients with CVD also suffer from metabolic dysfunction-associated steatohepatitis (MASH), which disrupts several xenobiotic transporters, affecting the pharmacokinetics of numerous drugs. Medications used in patients to treat comorbidities associated with MASH may be subject to this altered disposition and potential toxicity. This study aimed to assess how MASH alters the pharmacokinetics of VAL using a rodent model that mimics human MASH. MASH was induced in rats via a methionine- and choline-deficient (MCD) diet. Rats received VAL-a substrate of organic anion-transporting polypeptide (OATP) 1B1/1B3 and reported for multidrug resistance-associated protein-2-(2 mg/kg) through intravenous injection to isolate hepatic transport processes, and bile, serum, and liver concentrations measured using liquid chromatography-tandem mass spectrometry. Consistent with MASH progression, MCD rats presented with more gross pathology, including increased liver-to-body weight ratios, along with macrosteatosis, hepatocyte ballooning, and lobular inflammation. In MCD rats, the expression of Oatp1b2 was significantly reduced, and Mrp2 was internalized, resulting in higher systemic exposure to VAL compared with controls. Additionally, cumulative biliary excretion of VAL was lower in MCD rats. To further assess VAL disposition in MASH, transport kinetics were evaluated in human embryonic kidney 293 cells overexpressing OATP1B1 or OATP1B3, revealing similar affinity for VAL between both transporters. These findings suggest that changes in OATP function in MASH may alter VAL pharmacokinetics, which may have implications for personalized treatments. SIGNIFICANCE STATEMENT: Although expression of drug transporters in metabolic dysfunction-associated steatohepatitis (MASH) has been explored, the combined effect between MASH and genetic loss of transporters on the disposition of sartan drugs has not been determined. This study applied liquid chromatography-tandem mass spectrometry analyses and immunohistological staining to assess drug disposition and identify alterations to drug transporters in rodents on a methionine- and choline-deficient diet. The observations made in this study have significant implications regarding its disposition in the context of hepatic dysfunction associated with MASH.

Assessing the potential for oseltamivir-induced liver damage is essential to ensure its safe administration. The aim of this study was to examine the association between hepatotoxicity and oseltamivir use and to describe the features of oseltamivir-induced hepatotoxicity. Data were obtained from the Adverse Event Reporting System of the US Food and Drug Administration (FAERS). Disproportionality and proportionality analyses were performed to evaluate the safety profile of oseltamivir-related hepatotoxicity and the occurrence of hepatotoxicity-related adverse events across sex and age groups. The FAERS recorded 20,340,254 adverse event reports between 2004 and 2023, of which 16,960,996 reports were included in the analysis. We identified 14 types of oseltamivir-related adverse events that were hepatotoxic and showed positive signals. The most frequently reported adverse event was abnormal hepatic function (n =  54), and the most severe adverse event was fulminant hepatitis. Compared with that for male individuals, the reporting odds ratio (ROR) was 0.5 for female individuals; and for male individuals, the ROR, compared with that for female individuals, was 4.19. The median time to hepatotoxic adverse events, excluding mixed liver injury, was <  5 days. Oseltamivir can cause liver toxicity, which is influenced by sex and age. Liver function tests and monitoring for signs of liver disease are crucial when using oseltamivir.

This study evaluated the safety and pharmacokinetics (PK) of a single dose of leritrelvir, a novel inhibitor of 3-chymotrypsin-like cysteine protease (3CLpro), in patients with hepatic impairment versus healthy participants with normal hepatic function. Eight participants with mild (Child-Pugh A) hepatic impairment, eight with moderate (Child-Pugh B) hepatic impairment, and eight healthy matched control participants were enrolled in this open-label, parallel clinical trial. After administration of leritrelvir of 400 mg, PK parameters were calculated and compared across groups. In total, 24 participants were enrolled and completed the study. Leritrelvir was generally well tolerated, with no serious adverse events or deaths reported during the study. Compared to the group with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-∞ of leritrelvir in participants with mild hepatic impairment were 96.9% (69.3%, 135%), 92.2% (69.6%, 122%), and 92.1% (69.7%, 122%), respectively. For moderate hepatic impairment, the corresponding ratios were 91.6% (61.7%, 136%), 113% (80.0%, 160%), and 113% (80.0%, 159%). Leritrelvir exposures were comparable among the three groups. Overall, there was no clinically relevant difference in leritrelvir exposure in participants with hepatic impairment compared to normal controls. No dose adjustment is required for leritrelvir in patients with mild or moderate hepatic impairment.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06161259.

Everolimus presents significant dosing challenges due to between- and within-patient pharmacokinetic variabilities. This study aimed to develop and validate a model-informed precision dosing strategy for everolimus in liver transplant recipients. The dosing strategy was initially developed using retrospective data, employing nonlinear mixed-effects modeling. The model included readily measurable covariates, body surface area, albumin, and tacrolimus trough concentration. The dosing strategy was subsequently validated in a prospective trial, recommending 1 to 1.75 mg dosages every 12 h, depending on covariates. Lower dosages were recommended for patients with lower body surface area and albumin with adjustments based on tacrolimus trough concentration. The estimated pharmacokinetic parameters (typical value ± standard error), apparent clearance (CL/F: 15.0 ± 0.5 L/h), and apparent volume of distribution (Vd/F: 862 ± 79.3 L) were refined using prospective clinical data from 20 patients, reducing interindividual variations. This research successfully developed and validated a population pharmacokinetic model for everolimus. The developed "dosE" web-based platform translates our pharmacokinetic model into a practical tool for healthcare providers, exemplifying the application of pharmaceutical research in clinical practice and potentially improving therapeutic outcomes in liver transplantation.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic dynamic modeling approach that can be used to predict or retrospectively describe changes in drug exposure due to drug-drug interactions (DDIs). With advancements in commercially available PBPK software, PBPK DDI modeling has become a mainstream approach from early drug discovery through to late-stage drug development and is often used to support regulatory packages for new drug applications. This Minireview will briefly describe the approaches to predicting DDI using PBPK and static modeling approaches, the basic model structures and features inherent to PBPK DDI models, and key examples where PBPK DDI models have been used to describe complex DDI mechanisms. Future directions aimed at using PBPK models to characterize transporter-mediated DDI, predict DDI in special populations, and assess the DDI potential of protein therapeutics will be discussed. A summary of the 209 PBPK DDI examples published to date in 2023 will be provided. Overall, current data and trends suggest a continued role for PBPK models in the characterization and prediction of DDI for therapeutic molecules. SIGNIFICANCE STATEMENT: Physiologically based pharmacokinetic (PBPK) models have been a key tool in the characterization of various pharmacokinetic phenomena, including drug-drug interactions. This Minireview will highlight recent advancements and publications around physiologically based pharmacokinetic drug-drug interaction modeling, an important area of drug discovery and development research in light of the increasing prevalence of polypharmacology in clinical settings.

Hepatic impairment (HI) trials are traditionally part of the clinical pharmacology development to assess the need for dose adaptation in people with impaired metabolic capacity due to their diseased liver. This review aimed at looking into the data from dedicated HI studies, cluster these data into various categories and connect the effect by HI with reported pharmacokinetics (PK) properties in order to identify patterns that may allow waiver, extrapolations, or adapted HI study designs. Based on a ratio ≥ 2 or ≤ 0.5 in AUC or Cmax between hepatically impaired participants/healthy controls these were considered "positive" or "negative". In case of more than one HI severity stratum per compound included in the HI trial, the comparison of the AUC ratios for mild, moderate, or severe HI were used to investigate the increase across HI categories. For the in total 436 hits, relevant PK information could be retrieved for 273 compounds of which 199 were categorized negative, 69 positive ups and 5 positive downs. Fourteen out of 69 compounds demonstrated a steep increase in the AUC ratios from mild to severe HI. Compounds demonstrating a steep increase typically had a high plasma protein binding of > 95%, high volume of distribution, lower absolute bioavailability, minor elimination via the kidneys, were predominantly metabolized by CYP3A4 or CYP2D6 and the majority of these compounds were substrates of OATP1B1. While for compounds with steep increase studies in all severity strata may be warranted they may also offer the potential to estimate the appropriate doses in an HI trial. On the other hand, for compounds with slow or no increase across HI severity strata, reduced HI trials may be justified, e.g. only testing PK in moderate HI.

Bacterial infections are a leading cause of hospitalization and mortality in patients with decompensated cirrhosis. Antibiotic prophylaxis in cirrhotic patients has demonstrated significant short-term reductions in bacterial infections in randomized controlled trials, but at the cost of drug resistance and with uncertain survival benefits.

This review examines antibiotic use in cirrhosis, focusing on patients most likely to benefit from antibiotic prophylaxis, management strategies for infections through risk-based antibiotic selection and timely treatment initiation, challenges posed by the emergence of multidrug-resistant organisms, and principles of antimicrobial stewardship.

The efficacy of prophylaxis has decreased over time, and current registry data have questioned its use, emphasizing the need for better risk-based individualized strategies. When bacterial infections occur, the efficacy of antimicrobial therapies depends heavily on local epidemiological patterns and individual patient risk factors, necessitating tailored antibiotic selection based on regional resistance data and specific clinical scenarios. Nosocomial infections, colonization with multidrug-resistant organisms, and prior exposure to systemic antibiotics are key risk factors that should guide empirical therapy selection. Until evidence-based algorithms are available, clinicians should continue to adopt individualized approaches, guided by available evidence, local specificities, and antimicrobial stewardship principles to optimize patient outcomes.

The anticancer drug paclitaxel is primarily metabolized in the liver. Previous studies have indicated a correlation between impaired liver function and paclitaxel toxicity, which may indicate dose reduction. Since the evidence is limited, the aim of this study was to investigate the effect of impaired liver function on the hematological toxicity of paclitaxel, dose modifications and overall survival (OS).

For this single-center retrospective observational study, patients treated with paclitaxel for breast, esophageal and ovarian cancer at the University Medical Centre Utrecht between 2011 and 2022 were identified from the Utrecht Patient Oriented Database (UPOD). Based on regression analysis, the risk of developing Grade 3/4 hematological toxicity was compared between patients with normal and impaired (based on the NCI criteria for bilirubin and ASAT (aspartate aminotransferase) concentrations) liver function. Additionally, differences in the occurrence of toxicity-related dose modifications and OS were evaluated between the two groups.

A total of 569 patients were included. Breast cancer patients who were receiving advanced treatment and had mildly impaired liver function (ASAT ≤ 2x ULN, bilirubin ≤ ULN) had an increased risk of developing grade 3/4 neutropenia (HR = 4.39, 95% CI 1.20-16.02; p = 0.03). In addition, patients with impaired liver function treated according to the advanced ovarian cancer regimen had an increased risk of developing grade 3/4 leukopenia (HR = 12.64, 95% CI 2.12-75.22, p = 0.01) and dose modification (treatment discontinuation) (HR = 3.91, 95% CI 1.74-8.79, p < 0.01). Impaired liver function was also associated with decreased OS in inoperable esophageal and advanced ovarian cancer patients (HR = 7.65, 95% CI 2.54-23.1, p < 0.01 and HR = 2.98, 95% CI 1.36-6.54, p < 0.01, respectively). The risk of developing grade 3/4 hematological toxicity during lower-dose paclitaxel treatment protocols was not significantly different in patients with impaired liver function.

This study revealed that patients with impaired liver function treated with paclitaxel for breast and ovarian cancer in an advanced setting are at greater risk of developing hematological toxicity than patients with normal liver function at the start of therapy. Furthermore, in patients with ovarian (advanced) or inoperable esophageal cancer, impaired liver function is associated with decreased OS. Within these groups of patients, it is important to weigh the risk of upfront paclitaxel dose modifications versus an adaptive strategy.

Model-Informed Drug Discovery and Development (MID3) represents a transformative approach in pharmaceutical research, integrating quantitative models to inform and optimize decision-making throughout the drug development process. This review explores the current applications, challenges, and future prospects of MID3 within the Middle East and North Africa (MENA) region. By leveraging local data and advanced computational techniques, MID3 has the potential to significantly enhance the efficiency and success rates of drug development tailored to regional health priorities. We discussed successful case studies of applying MID3 at different phases of drug development and clinical trials. Furthermore, we emphasized the critical need for MENA countries to embrace MID3 by investing in workforce training, aligning regulatory frameworks, and fostering collaborative research initiatives. This call to action underscores the importance of a robust MID3 ecosystem, urging policymakers, academic institutions, and industry stakeholders to prioritize and support its integration into the MENA region's healthcare.

Studies evaluating the hepatic safety of medications have been limited by the inability to control for confounding from receipt of other hepatotoxic drugs.

The objective of this study was to develop an index (Hepatotoxicity Score) to adjust for concomitant hepatotoxic medication exposure within pharmacoepidemiology studies.

We identified 193 medications with ≥ 4 reports of hepatotoxicity and created cohorts of outpatient initiators in the Veterans Health Administration (2000-2021). Exposure occurred from initiation through 30 days after discontinuation or up to 1 year. We measured age-/sex-adjusted rates of hospitalization for severe acute liver injury (ALI) by chronic liver disease (CLD), identified drugs with high rates, and used these rates as weights in the score. To demonstrate real-world use, we calculated the score for proton pump inhibitor (PPI) initiators. We summed the weights of the drugs dispensed within 90 days prior to PPI initiation. Hazard ratios (HRs) of severe ALI (95% confidence intervals) were measured with and without adjustment for Hepatotoxicity Score.

Among 89 512 PPI initiators with CLD, HRs of severe ALI were higher for lansoprazole (HR = 2.17 [95% CI, 1.24-3.82]), but not pantoprazole (HR = 0.83 [95% CI, 0.61-1.13]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.99 [95% CI, 1.13-3.50]). Among 2 462 414 PPI initiators without CLD, HRs were not significantly higher for lansoprazole (HR = 1.66 [95% CI, 0.99-2.77]) but were significantly lower for pantoprazole (HR = 0.59 [95% CI, 0.37-0.95]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.52 [95% CI, 0.91-2.54]).

The Hepatotoxicity Score provides a tool to adjust for confounding due to concomitant hepatotoxic drug exposure within hepatic safety studies.

This review explores the pharmacokinetics, benefits, and risks of proton pump inhibitors (PPIs) in cirrhotic patients, focusing on the appropriateness of their use and potential adverse effects.

Recent studies highlight significant pharmacokinetic alterations in PPIs among cirrhotic patients, with marked increases in lansoprazole and pantoprazole exposure and relatively stable levels of esomeprazole. While effective for managing acid-related disorders and post-band ulcer rebleeding, evidence supporting PPI use for portal hypertension-related bleeding is lacking. Emerging research suggests potential adverse effects such as hepatic decompensation, spontaneous bacterial peritonitis, hepatic encephalopathy, and increased mortality, possibly linked to dysbiosis and bacterial translocation. PPI use in cirrhotic patients alters pharmacokinetics significantly, with esomeprazole potentially safer in advanced cirrhosis. The review advises caution in routine PPI use beyond acid-related conditions due to limited evidence and substantial risks. It underscores the need for careful risk-benefit assessments and exploration of alternative therapies. Future research should aim to identify safer management strategies for portal hypertension complications and to develop evidence-based guidelines for PPI use in patients with cirrhosis.

This parallel-group, open-label Phase I study evaluated the effect of mild to moderate hepatic impairment on pharmacokinetics (PK), pharmacodynamics (PD), and safety of a single oral dose of SHR4640. Participants with mild or moderate hepatic impairment were enrolled, with each cohort consisting of eight individuals, alongside eight well-matched controls with normal hepatic function. The participants were administered 10 mg SHR4640, and blood samples were collected for PK evaluation over 72 h. Additionally, serum uric acid (sUA) levels were measured to assess PD changes. Safety was evaluated through adverse events, laboratory tests, vital signs, and electrocardiograms. The Cmax of SHR4640 decreased by 15.0% in the mild hepatic impairment group (geometric least squares means of the ratios [GMR] = 0.850, 90% CI: 0.701-1.03) and by 17.5% in the moderate hepatic impairment group (GMR = 0.825, 90% CI: 0.681-1.00). These reductions were not statistically significant compared to the normal hepatic function group. AUC0-t and AUC0-inf were similar across all groups, indicating that overall exposure to the drug was not clinical significantly affected by hepatic impairment. Apparent clearance and volume of distribution of SHR4640 showed no association with the severity of hepatic impairment as measured by the Child-Pugh score. There were no significant differences in the changes in sUA levels from baseline across different levels of hepatic function. SHR4640 is well tolerated in participants with mild or moderate hepatic impairment. Mild and moderate hepatic impairment did not have a clinically relevant impact on PK, PD, and safety of SHR4640. SHR4640 can be used in patients with mild to moderate hepatic impairment without the need for dose adjustment.

Etrasimod is a newly FDA-approved Sphingosine-1-Phosphate modulator indicated for moderate and severe ulcerative colitis. It is extensively metabolized in the liver via the cytochrome P450 system and may accumulate markedly in patients with hepatic dysfunction, exposing them to toxicity. The aim of the current study is to utilize a physiologically-based pharmacokinetic modeling approach to evaluate the impact of hepatic impairment on the pharmacokinetic behavior of etrasimod and to appropriately select dosage regimens for patients with chronic liver disease; Methods: PK-Sim was used to develop the etrasimod PBPK model, which was verified using clinical data from healthy subjects and subsequently adapted to reflect the physiological changes associated with varying degrees of hepatic dysfunction; Results: Simulations indicated that hepatic clearance of etrasimod is clearly reduced in patients with Child-Pugh B and C liver impairment. Based on these findings, dosing adjustments were proposed to achieve therapeutic exposures equivalent to those in individuals with normal liver function. In the Child-Pugh B and C population groups, 75% and 62.5%, respectively, of the standard dose were enough to have comparable exposure to the healthy population. These adjusted dosages aim to mitigate the risk of drug toxicity while maintaining efficacy; Conclusions: The PBPK model provides a robust framework for individualizing drug therapy in patients with hepatic impairment, ensuring safer and more effective treatment outcomes. Further clinical studies are warranted to verify these dosing recommendations and to refine the model for broader clinical applications.

Remimazolam, a novel ultra-short-acting intravenous benzodiazepine, has garnered recent attention for its use as a general anesthetic. This narrative review aims to summarize and analyze the available literature on the effects of remimazolam use in cardiac surgical patients, including its effects on hemodynamics, safety in patients with baseline myocardial dysfunction, and impact on postoperative management including time to emergence and extubation. Finally, there is discussion regarding potential drawbacks of adopting remimazolam as a routine anesthetic for cardiac surgery.

This study aimed to investigate the risk factors and predictors of non-obese fatty liver disease in the Chinese population.

A total of 6,014 adults who underwent physical examinations at Union Hospital of Huazhong University of Science and Technology from March 2019 to March 2023 were included in this study. Fatty liver disease was diagnosed based on at least two of the following criteria: diffuse echo patterns relative to the liver, spleen, and kidney; ultrasonic beam attenuation; and poor intrahepatic visual details. The associations between non-obese fatty liver and gender, age, total bilirubin(TBIL), direct bilirubin(DBIL), alanine aminotransferase(ALT), aspartate aminotransferase(AST), glutamine transferase(GGT), alkaline phosphatase(ALP), triglycerides(TG), total cholesterol(TC), high-density lipoprotein cholesterol(HDLC), low-density lipoprotein cholesterol(LDLC), urea nitrogen(BUN), creatinine(Cr), uric acid(UA), Central nervous system sensitivity PTFQI, TSHI, TT4RI, TFQI, Peripheral sensitivity, free thyroxine(FT4), thyroid-stimulating hormone(TSH), triiodothyronine(FT3), fasting blood glucose(FBG), systolic blood pressure(SBP), diastolic blood pressure(DBP), body mass index(BMI) were analyzed via binary logistic regression. Correlation between non-obese fatty liver and high blood lipids, hypertension, hyperuricemia, diabetes, thyroid dysfunction were analyzed using the Pearson and Spearman methods. ROC curve was used to evaluate the diagnostic effect of the indicator.

Compared with the normal group, age, proportion of males, ALT, AST, GGT, ALP, TG, TC, BUN, Cr, UA, TSHI, TT4RI, FT3/FT4, TSH, FT3, FBG, SBP, DBP and BMI in the disease group were significantly higher. The prevalence of non-obese fatty liver was associated with hyperlipidemia, hypertension, hyperuricemia and diabetes. Gender, age, DBIL, ALT, ALP, TG, HDL-C, LDL-C, BUN, UA, FBG, DBP, BMI were independent risk factors for non-obese fatty liver.FT3/FT4 may be considered as a predictor of nonobese fatty liver.

Risk factors for non-obese fatty liver may include sex, age, TG, TC, BMI, etc. Hyperlipidemia, hypertension, hyperuricemia and diabetes mellitus are related to non-obese fatty liver. FT3/FT4 may be a predictor of non-obese fatty liver disease.

Patients with liver cirrhosis are prone to develop severe bacterial infections. Pharmacokinetics (PK) of antibiotics in cirrhosis are potentially affected by impaired biotransformation phases 0-3 and consequences of portal hypertension such as portovenous shunting, ascites formation and/or acute kidney injury (AKI). We aimed to elucidate to what extent PK of selected antibiotics and, therefore, dosage recommendations are affected in adults with cirrhosis.

We performed a systematic search in PubMed, Embase, Cochrane and CINAHL on effects of cirrhosis on PK profiles of ceftriaxone, fosfomycin, gentamicin, meropenem, nitrofurantoin, piperacillin/tazobactam and vancomycin in adults. Antibiotics were selected based on the lack of specific dosing recommendations for adults with cirrhosis. We included studies reporting on ≥1 of the following PK parameters: AUC, half-life (t½), CL, volume of distribution (Vd), peak (Cmax) or trough concentrations (Cmin).

We identified 15 studies (ceftriaxone, n = 5; gentamicin, n = 3; meropenem n = 5; vancomycin, n = 2), including 379 patients with cirrhosis, of which two were of high quality. No eligible studies were identified for fosfomycin, nitrofurantoin or piperacillin/tazobactam. Ceftriaxone unbound concentration increased in cirrhosis, but was mitigated by increased renal CL. Gentamicin levels in ascitic fluid were comparable to those in plasma. Meropenem PK parameters were not altered in cirrhosis without AKI, but in the presence of AKI a decrease in CL was observed. In contrast, vancomycin CL decreased in advanced cirrhosis.

Available data in studies of mostly moderate quality suggest that PK of ceftriaxone, meropenem and vancomycin are altered in cirrhosis. More advanced PK studies are needed to provide specific dosing recommendations.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD.

This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI.

Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD.

ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

When one considers the significant role of the liver in medication absorption and metabolism, clinicians must appreciate the important ramifications for medication dosing and monitoring in patients with cirrhosis. For many medications, dose adjustments may be necessary to minimize toxicities or avoid adverse effects from drug accumulation. Clinicians could be well served if they can understand in some detail how pharmacokinetic properties are altered in cirrhosis.

A PubMed search of the English medical literature starting with 1980 using keywords cirrhosis, pain management, and analgesics was performed, and additional papers were found using references from the first round of papers.

Patients with cirrhosis often have significant reductions in first-pass metabolism, altered volumes of distribution, and marked reductions in both renal and hepatic elimination of drugs. These factors may contribute to much higher levels of drug exposure compared to the general population. In terms of drug dosing, FDA labeling is often ambiguous and even incongruous with observed pharmacokinetic changes.

This article may provide guidance for clinicians to optimize pain management in people living with cirrhosis.

Current FDA labeling for dosing analgesic drugs in patients with cirrhosis is either vague or not consistent with findings from newer pharmacokinetic research. With this review, we hope to provide insight and guidance to clinicians on how to dose-adjust medications commonly utilized in pain management in these patients.

While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.

Omadacycline is a new broad-spectrum aminomethylcycline antibiotic. However, there have been limited pharmacokinetic and pharmacodynamic (PK/PD) studies of omadacycline in patients with hepatic impairment. The aim of this study was to explore the PK/PD of omadacycline intravenous administration in healthy and hepatically impaired populations.

A physiologically based pharmacokinetic (PBPK) model of omadacycline was developed and validated based on published demographic data and the physiochemical properties of omadacycline. The PK processes in healthy adults were simulated and then extrapolated to a hepatically impaired population. Monte Carlo simulations were performed for PD evaluation by calculating the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the approved dosages.

In the hepatically impaired population, there was no significant difference in the maximum concentration (Cmax) compared with the healthy population, while the area under the plasma concentration-time curve from the first data point extrapolated to infinity (AUC_inf) showed a slight increase. Monte Carlo simulations indicated that the dosage of 200 mg once daily or 100 mg twice daily intravenously (loading dose) and 100 mg once daily intravenously (maintenance dose) could cover the common pathogens of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) : Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus.

Hepatic impairment exerts little impact on the PK properties of omadacycline, and no dosage adjustments are necessary for patients with mild and moderate hepatic impairment. Current dosing regimens are predicted to produce satisfactory therapeutic effects against non-drug-resistant strains of Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae but may not produce the desired AUC/MIC ratios in patients with Escherichia coli or Klebsiella pneumoniae.

To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure.

Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included.

A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid.

In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0-24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61-0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66-0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97-1.24), p > 0.05) and 2 (ratio 1.03 (0.94-1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.

The development of technology and the processing speed of computing machines have facilitated the evaluation of advanced pharmacokinetic (PK) models, making modeling processes simple and faster. The present model aims to analyze the PK of brivaracetam (BRV) in healthy and diseased populations. A comprehensive literature review was conducted to incorporate the BRV plasma concentration data and its input parameters into PK-Sim software, leading to the creation of intravenous (IV) and oral models for both populations. The developed physiologically based pharmacokinetic (PBPK) model of BRV was then assessed using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for PK parameters including the maximum systemic concentration (Cmax), the area under the curve at time 0 to t (AUC0-∞), and drug clearance (CL). The PBPK model of BRV demonstrated that mean Robs/pre ratios of the PK parameters remained within the acceptable limits when assessed against a twofold error margin. Furthermore, model predictions were carried out to assess how AUC0-∞ is affected following the administration of BRV in individuals with varying degrees of liver cirrhosis, ranging from different child-pugh (CP) scores like A, B, and C. Moreover, dose adjustments were recommended by considering the variations in Cmax and CL in various kidney disease stages (mild to severe).

Nonclinical studies involve in vitro, in silico, and in vivo experiments to assess the toxicokinetics, toxicology, and safety pharmacology of drugs according to regulatory requirements by a national or international authority. In this review, we summarize the potential effects of various underlying diseases governing the absorption, distribution, metabolism, and excretion (ADME) of drugs to consider the use of animal models of diseases in nonclinical trials. Obesity models showed alterations in hepatic metabolizing enzymes, transporters, and renal pathophysiology, which increase the risk of drug-induced toxicity. Diabetes models displayed changes in hepatic metabolizing enzymes, transporters, and glomerular filtration rates (GFR), leading to variability in drug responses and susceptibility to toxicity. Animal models of advanced age exhibited impairment of drug metabolism and kidney function, thereby reducing the drug-metabolizing capacity and clearance. Along with changes in hepatic metabolic enzymes, animal models of metabolic syndrome-related hypertension showed renal dysfunction, resulting in a reduced GFR and urinary excretion of drugs. Taken together, underlying diseases can induce dysfunction of organs involved in the ADME of drugs, ultimately affecting toxicity. Therefore, the use of animal models of representative underlying diseases in nonclinical toxicity studies can be considered to improve the predictability of drug side effects before clinical trials.

Patients with hematological malignancies often require multidrug therapy using a variety of antineoplastic agents and supportive care medications. This increases the risk of drug-related problems (DRPs). Determining DRPs in patients hospitalized in hematology services is important for patients to achieve their drug treatment goals and prevent adverse effects. This study aims to identify DRPs by the clinical pharmacist in the multidisciplinary team in patients hospitalized in the hematology service of a university hospital in Turkey.

This study was conducted prospectively between December 2022 and May 2023 in the hematology service of Suleyman Demirel University Research and Application Hospital in Isparta, Turkey. DRPs were determined using the Pharmaceutical Care Network Europe (PCNE) 9.1 Turkish version.

This study included 140 patients. Older age, longer hospital stay, presence of acute lymphoblastic leukemia, presence of comorbidities, higher number of medications used, and polypharmacy rate were statistically significantly higher in the DRP group than in the non-DRP group (p < 0.05). According to multivariate logistic regression analysis, the probability of DRP in patients with polypharmacy was statistically significant 7.921 times (95% CI: 3.033-20.689) higher than in patients without polypharmacy (p < 0.001).Every 5-day increase in the length of hospital stay increased the likelihood of DRP at a statistically significant level (OR = 1.476, 95% CI: 1.125-1.938 p = 0.005). In this study, at least one DRP was detected in 69 (49.3%) patients and the total number of DRPs was 152. Possible or actual adverse drug events (96.7%) were the most common DRPs. The most important cause of DRPs was drug choice (94.7%), and the highest frequency within its subcategories was the combination of inappropriate drugs (93.4%).

This study shows the importance of including a clinical pharmacist in a multidisciplinary team in identifying and preventing DRPs in the hematology service.

One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure-response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk-based approach.

Metabolic reprogramming enables cancer cells to generate energy mainly through aerobic glycolysis, which is achieved by increasing the expression levels of glycolysis-related enzymes. Therefore, the development of drugs targeting aerobic glycolysis could be an effective strategy for cancer treatment. Icaritin (ICT) is an active ingredient from the Chinese herbal plant Epimedium with several biological activities, but its anti-cancer mechanism remains inconclusive. Using normal hepatocytes and hepatoma cells, our results showed that ICT suppressed cell proliferation and clonal formation and decreased glucose consumption and lactate production in liver cancer cells. In consistent, the mRNA and protein levels of several aerobic glycolysis-related genes were decreased upon ICT treatment. Furthermore, our results demonstrated that the expression levels of the aerobic glycolysis-related proteins were correlated with the p53 status in hepatoma cells. Using PFT-α or siRNA-p53, our results confirmed that ICT regulated aerobic glycolysis in a p53-dependent manner. In addition, ICT was found to stabilize p53 at the post-translational level which might be mediated by inhibiting MDM2 expression and affecting its interaction with p53. Finally, our results demonstrated that ICT increased the levels of ROS that activated p53 via the p38 MAPK pathway. In conclusion, ICT increased intracellular ROS levels in liver cancer cells, which promoted the stabilization and activation of p53, inhibiting the expression of aerobic glycolysis-related genes and glycolysis, and ultimately leading to the suppression of liver cancer development.

Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability, and safety profiles become critically important for medication selection.

This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the USA. Excluded from consideration are clozapine and non-oral formulations.

Among antipsychotics, there are many differences in adverse reactions observed in clinical trials, such as variable likelihood to cause sedation vs insomnia, weight gain and abnormalities in glucose/lipid metabolism, hyperprolactinemia, potential for impact on the QT interval, and motoric adverse effects. Additional safety data that can help with medication selection include safety in pregnancy and lactation, and potential for drug-drug interactions. Ultimately, working with patients to personalize treatment by focusing on safety and individual tolerability considerations for various adverse effects can help in building a therapeutic alliance and improving patients' outcomes.

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.

Pain is prevalent in patients with cirrhosis. Due to potential alterations in drug metabolism, risk for adverse effects, and complications from cirrhosis, physicians are often faced with difficult choices when choosing appropriate analgesics in these patients. Overall, acetaminophen remains the preferred analgesic. Despite its potential for intrinsic liver toxicity, acetaminophen is safe when used at 2 g/d. In contrast, non-selective nonsteroidals should be avoided due to their multiple side effects, including worsening renal function, blunting diuretic response, and increasing risk of portal hypertensive and peptic ulcer bleeding. Celecoxib can be administered for short term (≤5 days) in patients with Child's A and Child's B cirrhosis (50% dose reduction). Opioids carry the risk of precipitating hepatic encephalopathy and should generally be avoided, when possible. If clinical situation demands their use, opioid use should be limited to short-acting agents for short duration. Gabapentin and pregabalin are generally safe. Duloxetine should be avoided in hepatic impairment. Topical diclofenac and lidocaine seem to be safe in patients with cirrhosis.

Introduction: The application of voriconazole in patients with liver dysfunction lacks pharmacokinetic data. In previous study, we proposed to develop voriconazole dosing regimens for these patients according to their total bilirubin, but the regimens are based on Monte Carlo simulation and has not been further verified in clinical practice. Besides, there are few reported factors that significantly affect the efficacy of voriconazole. Methods: We collected the information of patients with liver dysfunction hospitalized in our hospital from January 2018 to May 2022 retrospectively, including their baseline information and laboratory data. We mainly evaluated the efficacy of voriconazole and the target attainment of voriconazole trough concentration. Results: A total of 157 patients with liver dysfunction were included, from whom 145 initial and 139 final voriconazole trough concentrations were measured. 60.5% (95/157) of patients experienced the adjustment of dose or frequency. The initial voriconazole trough concentrations were significantly higher than the final (mean, 4.47 versus 3.90 μg/mL, p = 0.0297). Furthermore, daily dose, direct bilirubin, lymphocyte counts and percentage, platelet, blood urea nitrogen and creatinine seven covariates were identified as the factors significantly affect the voriconazole trough concentration. Binary logistic regression analysis revealed that the lymphocyte percentage significantly affected the efficacy of voriconazole (OR 1.138, 95% CI 1.016-1.273), which was further validated by the receiver operating characteristic curve. Conclusion: The significant variation in voriconazole trough concentrations observed in patients with liver dysfunction necessitates caution when prescribing this drug. Clinicians should consider the identified factors, particularly lymphocyte percentage, when dosing voriconazole in this population.