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There are a lot of clinical variants of hepatic impairment ranging from asymptomatic increase in transaminases to acute liver failure and fulminant hepatitis. Hepatic impairment is a polietiologic syndrome. According to the epidemiological study conducted in the United States (19982008), the main causes of hepatic impairment were paracetamol overdose (46%), idiopathic liver dysfunction (14%), other drugs (excluding paracetamol, 11%), viral hepatitis B (7%), other infectious and non-infectious diseases with liver damage (except for viral hepatitis) 7%, autoimmune hepatitis (5%), ischemic hepatitis (syn. hypoxic hepatitis, liver infarction) 4%, viral hepatitis A (3%) and Wilson's disease (2%). Hepatic impairment have a direct impact on the pharmacokinetics and pharmacodynamics of drugs decreasing clearance, elimination and excretion of drugs. Also Transjugular intrahepatic porto-systemic shunts, which are often used to treat portal hypertension in patients with liver cirrhosis, can significantly reduce the presystemic elimination of drugs, thereby increasing their absorption. Moreover, in patients with liver cirrhosis, concomitant renal dysfunction also requires an adjustment of the dose of drugs. Correction of pharmacotherapy in accordance to pharmacokinetic and pharmacodynamic changes of drugs ingested by patients with impaired liver function will improve the quality of medical care and reduce the risks of adverse drug reactions.

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl4)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl4-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl4-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl4-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC50 values of 15.1 and 7.94 μM in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration.

This review summarizes the development processes of hepatic impairment (HI) PBPK models, examines current challenges, and proposes potential solutions. Because hepatic impairment can significantly alter a patient’s physiology, HI PBPK models must consider complex in vivo processes leading to potential changes in PK parameters. Adjustments need to be made to absorption, distribution, metabolism, and elimination parameters. Multiple studies already include changes in levels of CYP enzymes, UGTs, transporters, shunting, and protein binding in their HI models. However, despite recent progress, HI PBPK models face multiple challenges and may overpredict drug exposure with increasing severity of liver dysfunction. Foremost among these challenges is the use of the Child–Pugh scoring system in designing HI PBPK models. Furthermore, most HI PBPK models do not account for changes in certain drug parameters, potentially skewing resulting predictions. Ultimately, limitations with PBPK models can be traced to the scarcity of existing HI PBPK models and clinical data. Filling in this knowledge gap is critical to best support safe drug dosing adjustments for hepatically impaired patients. Recent advancements have enhanced the predictive power of HI PBPK models, enabling accurate reflections of clinical trials. However, significant obstacles in developing accurate PK predictions remain, especially for severe impairment.

Hepatic impairment in coronavirus disease 2019 (COVID-19) may derive from cholangiocyte damage in the beginning, but not from direct infection of hepatocytes. Chronic liver disease patients co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited overexpression of angiotensin-converting enzyme 2 receptors and overwhelming cytokine storm. Consensus has been reached that we should encourage as many people as possible to be vaccinated in order to achieve herd immunity. SARS-CoV-2 vaccines can prevent or alleviate severe infection and cytokine storm. It is recommended that all adult patients with chronic liver diseases and liver transplant recipients should receive COVID-19 vaccines using the standard dose and schedule. Data is not yet sufficient to compare the efficacy of different types of vaccines used in chronic liver disease patients.

PurposeOpioids are recommended for moderate-to-severe cancer pain; however, in patients with cancer, impaired hepatic function can affect opioid metabolism. The aim of this systematic review was to evaluate the evidence for the use of opioids in patients with cancer with hepatic impairment.MethodsA systematic review was conducted and the following databases searched: AMED (−2021), MEDLINE (−2021), EMBASECLASSIC + EMBASE (−2021) and Cochrane Central Register of Controlled Trials (−2021). Eligible studies met the following criteria: patients with cancer-related pain, taking an opioid (as defined by the WHO Guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents); >18 years of age; patients with hepatic impairment defined using recognised or study-defined definitions; clinical outcome hepatic impairment related; and primary studies. All eligible studies were appraised using the Grading of Recommendations Assessment, Development and Evaluation system.ResultsThree studies (n=95) were eligible but heterogeneity meant meta-analysis was not possible. Each individual study focused on only one each of oxycodone±hydrocotarnine, oxycodone/naloxone and morphine. No recommendations could be formulated on the preferred opioid in patients with hepatic impairment.ConclusionsMorphine is the preferred opioid in hepatic impairment owing to clinical experience and pharmacokinetics. This review, however, found little clinical evidence to support this. Dose adjustments of morphine and the oxycodone formulations reviewed remain necessary in the absence of quality evidence. Overall, the quality of existing evidence on opioid treatments in cancer pain and hepatic impairment is low and there remains a need for high-quality clinical studies examining this.

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically‐based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once‐daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady‐state total systemic exposures by 1.1‐, 1.5‐, and 1.6‐fold, respectively, for olanzapine, and by 1.2‐, 1.9‐, and 2.3‐fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.

Purpose The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI). Methods Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5–3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (max), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure–response (E–R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens. Results In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E–R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients. Conclusion These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI. Trial registration NCT03359850; registered December 2, 2017

Background: The liver is the core of metabolic activity in the body. Around 50% of the classes of drugs are known to be hepatotoxic. Thus prescribing medications in patients with liver disease is indeed a challenging task. Objectives: To study the prevalence and to carry out the drug utilization evaluation of the therapy prescribed among hepatic impairment patients. Methodology: A prospective observational study was carried out for six months among inpatients of the medicine department of Chigateri district hospital. Patients were enrolled on the basis of inclusion criteria; data was collected using a data collection form and results were analyzed using MS Excel. Results: A total of 160 patients were enrolled, the most prevalent condition was alcoholic liver disease (n=66, 41.25%) followed by chronic liver disease (n=47, 29.38%) and hepatic encephalopathy (n=12, 7.5%). Out of 1466 drugs been prescribed, 795 drugs were used specifically for hepatic impairment. Drugs used to treat oedema (diuretics) were most commonly prescribed (n=198, 25%) followed by gall stone dissolution agents (n=124, 16%) and sugars (n=97, 12%). Conclusion: Alcoholic liver disease was the most prevalent hepatic condition, followed by chronic liver disease. The diuretics were the most widely used hepato-specific drugs among the patients. Key words: Drug utilization pattern, Hepatic impairment, Abstinence, Diuretics.

Background Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child-Pugh score. Child-Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity. Aims To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients. Methods Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically-based pharmacokinetic (PBPK) modelling. Results PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug-metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically-impaired populations. These variables might not correlate with Child-Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child-Pugh score. Conclusions Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child-Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child-Pugh alternatives are recommended to allow better prediction of drug exposure.

Purpose Panitumumab is a human monoclonal antibody targeting the epidermal growth factor receptor for the treatment of wild-type RAS metastatic colorectal cancer (mCRC). Currently, no dedicated clinical studies have evaluated the effect of organ impairment on the pharmacokinetics of panitumumab. Here, we present data from late phase studies of panitumumab in patients with mCRC and analyses of the effect of hepatic or renal impairment on the exposure of panitumumab. Methods From three multicenter, open-label, phase 2 and phase 3 studies, 349 and 351 patients were included in hepatic and renal function subgroup analyses, respectively. Patients who received IV panitumumab and serum exposures were compared to patients with varying degrees of hepatic and renal organ dysfunction. Results The Cmax and Ctrough values for patients with mild (n = 119) and moderate (n = 4) hepatic impairment were within the range of serum concentrations of panitumumab for the normal hepatic function subgroup. The distributions of serum concentration of panitumumab in patients with mild (n = 85) or moderate (n = 19) renal impairment were similar to the serum concentrations of panitumumab in the normal renal function subgroup. Population pharmacokinetic modeling and covariate analysis results were also consistent with lack of any significant effect of renal or hepatic impairment on the pharmacokinetics of panitumumab. Additionally, real-world evidence from case studies of patients with mCRC and severe hepatic or renal impairment, which is a rare patient population to study, indicated lack of clinically relevant differences in exposure of panitumumab compared with patients with mCRC and normal hepatic or renal function. Conclusions Mild-to-moderate hepatic or renal dysfunction had no clinically meaningful impact on the pharmacokinetics of panitumumab in patients with mCRC. No dose adjustments for panitumumab are warranted in patients with mCRC with mild-to-moderate hepatic or renal dysfunction. Trial registration ClinicalTrials.gov; NCT00083616, NCT00089635, NCT00113763

Spathodea campanulata Beauv. is an important plant widely used in traditional medicine for the treatment of hepatic disease. In the present study, we evaluate the phytochemical composition and hepatoprotective potential effect of the stem and root bark extracts of Spathodea companulata on dimethylnitrosamine (DEN) induced hepatic impairment in albino rats. Phytochemical compositions were analyzed using standard protocols. Forty-five male rats were grouped into 9 (A-I) of 5 rats each. Groups A-F were treated with stem bark extract, root bark extract, quercetin, DEN + stem bark extract, DEN + root bark extract, DEN + quercetin respectively while groups G-1 serve as control groups and were treated with corn oil only (Vehicle control), DEN only (Toxicant control), and distilled water (normal control) respectively. DEN was given at 25 mg/kg b.w., i.p on a weekly basis while all treatments were administered at 100 mg/kg BW orally for 60 days. Serum transaminase activities, body weight, and liver body weight ratio were evaluated. Results revealed the presence of alkaloids, cardiac glycoside, saponins, anthraquinone, steroids, and flavonoids in stem bark extract of Spathodea companulata, while the root bark contains cardiac glycoside, saponins, anthraquinonoid, steroids, and flavonoid. The DEN non-treated rat exhibited significant (p

The present study investigated the antitrypanosomal activities of crude and an alkaloidal fraction of Diospyros mespiliformis in Trypanosoma evansi - infected rats. A total of twenty-one (21) rats were divided into seven (7) groups of three (3) rats each. Groups 1-6 were infected with the T. evansi parasite and were treated with 100 and 200 mg/kg BW crude extract, 200 and 400 mg/kg BW of the alkaloid fraction of D. mespiliformis, 3.5mg/kg of berenil (standard control) and 0.2 mL/kg BW of normal saline (negative control) respectively. Group 7 serves as the normal control (non-infected and non-treated) rats. Results revealed that the crude extract at 400 mg/kg BW and alkaloid fraction at all doses tested (100 and 200 mg/kg BW) significantly (P

Study objective Lefamulin is a novel pleuromutilin recently approved by the FDA for the treatment of community-acquired bacterial pneumonia. Given that lefamulin is primarily metabolized by CYP450 Phase-1 reactions, this study evaluated the pharmacokinetics of IV lefamulin in subjects with various degrees of hepatic impairment as compared with matched healthy subjects. Design Open-label, Phase 1 clinical pharmacokinetic study SETTING: Research Study Center PATIENTS: Twenty-seven subjects; comprised of 11 individuals with normal hepatic function and eight each with moderate or severe hepatic impairment were included, as classified by Child-Pugh scores. Measurements and main result Subjects were administered a single dose of IV lefamulin 150 mg over 1 hour. Plasma was collected for 48 hours and analyzed for lefamulin and its major metabolite, BC-8041, concentrations in addition to assessing lefamulin plasma protein binding. Pharmacokinetics were evaluated by noncompartmental analysis. Pharmacokinetic parameters were compared using least square geometric mean ratios. Lefamulin was well tolerated in all hepatic function groups. Statistical analyses revealed reductions in Cmax and increases in renal clearance for Moderate and Severe groups, as well as, increased volume of distribution for the Severe group. Lefamulin plasma AUC mean (SD) was similar across groups at 7615 (1554), 8233 (2286), and 8938 (1640) h·ng/mL for Normal, Moderate, and Severe groups, respectively, despite decreased clearance observed primarily during terminal elimination phases. Decreased plasma protein binding was seen in hepatically-impaired versus normal subjects. Conclusion Lefamulin was generally well tolerated. Differences in lefamulin and BC-8041 pharmacokinetics were small, relative to the overall variability, and any changes appear to be compensated by increases in renal clearance and decreased protein binding.

AimThis phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function.MethodsPatients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients.ResultsThirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug.ConclusionsHepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.

Introducción: el uso de sales de platinos en patologías oncológicas es ampliamente usado, una de las preocupaciones de los profesionales de la salud es la presencia de eventos adversos en este grupo de pacientes que suelen ser vulnerables, por lo que es necesario la generación de consensos para realizar una selección óptima de pacientes candidatos a terapias basadas en platinos Objetivo: Realizar un consenso de expertos para la inelegibilidad al uso de platinos de acuerdo a varios criterios para realizar un tratamiento óptimo de acuerdo a la selección y categorización de pacientes Pregunta de salud cubierta por la Guía: ¿Qué pacientes portadores de cáncer de origen otorrinolaringológico no son elegibles para tratamiento con platinos? Población: La población objetivos son pacientes adultos con cáncer otorrinolaringológico. Resultados: Se establecieron consensos para la inelegibilidad al uso de platinos sobre los siguientes criterios: Edad >70 años, ECOG >1, Pérdida involuntaria de peso >20%, función auditiva “borderline”: alteraciones Grado I, Alteraciones neurológicas Grado I, Trastornos de la función renal: CrCL

Coronavirus disease 2019 (COVID-19) is a devastating worldwide pandemic infection caused by a severe acute respiratory syndrome namely coronavirus 2 (SARS-CoV-2) that is associated with a high spreading and mortality rate. On the date this review was written, SARS-CoV-2 infected about 96 million people and killed about 2 million people. Several arguments disclosed the high mortality of COVID-19 due to acute respiratory distress syndrome or change in the amount of angiotensin-converting enzyme 2 (ACE2) receptor expression or cytokine storm strength production. In a similar pattern, hepatic impairment patients co-infected with SARS-CoV-2 exhibited overexpression of ACE2 receptors and cytokine storm overwhelming, which worsens the hepatic impairment and increases the mortality rate. In this review, the impact of SARS-CoV-2 on hepatic impairment conditions we overviewed. Besides, we focused on the recent studies that indicated cytokine storm as well as ACE2 as the main factors for high COVID-19 spreading and mortality while hinting at the potential therapeutic strategies.

Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, is under development for the treatment of atopic dermatitis. This phase 1, nonrandomized, open-label, single-dose study (NCT03660241) investigated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites following a 200-mg oral dose. Twenty-three subjects with varying degrees of renal function (normal, moderate, and severe impairment) were enrolled. Active moiety exposures were calculated as the sum of unbound exposures for abrocitinib and its active metabolites. For abrocitinib, the adjusted geometric mean ratios (GMRs; %) for area under the concentration-time curve from time 0 extrapolated to infinite time (AUCinf ) and maximum plasma concentration (Cmax ) were 182.91 (90% CI, 117.09-285.71) and 138.49 (93.74-204.61), respectively, for subjects with moderate renal impairment versus normal renal function; corresponding GMRs were 121.32 (68.32-215.41) and 99.11 (57.30-171.43) for subjects with severe impairment versus normal renal function. Metabolite exposures generally increased in subjects with renal impairment. The GMRs of unbound AUCinf and Cmax of active moiety were 210.20 (154.60-285.80) and 133.87 (102.45-174.92), respectively, for subjects with moderate renal impairment versus normal renal function. Corresponding values were 290.68 (217.39-388.69) and 129.49 (92.86-180.57) for subjects with severe renal impairment versus normal renal function. Abrocitinib was generally safe and well tolerated. Both moderate and severe renal impairment led to higher exposure to abrocitinib active moiety, suggesting that abrocitinib dose should be reduced by half for patients with moderate or severe renal impairment. ClinicalTrials.gov identifier: NCT03660241 This article is protected by copyright. All rights reserved.

Synthetic nucleotides that utilize RNA‐centric pharmacology can target diseases at the RNA level, thus altering protein expression in ways previously inaccessible to small molecules and therapeutic biologics. Recognizing that the unique pharmacology of oligonucleotides may require specific considerations in pre‐approval assessment, clinical and nonclinical pharmacology studies being conducted for a selected set of oligonucleotide therapies in a 6‐year period were assessed. This investigation focused primarily on the four following areas: (i) drug‐drug interaction (DDI) potential, (ii) organ impairment (i.e., renal and hepatic impairment), (iii) immunogenicity, and (iv) cardiac safety. Data were summarized and assessed from 14 Investigational New Drug programs and 7 New Drug Applications submitted to the US Food and Drug Administration (FDA) from the period of January 2012 to August 2018, encompassing 152 unique studies. The assessment of DDI potential was largely consistent with the recommendations of current DDI‐relevant guidances. Limited data were available to provide recommendations across organ impairment categories. Limited data on immunogenicity indicate impact on pharmacokinetic, the impact on safety and efficacy, although not extensively evaluated, appeared negligible. Cardiac safety evaluation indicated a potential for discordant translation of risk from nonclinical studies to clinical findings. Continued experience with synthetic oligonucleotide therapies will help inform the development of best practices to support their development and regulatory approval.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open‐label, multicenter, 2‐part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects. Compared to subjects with normal hepatic function, gepotidacin plasma area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) and maximum concentration significantly increased by 1.7‐ and 1.9‐fold, respectively, in severe hepatic impairment; increases in moderate impairment were not statistically significant. No significant effect was observed for gepotidacin plasma elimination half‐life (geometric mean range, 8.2–9.1 hours) across hepatic groups. Renal clearance increased in moderate (16%) and severe (52%) hepatic impairment vs normal. The mean fraction of gepotidacin dose excreted in urine increased with increasing hepatic impairment (normal, 7.5%; moderate, 11.2%; and severe, 19.9%). Urine gepotidacin concentrations remained high for 12 hours in all hepatic groups after dosing. Saliva gepotidacin concentrations displayed a linear relationship with plasma concentrations (R2 = 0.76). The ratio of saliva AUC to unbound plasma AUC and elimination half‐life were not affected by hepatic impairment. These data indicate that gepotidacin dose adjustment is not required in mild to moderate hepatic impairment; severe hepatic impairment may require increases in dosing interval or dose reduction.

The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.

Aim Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment. Methods An open-label, parallel-group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age, and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8). Results Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (Cmax ) and area under the time-concentration curves from 0 to 120 h (AUClast ) values; the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (Cmax and AUClast ) was increased by about 40% in patients with moderate hepatic impairment-the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects. Conclusion Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted. Clinicaltrials.gov number: NCT02754219.

In recent years, a number of tyrosine kinase inhibitors (TKIs) have been approved for the treatment of non‑small cell lung cancer. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. TKIs are administered orally, which has the advantages of improved flexibility and convenience for the patients. However, challenges have arisen in the use of these novel agents. Prescribing drugs for patients with hepatic or renal function impairment poses a challenge for clinicians due to the large pharmacokinetic variability in each individual patient. Moreover, several TKIs have been shown to cause laboratory test abnormalities normally associated with hepatic or renal injury. The aim of the present review was to discuss the effects of hepatic and renal function impairment on the pharmacokinetic variability of 17 TKIs and their potential hepatotoxicity and nephrotoxicity, and to recommend dose adjustment for patients with hepatic or renal impairment.

The objective of this study was to investigate the cumulative fraction of response (CFR) of various tigecycline dosing regimens in patients with hepatic or renal impairment.Monte Carlo simulations were performed using pharmacokinetic parameters and microbiological data to evaluate various tigecycline regimens in patients with hepatic or renal impairment.For HAP and cIAI, the regimen of 25 mg q12h achieved CFR values of90% in Child-Pugh C patients against Gram-positive bacteria and partial Gram-negative bacteria (It is necessary to optimize tigecycline dosage regimens in patients with hepatic or renal impairment in order to maximise clinical response and minimise the probability of exposure-related toxicity.

Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child‐Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child‐Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA‐approved oncology compounds. Discordance between Child‐Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child‐Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child‐Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child‐Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child‐Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child‐Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child‐Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child‐Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions.

Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies. In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5–12, and had their end-of-study visit between days 14 and 16. Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration–time curve from time 0 to infinity (AUCinf) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUCinf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment–emergent adverse events were gastrointestinal and mild. Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.

Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model.Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/10

Dalbavancin is a novel semi-synthetic glycopeptide antibiotic. In this study, we aimed to optimize the dosage regimen of dalbavancin in patients with hepatic or renal impairment by Mote Carlo simulation. Pharmacokinetic parameters and microbiological data were collected about dalbavancin. 10,000 patients with renal or hepatic impairment analyzed by Crystal Ball to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR). We found that all bacterial PTA and CFR were more than 90% for dalbavancin in patients with hepatic or renal impairment, except for Enterococcus faecium. There is no need to adjust the dosage regimen of dalbavancin in patients with hepatic or renal impairment.

Introduction: The global burden of cirrhosis is rising, and clinicians increasingly face the challenge of safely prescribing medicines for complications of hepatic disease and comorbidities. Prescribing in patients with cirrhosis is complicated by alterations that can occur in the pharmacology of medicines.Areas covered: This paper provides an overview of current knowledge on the pharmacokinetics and pharmacodynamics of medicines in patients with cirrhosis. We describe the pathophysiological changes that occur and their consequences on pharmacokinetic parameters. We explain that the influence of cirrhosis on the pharmacokinetics depends on several drug and patient characteristics. Patients with cirrhosis also have an increased susceptibility to some toxicological effects of medicines, such as renal impairment and hematological toxicity, which we describe in detail. In addition, we discuss approaches to apply this knowledge in practice and improve safe medication use in patients with cirrhosis.Expert opinion: Tailored pharmacotherapy is needed to ensure safe and appropriate use of medicines in patients with cirrhosis. Clinicians are supported by freely available recommendations on safe drug use in cirrhosis published on a website. In addition, a regular evaluation of medication use in patients with cirrhosis could resolve and prevent medication-related problems.

Introduction The mineralocorticoid receptor (MR) blocker esaxerenone is a new treatment for hypertension in Japan and under development for treatment of diabetic nephropathy. Hepatic impairment is known to impact the pharmacokinetics (PKs) of other MR blocking drugs. The aim of the present study was to characterise the PKs and safety of a single oral dose of esaxerenone in Japanese subjects with mild–moderate hepatic impairment. Methods In this open-label, parallel-group study, subjects with mild (Child–Pugh grade A) or moderate (grade B) hepatic impairment, and healthy controls with normal hepatic function matched by age and BMI (all groups n = 6), received a single 2.5-mg oral dose of esaxerenone. Plasma concentrations were measured by liquid chromatography–tandem mass spectrometry, and PK parameters were calculated using non-compartmental analysis. Results Geometric least-squares mean (GLSM) ratios (90% confidence intervals [CIs]) for area under the plasma concentration–time curve (up to the last quantifiable time, up to infinity) in subjects with mild hepatic impairment versus normal hepatic function were 0.837 (0.637, 1.099) and 0.824 (0.622, 1.092), respectively. Corresponding values for moderate hepatic impairment versus normal hepatic function were 1.078 (0.820, 1.415) and 1.098 (0.829, 1.454). GLSM ratios (90% CIs) for peak plasma concentration (Cmax) were 0.959 (0.778, 1.182) for mild hepatic impairment versus normal hepatic function and 0.804 (0.653, 0.992) for moderate hepatic impairment versus normal hepatic function. Time to Cmax and clearance values were comparable between groups. The incidence of adverse events (AEs) was 16.7% in the moderate hepatic impairment and normal hepatic function groups. One serious AE (hepatic encephalopathy) occurred in one subject with moderate hepatic impairment. Conclusions Mild to moderate hepatic impairment had no clinically relevant effect on esaxerenone exposure. Esaxerenone dosage adjustment based on PKs is unlikely to be needed in patients with mild to moderate hepatic impairment. Trial Registration JapicCTI-163339. Funding Daiichi Sankyo Co., Ltd.

In terminal illness careful control to avoid long-term complications is not required. Management of diabetes during terminal illness will not only depend on the type of diabetes, but also on prognosis, oral intake and the presence of co-existing disease such as renal and hepatic impairment. All dietary restrictions relating to diabetes are removed from the early stage of terminal illness. In both T1DM and T2DM, glucose monitoring should be reduced to an acceptable minimum. In the case of a patient treated with insulin, this may be 2–3 times per week and for a patient treated with oral agent’s blood glucose could be monitored 1–2 times per week., only in case of special situation frequent monitoring is advisable. This may include: hypoglycaemia, poor food intake, nausea and vomiting, enteral or parenteral feeding or corticosteroid use. The clear aim is to avoid hypoglycaemia and osmotic symptoms, so the recommendations suggest a target blood glucose range between 10 and 15 mmol/l in the early stage of terminal illness with a more liberal range of 5–20 mmol/l in the later stages. Subsequently there are no agreed, evidence-based strategies to manage diabetes at the end of life or during terminal illness. Therefore, in this review I will try to uncover some of the challenges and discuss the available guidelines associated with managing diabetes at the end of life and terminal illness from the available scientific evidence.

Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics (PK) and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's PK, safety, and tolerability following a 200-μg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percent free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf, u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf, u = 1.64 [90% CI, 1.25-2.16]; Cmax,u = 1.30 [0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf, u (1.61 [1.04-2.49]) and comparable Cmax,u (1.02 [0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment. This article is protected by copyright. All rights reserved.

Background We have previously shown that in hepatically impaired CHB patients, switching to TAF from TDF and/or other OAVs maintains high rates of viral suppression with stable bone and renal safety parameters through 48 weeks. Here we present our final 2-year (Week 96) results. Methods In this Phase 2 study (NCT03180619), virally suppressed CHB patients (HBV DNA Results Of 31 patients enrolled, mean age was 55 y (29% ≥60 y), 68% male, 81% Asian, and 90% HBeAg-negative; median (Q1, Q3) CTP and MELD scores were 6 (5, 8) and 10 (7.5, 14.2), respectively, median eGFRCG98.5 mL/min; 19% had osteoporosis on spine DXA. Twenty-five (81%) patients completed 96 weeks of TAF treatment (6 discontinued early: 2-withdrew consent, 1-adverse event [AE; Grade 2 creatinine increase], 1-investigator decision, and 2-death [respiratory failure and aspiration pneumonia - both not treatment-related]). Week 96 efficacy/safety results are summarized in the Table. 96% of patients on TAF treatment had HBV DNA Conclusions At 2 years, CHB patients with hepatic impairment who were switched to TAF maintained high rates of viral suppression and normal ALT values while bone and renal parameters remained stable.

The majority of drugs are metabolised in liver and are known to be hepatotoxic. So, the Drug Utilization Evaluation (DUE) studies become potential tool in hepatic impairment patient to ensure drugs are used appropriately, safely and effectively in order to improve overall health of patient. Drug-Drug Interactions are major cause of concern among hepatic impairment patients due to co-morbidity conditions and wide class of drugs they receive. The clinical result of DDI may manifest as synergism, antagonism or idiosyncratic. This study is aimed to generate data on drug utilization pattern and to assess the prevalence of potential drug-drug interactions (pDDIs) among hospitalised hepatic impairment patients. A prospective observational study was carried out for six months among inpatients of the medicine department of Chigateri District Hospital, Karnataka, India. Potential drug-drug interactions (pDDIs) were analysed using Lexicomp, Medscape drug interaction checker, Stockley’s drug interaction checker. Overall 135 patients were enrolled the study. In this study, 80.68% patients were male. The most common affected age group was 40-59 years. Alcoholic liver disease (46.66%) and chronic liver disease (27.40%) were the most prevalent hepatic condition. Anemia and portal hypertension were the most likely associated comorbidities. Out of 1097 drugs, 569 drugs were used specifically for hepatic impairment. Diuretics (23.02%) were the most frequently prescribed drugs followed by gallstone dissolution agents (18.27%). Total of 264 pDDIs, were identified, of which 76(28.78%) were minor, 180(68.18%) were moderate and 8(3.03%) were major. Potential DDIs were significantly higher in patients taking ?9 medicines (63.63%), hospitalization ?7 days (67.64%) and with one co-morbidity conditions (43.18%). Pharmacodynamic interaction 197 (74.62%) was observed more than that of pharmacokinetic interactions 67(25.37%). The prevalence of alcoholic liver disease in this study was reported th

Aims Pemigatinib, an inhibitor of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases, is approved for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma. Pemigatinib is predominantly metabolized by CYP3A4 with minimal renal elimination. Methods Separate hepatic and renal impairment studies were conducted to evaluate the effect of these impairments on pemigatinib pharmacokinetics (PK). Each study was of open-label, parallel-group design, conducted in participants with normal organ function and with hepatic or renal impairment. Plasma concentrations of pemigatinib were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS) and pemigatinib PK parameters were derived by noncompartmental analysis. Geometric mean ratios and two-sided 90% confidence intervals of Cmax , AUC0-t , and AUC0-∞ were compared by analysis of variance (ANOVA). Results Compared with healthy matched participants: Cmax and AUC0-∞ ratio (90% confidence interval) in participants with moderate hepatic impairment were 96.7% (59.4%, 157%) and 146% (100%, 212%), respectively; Cmax and AUC0-∞ ratio in participants with severe hepatic impairment were 94.2% (68.9%, 129%) and 174% (116%, 261%), respectively; Cmax and AUC0-∞ ratio in participants with severe renal impairment were 64.6% (44.1%, 94.4%) and 159% (95.4%, 264%), respectively; Cmax and AUC0-∞ ratio in participants with end-stage renal disease (ESRD) before haemodialysis (HD) were 77.5% (51.2%, 118%) and 76.8% (54.0%, 109%), respectively; Cmax and AUC0-∞ ratio in participants with ESRD after HD were 90.0% (59.3%, 137%) and 91.3% (64.1%, 130%), respectively. Conclusion Pemigatinib dose should be reduced for patients with severe hepatic or renal impairment, and no dose adjustment is required for patients with moderate hepatic impairment or in ESRD patients undergoing HD.

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.

BACKGROUND: The interaction between hepatitis B virus (HBV) load and anti-programmed cell death (PD)-1 in combination with (+) antiangiogenic therapy remains controversial, especially for hepatocellular carcinoma (HCC) patients. This study sought to explore the effects of HBV load and antiviral therapy on anti-PD-1+ antiangiogenic therapy, and the rate of HBV reactivation during anti-PD-1+ antiangiogenic treatment. METHODS: We performed a multicenter retrospective cohort study of camrelizumab combined with apatinib (C+A) therapy between January 1, 2019 and January 1, 2021 in patients with unresectable HCC who were seropositive for hepatitis B surface antigen (HBsAg) and received antiviral therapy before C+A involvement. The effects of HBV load and antiviral therapy on C+A and the rate of HBV reactivation during C+A treatment were examined. RESULTS: Eighty-six patients were included in the analysis. The patients had a mean age of 55 years, and 72 (83.7%) were male. The objective response rates (ORRs) in patients with low (

Ipatasertib is a highly selective small-molecule pan-Akt inhibitor in clinical development. Ipatasertib is predominantly eliminated by the liver, and therefore the effect of hepatic impairment on ipatasertib pharmacokinetics (PK) was evaluated. In this Phase I open-label, parallel group study, the PK of ipatasertib was evaluated in subjects with hepatic impairment based on both, the Child-Pugh and the National Cancer Institute-Organ Dysfunction Working Group (NCI-ODWG) classification for hepatic impairment. A single dose of ipatasertib at 100 mg was administered and the PK was characterized in healthy subjects with normal hepatic function or mild, moderate and severe hepatic impairment. Based on Child-Pugh classification, subjects with moderate or severe hepatic impairment had an approximately 2- and 3-fold increase in systemic exposure (AUC0-∞ ) to ipatasertib, respectively, compared to subjects with normal hepatic function. Systemic exposure (AUC0-∞ ) to ipatasertib in subjects with mild hepatic impairment was comparable to that in subjects with normal hepatic function. In accordance with reduced clearance capacity, subjects with mild to severe hepatic impairment showed lower systemic exposure (AUC0-∞ ) of ipatasertib metabolite M1 (G-037720). Overall results were comparable between Child-Pugh and NCI-ODWG classification criteria. Based upon the results from this study, no dosage adjustment is required for ipatasertib when treating patients with mild hepatic impairment, whereas a dose reduction would be recommended for subjects with moderate or severe hepatic impairment. Based on real world data analysis, ∼2% of intended patient population is expected to need a modified dose due to moderate or severe hepatic impairment. This article is protected by copyright. All rights reserved.

Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function.This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function.Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78).Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.

Asciminib is an investigational, first-in-class, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes the findings from 2 phase 1 studies assessing the pharmacokinetic (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49%-56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (Cmax ), than matched healthy controls. Based on these findings, as per the protocol, the PK of asciminib in individuals with mild or moderate renal impairment was not assessed. In individuals with mild and severe hepatic impairment, asciminib AUC was 21%-22% and 55%-66% higher, respectively, and Cmax was 26% and 29% higher, respectively, compared with individuals with normal hepatic function. Individuals with moderate hepatic impairment had similar asciminib AUC and Cmax than matched healthy controls. The increase in asciminib AUC and Cmax in the mild hepatic impairment cohort was mainly driven by 1 participant with particularly high exposure. Asciminib was generally well tolerated, and the safety data were consistent with its known safety profile. In summary, these findings indicate that renal or hepatic impairment has no clinically meaningful effect on the exposure or safety profile of asciminib, and support its use in patients with varying degrees of renal or hepatic dysfunction.

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available via www.palliativedrugs.com. The series editors welcome feedback on the articles.

Lei Sun,1 Sergey Yagoda,2 Yangchun Du,3 Lisa von Moltke21Department of Clinical Pharmacology and Translational Medicine, Alkermes, Inc., Waltham, MA, USA; 2Department of Clinical Research, Alkermes, Inc., Waltham, MA, USA; 3Department of Biostatistics, Alkermes, Inc., Waltham, MA, USACorrespondence: Lei SunClinical Pharmacology and Translational Medicine, Alkermes, Inc., 852 Winter Street, Waltham, MA 02451, USATel +1 781 609 6151Fax +1 781 609 5851Email lei.sun@alkermes.comBackground: A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain.Methods: Two multicenter, open-label, parallel-cohort studies were performed to evaluate the effect of moderate hepatic impairment (Child-Pugh score 7–9 [class B]; study 1) and severe renal impairment (estimated glomerular filtration rate: 15–29mL/min/1.73m2,; study 2) on the pharmacokinetics, safety, and tolerability of a single dose of OLZ/SAM 5/10mg.Results: There was a 1.67-fold increase in area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and a 2.17-fold increase in maximum plasma concentration (Cmax) of olanzapine, and a 1.52-fold increase in AUC0-∞ and a 1.63-fold increase in Cmax of samidorphan, in subjects with moderate hepatic impairment compared with healthy control subjects. Compared with healthy control subjects, subjects with severe renal impairment had a 33% and 56% reduction in clearance, a 1.51- and 2.31-fold increase in AUC0-∞, and a 1.32- and 1.37-fold increase in Cmax of olanzapine and samidorphan, respectively.Conclusion: OLZ/SAM 5/10mg was generally well tolerated under the conditions of the studies, with a safety profile consistent with that observed in other clinical studies of OLZ/SAM.Keywords: olanzapine, samidorphan, renal impairment, hepatic impairment, pharmacokinetics &nbsp

Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open‐label, single‐dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15‐mg dose of the upadacitinib extended‐release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child‐Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration‐versus‐time profile from time 0 to infinity (AUCinf) for subjects with mild and moderate hepatic impairment were 1.28 (0.91‐1.79) and 1.24 (0.87‐1.76), respectively. The central ratios of upadacitinib maximum observed concentration (Cmax) were 1.04 (0.77‐1.39) and 1.43 (1.05‐1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics.

The pharmacokinetics and safety of a single oral dose of 200‐mg plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD) in oral solution (Epidiolex in the United States; 100 mg/mL) were assessed in subjects with mild to severe hepatic impairment (n = 8 each for mild and moderate, n = 6 for severe) relative to matched subjects with normal hepatic function (n = 8). Blood samples were collected until 48 hours after dosing and evaluated by liquid chromatography and tandem mass spectrometry. Pharmacokinetic parameters (primarily maximum measured plasma concentration, area under the plasma concentration–time curve from time zero to time t, area under the concentration‐time curve from time zero to infinity, time to maximum plasma concentration, and terminal half‐life) of CBD and its major metabolites were derived using non‐compartmental analysis. CBD was rapidly absorbed in all groups independent of hepatic function (median time to maximum plasma concentration, 2‐2.8 hours). Exposure (area under the concentration–time curve from time zero to infinity) to total CBD slightly increased in subjects with mild hepatic impairment (geometric mean ratio [GMR], 1.48; 90% confidence interval [CI], 0.90‐2.41). However, there were clinically relevant increases in subjects with moderate (GMR, 2.45; 90%CI, 1.50‐4.01) and severe (GMR, 5.15; 90%CI, 2.94‐9.00) hepatic impairment, relative to subjects with normal hepatic function. Exposure to the CBD metabolites (6‐hydroxy‐CBD and 7‐hydroxy‐CBD) also increased in subjects with moderate and severe hepatic impairment, but to a lesser extent than the parent drug. The 7‐carboxy‐CBD metabolite exposure was lower in subjects with severe hepatic impairment when compared with subjects with normal liver function. These findings indicate that dose modification is necessary in patients with moderate and severe hepatic impairment, and a lower starting dose and slower titration are necessary based on benefit‐risk. CBD was well tolerated, and there were no serious adverse events reported during the trial.

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre‐exposure prophylaxis of HIV‐1 infection. Liver disease is a major cause of morbidity and mortality in HIV‐infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30‐mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least‐squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50‐1.06) for AUC0‐∞, 0.69 (0.51‐0.93) for Cmax, 1.40 (0.80‐2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82‐2.94) for CU at 24 hours, 2.14 (1.57‐2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14‐3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment.

Blood-borne miRNAs serve as disease diagnostic biomarkers and await clinical validation. Here, we evaluated Cel-miR-39–3p and miRNA16–5p as calibrator for the quantification of 15 miRNAs linked to hepatic impairment. We added defined copy numbers of Cel-miR-39–3p to plasma of healthy controls (N = 5) and patient samples undergoing liver resection (N = 51). The miRNAs were isolated according to SOPs and quantified by RT-qPCR using the 2-(ΔΔ−CT)-method. Although miRNA16–5p and the spike-in control behaved similar in qPCR assays (R2 = 0.8591) the spike-in control suffered from high inter-patient variability (median 7.6-fold) and low recoveries (median 5.6%, 95% CI 1.5–11.8%). Adding Cel-miR-39–3p to blood samples prior to RNA-isolation improved the recoveries (median 105.7%; 95% CI 29.9–219.9%), yet the inter-patient variability remained high (median 7.2-fold). Alike, we observed significant variability in CT-values for miRNA16–5p (range 14.7-fold) thus rendering this internal, blood-borne reference gene unacceptable as comparator. Specifically, 10 out of 15 diagnostic miRNAs failed the criteria R2 ≥ 0.8 even though we added a defined copy number of Cel-miR-39–3p. This suggests interference of the spike-in control with individual miRNAs in the assay. Our study highlights current limitations in the quantification of blood-borne miRNAs that is of particularly importance when used for disease diagnostic and therapeutic interventions.

Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open‐label, parallel‐group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child–Pugh class A) or moderate (Child–Pugh class B) HI and healthy age‐, sex‐, and body mass index (BMI)‐matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax] and area under the curve extrapolated to infinity [AUC0‐inf]) increased by ~58% (Cmax) and ~25% (AUC0‐inf) in subjects with mild HI and ~22% (Cmax) and ~54% (AUC0‐inf) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060–0.065). All treatment‐emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups., Lemborexant is a dual orexin receptor antagonist approved for the treatment of adults with insomnia. The effect of mild hepatic impairment (HI) on lemborexant (LEM) exposure was small; therefore, a dose adjustment is not warranted in patients with mild HI. However, moderate HI increased overall LEM exposure, thereby warranting a maximum dose recommendation of no more than 5 mg once‐nightly in patients with moderate HI. Lemborexant has not been studied in subjects with severe HI and is not recommended for use in such patients.

Resumen Introducción: la enfermedad de Wilson es una enfermedad heterogénea causada por mutaciones en el gen ATP7B. La presentación clínica es variable, en fenotipos hepáticos y neuropsiquiátricos. El objetivo de este estudio es describir una cohorte retrospectiva de pacientes. Materiales y métodos: estudio retrospectivo descriptivo de pacientes atendidos en el Hospital Pablo Tobón Uribe desde enero de 2004 a septiembre de 2017. Resultados: se reportaron 27 pacientes, 17 hombres y 10 mujeres. El tiempo de seguimiento medio fue de 2,18 años, el 40% presentó síntomas neurológicos; el 29%, psiquiátricos; y el 85%, alteración hepática. En el laboratorio, el 85% presentó ceruloplasmina baja; 55%, cobre urinario alto; en casos con biopsia hepática, 7 tenían depósito de cobre en coloraciones especiales. En neuroimágenes, el 84% presentó hallazgos sugestivos de enfermedad de Wilson y en 3 casos se documentó una mutación genética patogénica. Durante el seguimiento, el 51% mejoró clínica o bioquímicamente, el 11% se mantuvo estable y el 18% se deterioró. El 88% de los casos sobrevivió al final del seguimiento. Conclusiones: este estudio es la cohorte retrospectiva más grande de Colombia. Los resultados son base para nuevos estudios poblacionales buscando de manera activa la enfermedad para documentarla en su fase preclínica y, de este modo, impactar en el pronóstico. Abstract Introduction: Wilson’s disease is a heterogeneous disorder caused by mutations in the ATP7B gene. Its clinical presentation is variable in hepatic and neuropsychiatric phenotypes. The aim of this study is to describe a retrospective cohort of patients. Materials and methods: A descriptive retrospective study was carried out in patients treated at the Hospital Pablo Tobón Uribe from January 2004 to September 2017. Results: 27 patients were reported, 17 men and 10 women. The mean follow-up time was 2.18 years. 40% of the patients had neurological symptoms, 29% psychiatric symptoms, and 85% hepatic impairment. Lab tests showed that 85% had low ceruloplasmin and 55% had increased urinary copper. In cases that underwent liver biopsy, 7 had special copper colorations. Neuroimaging revealed that 84% had findings suggestive of Wilson’s disease and a pathogenic genetic mutation was documented in 3 cases. During follow-up, 51% improved clinically or biochemically, 11% remained stable, and 18% deteriorated. 88% of cases survived at the end of follow-up. Conclusions: This study is the largest retrospective cohort carried out in Colombia. The results are the basis for new population-based studies actively seeking this disease to describe its preclinical development and thus impact prognosis.