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Bepirovirsen is a developmental antisense oligonucleotide (ASO) for treatment of chronic hepatitis B virus infection. No pharmacokinetic (PK) studies comparing participants with hepatic impairment (HI) and healthy participants (HPs) have been conducted with ASOs. Given the target patient population, characterization of bepirovirsen PK in HI was imperative. This phase 1, nonrandomized, open‐label study (NCT04971928) evaluated the PKs of a single 300‐mg dose of bepirovirsen in participants with HI and matched HPs, enrolled in 2 parts (Part 1: moderate HI; Part 2: mild HI). If no predefined difference in the area under the concentration‐time curve from time 0 (predose) to infinite time (AUC0‐∞) and maximum observed concentration (Cmax; geometric mean ratio [GMR] 0.5‐1.5) was identified in Part 1, findings were applied to mild HI, eliminating Part 2. Participants were monitored for 50 days post‐treatment and noncompartmental analysis estimated PK parameters. Twenty‐four participants (moderate HI, n = 12; HP, n = 12) received bepirovirsen and completed Part 1. AUC0‐∞ and Cmax were lower in participants with moderate HI (GMR 0.69 and 0.67, respectively) than in HPs, while apparent clearance (CL/F) and apparent terminal phase volume of distribution (Vz/F) were higher (GMR 1.44 and 1.64, respectively), but fell within the predefined thresholds of difference for this study. Part 2 was omitted. Adverse events were mild. Moderate HI did not have a clinically relevant impact on bepirovirsen PK or safety. [ABSTRACT FROM AUTHOR]

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA‐acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment. [ABSTRACT FROM AUTHOR]

This study compared the safety and pharmacokinetics of a single oral dose of onradivir, an inhibitor of polymerase basic protein 2 in influenza A virus, in patients with hepatic impairment and healthy participants with normal hepatic function. Eight participants with mild hepatic impairment (Child‐Pugh A), eight participants with moderate hepatic impairment (Child‐Pugh B), and eight healthy matched controls were enrolled in this open‐label, parallel‐group clinical trial. After the administration of 600 mg of onradivir, pharmacokinetic parameters were calculated for each cohort and compared. Onradivir was generally well tolerated by all participants. No serious adverse events (AEs) and no deaths were reported during the study. Six patients with moderate hepatic impairment and three patients with mild hepatic impairment reported AEs, all of which were mild and quickly resolved. Compared with the normal liver function group, the maximum concentration, area under the curve from time zero to the last measurable concentration, and area under the curve from time zero to infinity were 103%, 68.5%, and 69.2% higher, respectively, in the mild hepatic impairment group. In the moderate hepatic impairment group, these increases were 101%, 197%, and 204%, respectively. Overall, there were clinically relevant differences in onradivir exposure between patients with mild or moderate hepatic impairment and normal controls. These data imply that onradivir dose adjustment is warranted in patients with mild or moderate hepatic impairment. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05856513). [ABSTRACT FROM AUTHOR]

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child–Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver–gallbladder–compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) is a global health issue that has profound medical and research implications. Methods: This retrospective study examined changes in renal and liver function, as well as lipid metabolism, over a 12-month period in 49 adult patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). All cases were admitted, managed, and followed up with in the PH Center, County Emergency Clinical Hospital of Targu Mures, Romania. Results: Kidney dysfunction was observed in 12.24% of cases at baseline, decreasing to 8.16% at 12 months, and CTEPH patients were more affected. In particular, CTEPH patients exhibited an improvement in renal function, confirmed by an increase in their glomerular filtration rates. Hepatic impairment was present in 57.14% of subjects at baseline, declining to 42.86% at 12 months, with significant improvements noted in the PAH group. Lipid metabolic dysregulations were experienced by 22.45% of all patients at baseline, decreasing to 16.33% at 6 months, with a slow elevation to 24.49% at 12 months, but with no statistically significant differences. Pharmacological regimens were adjusted in accordance with the PH groups, a patient's functional and clinical response, and laboratory tests. Conclusions: Our results demonstrate the multi-organ damage in PH and the importance of individualized treatment approaches. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Trilaciclib is a first‐in‐class, intravenous cyclin‐dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy‐induced myelosuppression in adult patients with extensive‐stage small cell lung cancer receiving a platinum/etoposide‐containing or topotecan‐containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open‐label, parallel‐group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child–Pugh B, n = 8) and severe (Child–Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m2. The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration‐time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child–Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration‐approved trilaciclib dose of 240 mg/m2 should be reduced by ∼30%, to 170 mg/m2, for patients with moderate or severe HI. [ABSTRACT FROM AUTHOR]

This phase 1, open‐label, three‐arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK‐935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child‐Pugh B) or mild (Child‐Pugh A) hepatic impairment or normal hepatic function (matched to hepatic‐impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK‐935‐G (M3) and M‐I were assessed and compared by group. The incidence of treatment‐emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [Cmax], area under the concentration‐time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC∞]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M‐I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M‐I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment. [ABSTRACT FROM AUTHOR]

Introduction: Trofinetide is the first drug to be approved for the treatment of Rett syndrome. Hepatic impairment is not expected to affect the pharmacokinetic (PK) profile of trofinetide because of predominant renal excretion. This study was conducted to help understand the potential impact of any hepatic impairment on trofinetide PK. Methods: This study used physiologically based PK modeling to estimate trofinetide exposure (maximum drug concentration and area under the concentration-time curve from time zero to infinity) in virtual patients with mild, moderate, and severe hepatic impairment (per Child-Pugh classification) compared with virtual healthy subjects following a 12 g oral trofinetide dose. Results: In individual deterministic simulations for matched individuals and stochastic simulations at the population level (100 virtual individuals simulated per population), as anticipated, predicted plasma exposures were similar for healthy subjects and for patients with mild, moderate, and severe hepatic impairment. However, predicted blood concentration exposures slightly increased with increasing severity of hepatic impairment because of change in hematocrit levels. Conclusion: This study indicates that hepatic impairment is not expected to have a clinically relevant effect on exposure to trofinetide. Plain Language Summary: Trofinetide is the first approved treatment for Rett syndrome, a rare genetic condition that affects brain development. When a person takes trofinetide, most is removed from the body via the urine in its unchanged form (no chemical alteration). Regulatory requirements mean researchers must confirm the safety of any pharmaceutical drug and evaluate whether changes in liver function lead to harmful levels of drug exposure. Researchers used a computer model to predict how much trofinetide would be present in the blood and plasma (the liquid portion of blood) over time in virtual healthy subjects and virtual patients with varying degrees of liver disease (mild, moderate, or severe). Computer simulations showed that predicted trofinetide levels in plasma were similar in virtual healthy subjects and each virtual patient group with liver disease. Predicted levels of trofinetide in blood were slightly elevated with increasing severity of liver disease. This is because people with liver disease have fewer red blood cells, so the cell portion of blood becomes smaller relative to the liquid portion (plasma), which leads to higher trofinetide concentrations in whole blood (trofinetide minimally enters the red blood cell). The small increase in trofinetide levels in blood and the absence of any change in trofinetide levels in plasma means that people with Rett syndrome and liver disease are unlikely to be exposed to harmful levels of trofinetide after a 12 g oral dose. [ABSTRACT FROM AUTHOR]

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment. The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability. Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path. [ABSTRACT FROM AUTHOR]

Firsocostat is an oral, liver‐targeted inhibitor of acetyl‐coenzyme A carboxylase in development for the treatment of metabolic dysfunction‐associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho‐glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child–Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7‐fold, and 30‐fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment. [ABSTRACT FROM AUTHOR]

Fenfluramine (Fintepla®) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox–Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child–Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area‐under‐the‐curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC0‐∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36–2.90), 2.13 (1.43–3.17), and 2.77 (1.82–4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure–response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant. [ABSTRACT FROM AUTHOR]

Dersimelagon is an orally administered selective melanocortin‐1 receptor agonist being investigated for treatment of erythropoietic protoporphyria, X‐linked protoporphyria, and diffuse cutaneous systemic sclerosis. Dersimelagon is extensively metabolized in the liver, and potential recipients may have liver dysfunction. Further, effects of renal impairment on pharmacokinetic properties should be established in drugs intended for chronic use. Two separate studies (ClinicalTrials.gov: NCT04116476; NCT04656795) evaluated the effects of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability. Participants with mild (n = 7) or moderate (n = 8) hepatic impairment or normal hepatic function (n = 8) received a single oral 100‐mg dersimelagon dose. Participants with mild (n = 8), moderate (n = 8), or severe (n = 8) renal impairment or normal renal function (n = 8) received a single 300‐mg dose. Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56‐fold higher; area under the plasma concentration‐time curve from time 0 extrapolated to infinity, 1.70‐fold higher) compared with normal hepatic function. Maximum observed plasma concentration and area under the plasma concentration‐time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86‐ and 1.87‐fold higher, respectively) and severe (1.17‐ and 1.45‐fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated. [ABSTRACT FROM AUTHOR]

The evaluation of transporter-mediated drug–drug interactions (DDIs) during drug development and post-approval contributes to benefit–risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations. [ABSTRACT FROM AUTHOR]

This work aimed to assess the feasibility of using population pharmacokinetics (popPK) to generate virtual healthy control groups in organ impairment studies. Data from 11 organ impairment studies containing 18 organ impairment arms and 13 healthy control groups across 7 drugs were analyzed. Area under the concentration‐time curve (AUC) and maximum concentration (Cmax) were calculated from popPK‐simulated individual concentration‐time profiles for participants in the healthy control groups, accounting for the participant's specific covariate(s) (N = 1000 replicates). The AUC and Cmax geometric mean ratios (GMRs; simulated healthy control/observed healthy control and observed organ impairment/simulated healthy control) were calculated. The simulated healthy control group geometric mean exposures were within 30% of the observed geometric mean exposures in 8 of the 11 studies (73%). The number of organ impairment arms for which the observed GMR (observed organ impairment/observed healthy control) and median of simulation‐based GMRs (observed organ impairment/simulated healthy control) for AUC and Cmax being within the same fold change were 12 (67%) and 13 (72%) arms, respectively. The number of organ impairment arms for which the median of simulation‐based AUC and Cmax GMRs were within the 90% confidence interval of the observed GMRs were 14 (72%) and 15 (83%), respectively. Poor concordance was observed for 1 drug (3 arms), where healthy participants' data were not incorporated in the popPK model. This work supports using popPK‐based virtual control groups in organ impairment studies. Subsequent work should aim to establish best practices for constructing popPK‐based virtual control groups. [ABSTRACT FROM AUTHOR]

Introduction: Rezafungin is a second‐generation, once‐weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open‐label, single‐dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function. Methods: Eight subjects each with moderate (Child‐Pugh B) or severe (Child‐Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400‐mg, intravenous, 1‐h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non‐compartmental analysis. Safety was assessed throughout. Results: All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least‐squares (LS) mean ratios, the area under the plasma concentration–time curve from time zero (prior to the start of infusion) to infinity (AUC0–∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child‐Pugh score) on AUC0–∞ or Cmax (p > 0.05). Treatment‐emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal. Conclusions: Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy. [ABSTRACT FROM AUTHOR]

Abstract This phase 1, open‐label, three‐arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK‐935) in participants with hepatic impairment. Participants aged ≥18 to

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child–Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child–Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0–∞]) to pralsetinib, with AUC0–∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0–∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population. [ABSTRACT FROM AUTHOR]

The use of mosquito coils is one method adopted to control malaria Inhalation of the coil smoke causes adverse effects, including hepatic and haematological toxicities associated with oxidative stress. Therefore, this study investigated the effects of phytochemical antioxidants (Quercetin and Omega-3) on mosquito coil smoke-induced haematological and hepatic impairments. Twenty male Wistar rats were divided into 4 groups viz control, mosquito coil-only (MC), mosquito coil+Quercetin (MC+Q) and mosquito coil+Omega-3 (MC+OM3) groups of five rats each. Quercetin and Omega-3 were administered daily at 20mg/kg and 600mg/kg respectively. The duration of daily exposure and treatment was 42 days after which blood samples were collected via cardiac puncture for determination of relevant haematological and hepatic parameters. The RBC count was significantly reduced in the MC group compared with the control (P<0.05) but was higher in the MC+Quercetin group than in the MC group. Haemoglobin was decreased in the MC and MC+Omega-3 groups compared with the control (P<0.05). White blood cell count was higher in the MC group than in the control group (P<0.05) but lower in the MC+OM3 and MC+Q groups than in the MC group (P<0.05). The lymphocyte count was higher in the MC group than in the control group (P<0.05). Serum aspartate transaminase and alanine transaminase were significantly increased (P<0.05) in the MC group compared with the control group but were reduced (P<0.05) in the MC+OM3 and MC+Q groups compared with the MC group. Serum alkaline phosphatase was significantly higher (P<0.05) in the MC group than in control (P<0.05) but significantly lower (P<0.05) in the MC+OM3 group than in the MC group. Serum total bilirubin was significantly elevated in the MC group compared to that in the control group (P<0.05). The serum concentration of direct bilirubin was significantly higher (P<0.05) in the MC group than in the control group. We conclude that Omega-3 and Quercetin ameliorate haematological and hepatic function impairments in Wistar rats exposed to mosquito coil smoke. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is frequently encountered across various specialties. The management of VTE has become more nuanced, requiring consideration of several factors when deciding on the choice and duration of anticoagulation. This evidence-based review article summarises the current practice and evidence behind anticoagulation in VTE, incorporating national and international guidelines. Factors influencing decision-making around the choice and duration of anticoagulation, along with special circumstances such as cancer and antiphospholipid syndrome, are discussed. The clinical utility of thrombophilia screening is also addressed. [ABSTRACT FROM AUTHOR]

Background: Apixaban is a factor Xa inhibitor with a limited therapeutic index that belongs to the family of oral direct anticoagulants. The pharmacokinetic (PK) behavior of apixaban may be altered in elderly populations and populations with renal or hepatic impairment, necessitating dosage adjustments. Methods: This study was conducted to examine how the physiologically based pharmacokinetic (PBPK) model describes the PKs of apixaban in adult and elderly populations and to determine the PKs of apixaban in elderly populations with renal and hepatic impairment. After PBPK models were constructed using the reported physicochemical properties of apixaban and clinical data, they were validated using data from clinical studies involving various dose ranges. Comparing predicted and observed blood concentration data and PK parameters was utilized to evaluate the model's fit performance. Results: Doses should be reduced to approximately 70% of the healthy adult population for the healthy elderly population to achieve the same PK exposure; approximately 88%, 71%, and 89% of that for the elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 96%, 81%, and 58% of that for the Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment elderly populations, respectively to achieve the same PK exposure. Conclusion: The findings indicate that the renal and hepatic function might be considered for apixaban therapy in Chinese elderly patients and the PBPK model can be used to optimize dosage regimens for specific populations. [ABSTRACT FROM AUTHOR]

Nirmatrelvir, a novel, potent, orally bioavailable severe acute respiratory syndrome coronavirus 2 main protease inhibitor, coadministered with ritonavir for pharmacokinetic (PK) enhancement is licensed for the treatment of mild to moderate COVID‐19 in individuals at increased risk of progression to severe disease. Cytochrome P450 3A4 is the primary metabolic enzyme responsible for nirmatrelvir metabolism; however, when cytochrome P450 3A4 is inhibited by ritonavir, nirmatrelvir is primarily excreted, unchanged, in urine. Because of intended use of nirmatrelvir among individuals with hepatic impairment, this Phase 1 study (NCT05005312) evaluated the effects of hepatic impairment on nirmatrelvir PK parameters to assess the potential need for any dose adjustments in this population. Participants with normal hepatic function or moderate hepatic impairment (n = 8 each) were administered a single 100‐mg nirmatrelvir dose, with 100 mg of ritonavir administered 12 hours before, together with, and 12 and 24 hours after nirmatrelvir. Nirmatrelvir median plasma concentrations and systemic exposure measured by area under the plasma concentration–time curve from time zero extrapolated to infinite time and maximum observed plasma concentration values were comparable in both groups. Nirmatrelvir/ritonavir had an acceptable safety profile in both groups, and no clinically significant changes in laboratory measurements, vital signs, or electrocardiogram assessments were observed. Based on these results, no dose adjustment is deemed necessary in patients with moderate hepatic impairment and, by extension, in patients with mild hepatic impairment. [ABSTRACT FROM AUTHOR]

To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates. [ABSTRACT FROM AUTHOR]

Nalbuphine (NAL) is a mixed κ-agonist/μ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child–Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver–gallbladder–compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition.

Background: Pulmonary hypertension (PH) is a global health issue that has profound medical and research implications. Methods: This retrospective study examined changes in renal and liver function, as well as lipid metabolism, over a 12-month period in 49 adult patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). All cases were admitted, managed, and followed up with in the PH Center, County Emergency Clinical Hospital of Targu Mures, Romania. Results: Kidney dysfunction was observed in 12.24% of cases at baseline, decreasing to 8.16% at 12 months, and CTEPH patients were more affected. In particular, CTEPH patients exhibited an improvement in renal function, confirmed by an increase in their glomerular filtration rates. Hepatic impairment was present in 57.14% of subjects at baseline, declining to 42.86% at 12 months, with significant improvements noted in the PAH group. Lipid metabolic dysregulations were experienced by 22.45% of all patients at baseline, decreasing to 16.33% at 6 months, with a slow elevation to 24.49% at 12 months, but with no statistically significant differences. Pharmacological regimens were adjusted in accordance with the PH groups, a patient’s functional and clinical response, and laboratory tests. Conclusions: Our results demonstrate the multi-organ damage in PH and the importance of individualized treatment approaches.

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 0.5 mg 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.

Saroglitazar magnesium, a dual peroxisome proliferator–activated receptor agonist, is under evaluation for treating various liver conditions. While the pharmacokinetics (PK) of saroglitazar have been extensively studied in diverse preclinical models and healthy subjects, a comprehensive assessment of its PK behavior under conditions of hepatic impairment is lacking. In this Phase 1, open‐label, parallel‐group study, the PK of a single dose of 4‐mg saroglitazar magnesium was investigated in subjects having varying degrees of hepatic impairment with and without portal hypertension compared with appropriately matched individuals having normal hepatic function. Treatment‐emergent adverse events for safety were also evaluated. Thirty‐two subjects were enrolled in the hepatic‐impaired groups and 23 subjects in the normal hepatic function group. Mild and moderate hepatic impairment did not significantly affect the PK of saroglitazar, compared with normal hepatic function. Although severe hepatic impairment did not alter maximum observed plasma concentration and half‐life; saroglitazar exposure (area under the plasma concentration–time curve from time 0 to infinity) increased 3‐fold, while the clearance was 61% lower compared to the subjects with normal hepatic function. This may require close monitoring or dose adjustments in individuals with severe hepatic impairment. A single oral dose of saroglitazar magnesium 4 mg was found to be safe and well tolerated in subjects with varying degrees of hepatic function. [ABSTRACT FROM AUTHOR]

Background: Petrol Pump attendants (PPA) in India wear a variety of safety gear, including as overalls, masks, and gloves. It is still entirely unknown if they can effectively protect vulnerable organs like the liver and kidney. The study's objective is to examine the hepato-renal axis' biochemical characteristics in PPA employees who wore protective gear while on duty and those who did not. Methods: The research population was divided into three Groups. Group A consisted of 15 adults male PPAs who had consistently implemented protective measures when administering petroleum products. 32 PPA who did not wear protective gear made up Group B. A total of twenty-eight male adults who had not been exposed to petroleum products made up Group C, the control Group. For PPA selected for the research, a minimum of five years of exposure was required. Through the administration of a questionnaire, data on worker safety was gathered about the usage of self-protective gear as a standard safety procedure for personal protection. To evaluate biochemical indicators of hepato-renal functioning, serum was used. Both the Student's t test and the analysis of variance were used to find statistical differences. It was deemed significant at p 0.05. Results: ALP, AST, ALT, creatinine, urea, albumin, and total protein activities or levels in both Group A and Group B were substantially different from control (Group C), suggesting liver impairment. Conclusion: Data from this study indicate that none of the three protective gear options employed by PPA in Group B significantly decreased exposure. [ABSTRACT FROM AUTHOR]

Background: Dengue virus infection has become a major public health concern in recent years due to an increase in its complex and unusual symptoms. Hepatomegaly increased liver enzymes to fulminant hepatic failure are just a few of the diverse signs of dengue's hepatic involvement. Material and Methods: At the Department of Paediatrics, Vishwanharathi Medical College & General Hospital, R T Nagar Near Penchikalapadu, Kurnool, Andhra Pradesh, India, this was the prospective Cohort Study that was planned. The study used 50 people who were treated with a Dengue infection and had a positive test for Dengue. Patients with a Dengue Sero positive are chosen and checked for hepatomegaly and jaundice. They also get a full blood count, Liver function tests, and an ultrasound of the abdomen, PT, APTT, HBsAg, HCV and Widal. Study was done between February 2022 to January 2023. Results: Early detection of dengue's hepatic dysfunction could help determine how serious the condition is. Massive hemorrhage and other life-threatening consequences could be avoided with early management. Future research should test the role of hepatoprotective medications in dengue to promote early recovery and lower morbidity and mortality. Conclusion: There have been various reports of dengue outbreaks increasing hepatic involvement in emerging nations like India. Early detection of hepatic dysfunction should help to prevent lifethreatening consequences because it is temporary and reversible in dengue. [ABSTRACT FROM AUTHOR]

Hepatic impairment (HI) influences the pharmacokinetics and pharmacodynamics of drugs and represents an important risk factor for drug safety. A reliable screening tool for HI identification at hospital admission by pharmacists would be desirable but is currently lacking. Therefore, we tested four liver scores as potential screening instruments. We retrospectively recorded liver/bile diagnoses, symptoms and abnormalities (summarized as hepatic findings) of 200 surgical patients followed by an assessment of the relevance of these findings for drug therapy (rating). The agreement between the Model of Endstage Liver Disease (MELD), Non-alcoholic fatty liver disease fibrosis score (NFS), Fibrosis 4 index (FIB-4), and aspartate-aminotransferase to platelet ratio index (APRI) and the rating was quantified by Cohen's Kappa. The performance of the scores in this setting was further evaluated by their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Of 200 patients, 18 (9%) had hepatic findings relevant for drug therapy. Fair agreement was found for FIB-4 and MELD and slight agreement for APRI and NFS compared to the rating. The highest values for sensitivity, specificity, PPV, and NPV were 41.2% (MELD), 99.3% (APRI), 66.7% (APRI), and 93.6% (MELD), respectively. Due to low performance, none of the scores can be recommended for clinical use as a single screening tool for HI at hospital admission. [ABSTRACT FROM AUTHOR]

The evaluation of transporter-mediated drug–drug interactions (DDIs) during drug development and post-approval contributes to benefit–risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations.

Background: Petrol Pump attendants (PPA) in India wear a variety of safety gear, including as overalls, masks, and gloves. It is still entirely unknown if they can effectively protect vulnerable organs like the liver and kidney. The study's objective is to examine the hepato-renal axis' biochemical characteristics in PPA employees who wore protective gear while on duty and those who did not. Methods: The research population was divided into three Groups. Group A consisted of 15 adults male PPAs who had consistently implemented protective measures when administering petroleum products. 32 PPA who did not wear protective gear made up Group B. A total of twenty-eight male adults who had not been exposed to petroleum products made up Group C, the control Group. For PPA selected for the research, a minimum of five years of exposure was required. Through the administration of a questionnaire, data on worker safety was gathered about the usage of self-protective gear as a standard safety procedure for personal protection. To evaluate biochemical indicators of hepato-renal functioning, serum was used. Both the Student's t test and the analysis of variance were used to find statistical differences. It was deemed significant at p 0.05. Results: ALP, AST, ALT, creatinine, urea, albumin, and total protein activities or levels in both Group A and Group B were substantially different from control (Group C), suggesting liver impairment. Conclusion: Data from this study indicate that none of the three protective gear options employed by PPA in Group B significantly decreased exposure.

Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child–Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP‐A or B; 10 mg for CP‐C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration–time curve was 76%, 2.5‐fold, and 6.3‐fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration–time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2‐fold, and 3.16‐fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α‐hydroxy‐4‐cholesten‐3‐one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor‐related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI. [ABSTRACT FROM AUTHOR]

Purpose: 5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment. Methods: Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment. Results: The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes′ activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics. Conclusions: PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios. [ABSTRACT FROM AUTHOR]

Rimegepant is a small‐molecule calcitonin gene–related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75‐mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open‐label, single‐dose, 4‐group phase 1 study. Thirty‐six subjects aged 41‐71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0‐ and 3.9‐fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration–time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration–time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment‐emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment. [ABSTRACT FROM AUTHOR]

Yiming Cheng,1 Ying Ye,1 Allison Gaudy,1 Atalanta Ghosh,2 Yongjun Xue,3 Alice Wang,1 Simon Zhou,1 Yan Li1 1Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, Princeton, NJ, USA; 2Global Biometrics and Data Sciences, Bristol Myers Squibb, Princeton, NJ, USA; 3Nonclinical Research & Development, Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Yan Li, Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, 556 Morris Ave, Summit, Princeton, NJ, 07901, USA, Tel +1 908-481-6203, Email Yan.Li@bms.comIntroduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12.Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful.Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.Keywords: hepatic impairment, iberdomide, pharmacokinetics

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child–Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child–Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0–∞]) to pralsetinib, with AUC0–∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0–∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

The article discusses the challenges and future considerations in evaluating pharmacokinetics (PK) in liver disease, particularly hepatic dysfunction (HI), and the benefit of in silico methods. It highlights the prevalence of liver disease in the United States and the exclusion of patients with underlying liver disease from clinical trials. It also mentions the potential use of physiologically based pharmacokinetic (PBPK) modeling to predict PK changes in silico.

The kidneys and liver are major organs involved in eliminating small-molecule drugs from the body. Characterization of the effects of renal impairment (RI) and hepatic impairment (HI) on pharmacokinetics (PK) have informed dosing in patients with these organ impairments. However, the knowledge about the impact of organ impairment on therapeutic peptides and proteins is still evolving. In this study, we reviewed how often therapeutic peptides and proteins were assessed for the effect of RI and HI on PK, the findings, and the resulting labeling recommendations. RI effects were reported in labeling for 30 (57%) peptides and 98 (39%) proteins and HI effects for 20 (38%) peptides and 55 (22%) proteins. Dose adjustments were recommended for RI in 11 of the 30 (37%) peptides and 10 of the 98 (10%) proteins and for HI in 7 of the 20 (35%) peptides and 3 of the 55 (5%) proteins. Additional actionable labeling includes risk mitigation strategies; for example, some product labels have recommended avoid use or monitor toxicities in patients with HI. Over time, there is an increasing structural diversity of therapeutic peptides and proteins, including the use of non-natural amino acids and conjugation technologies, which suggests a potential need for reassessing the need to evaluate the effect of RI and HI. Herein, we discuss scientific considerations for weighing the risk of PK alteration due to RI or HI for peptide and protein products. We briefly discuss other organs that may affect the PK of peptides and proteins administered via other delivery routes. [ABSTRACT FROM AUTHOR]

JNJ‐73763989 is comprised of 2 short interfering RNAs (siRNAs), JNJ‐73763976 and JNJ‐73763924, that target hepatitis B virus (HBV) mRNAs for degradation, thereby inhibiting HBV replication. JNJ‐56136379 is a capsid assembly modulator that inhibits HBV replication by inducing the formation of empty capsids (CAM‐E). In 2 phase 1, open‐label, non‐randomized, single‐center studies, the single‐dose pharmacokinetics, safety, and tolerability of JNJ‐73763989 or JNJ‐56136379 were assessed in participants with moderate hepatic impairment (Child–Pugh Class B) versus participants with normal liver function. Participants in both studies received a single subcutaneous dose of JNJ‐73763989 200 mg or oral JNJ‐56136379 250 mg, followed by an evaluation of plasma pharmacokinetic parameters and safety assessments. Plasma exposure to JNJ‐73763976, JNJ‐73763924, and JNJ‐56136379 was 1.3‐ to 1.4‐, 1.8‐ to 2.2‐, and 1.1‐ to 1.3‐fold higher in participants with moderate hepatic impairment versus participants with normal liver function; however, these increases were not considered clinically relevant. Both drugs were well tolerated and safe, with 7 (21.9%) participants experiencing 1 or more treatment‐emergent adverse events, 3 of which were related to JNJ‐56136379. Overall, the plasma exposures of JNJ‐73763989 and JNJ‐56136379 were higher in participants with moderate hepatic impairment, but both were well tolerated. Further studies are needed to evaluate the effect of hepatic impairment under multiple‐dose administration. [ABSTRACT FROM AUTHOR]

Summary: Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. This open-label, parallel-group study investigated the effect of chronic hepatic impairment on the pharmacokinetics (PK) of brigatinib to inform dosing recommendations for these patients. Participants with hepatic impairment classified according to Child-Pugh categories of mild (A), moderate (B), or severe (C) and matched-healthy participants with normal hepatic function received a single oral dose of 90-mg brigatinib. Plasma samples were collected for the determination of brigatinib plasma protein binding and estimation of plasma PK parameters. Twenty-seven participants were enrolled (Child-Pugh A–C, n = 6 each; matched-healthy participants, n = 9). The mean fraction of free plasma brigatinib was comparable for the Child-Pugh A (11.1%), Child-Pugh B (10.8%), and healthy participant groups (8.5%); free brigatinib was higher in the Child-Pugh C group (23.1%). There were no clinically meaningful effects of mild or moderate hepatic impairment on unbound systemic exposures (area under the plasma concentration-time curve [AUC]) of brigatinib (geometric least-squares mean ratios [90% CI] of 89.32% [69.79%–114.31%] and 99.55% [77.78%–127.41%], respectively). In the severe hepatic impairment group, brigatinib unbound AUC was approximately 37% higher (geometric least-squares mean ratio [90% CI] of 137.41% [107.37%–175.86%]) compared with healthy participants with normal hepatic function. Brigatinib was well tolerated in healthy participants and in participants with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. The brigatinib dose should be reduced by approximately 40% for patients with severe hepatic impairment. [ABSTRACT FROM AUTHOR]

Histopathologic, transcriptomic, pathophysiologic, and clinical characteristics of COVID-induced liver injury from the mitochondria' eye view. [Display omitted] • Patients with COVID-19 are at high risk of liver damage. • The underlying mechanism is still undefined. • SARS-CoV-2 can damage mitochondria directly or through systemic inflammation. • COVID-induced liver injury is more in patients with weaker mitochondria. • Boosting mitochondria can protect liver from COVID-induced injury. Liver damage is a common sequela of COVID-19 (coronavirus disease 2019), worsening the clinical outcomes. However, the underlying mechanism of COVID-induced liver injury (CiLI) is still not determined. Given the crucial role of mitochondria in hepatocyte metabolism and the emerging evidence denoting SARS-CoV-2 can damage human cell mitochondria, in this mini-review, we hypothesized that CiLI happens following hepatocytes' mitochondrial dysfunction. To this end, we evaluated the histologic, pathophysiologic, transcriptomic, and clinical features of CiLI from the mitochondria' eye view. Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the causative agent of COVID-19, can damage hepatocytes through direct cytopathic effects or indirectly after the profound inflammatory response. Upon entering the hepatocytes, the RNA and RNA transcripts of SARS-CoV-2 engages the mitochondria. This interaction can disrupt the mitochondrial electron transport chain. In other words, SARS-CoV-2 hijacks the hepatocytes' mitochondria to support its replication. In addition, this process can lead to an improper immune response against SARS-CoV-2. Besides, this review outlines how mitochondrial dysfunction can serve as a prelude to the COVID-associated cytokine storm. Thereafter, we indicate how the nexus between COVID-19 and mitochondria can fill the gap linking CiLI and its risk factors, including old age, male sex, and comorbidities. In conclusion, this concept stresses the importance of mitochondrial metabolism in hepatocyte damage in the context of COVID-19. It notes that boosting mitochondria biogenesis can possibly serve as a prophylactic and therapeutic approach for CiLI. Further studies can reveal this notion. [ABSTRACT FROM AUTHOR]

Encorafenib, a potent BRAF kinase inhibitor gets significantly metabolised by CYP3A4 (83%) and CYP2C19 (16%) and is a substrate for P-glycoprotein (P-gp). Due to significant metabolism by CYP3A4, encorafenib exposure can increase in hepatic and renal impairment and may lead to altered magnitude of drug-drug interactions (DDI). Hence, it is necessary to assess the exposures & DDI's in impaired population. Physiologically based pharmacokinetic modelling (PBPK) was utilised to determine the exposures of encorafenib in hepatic and renal impairment along with altered DDI's. Prospective DDI's were predicted with USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors and CYP3A4 inducers. PBPK models for encorafenib, perpetrators simulated PK parameters within 2-folds error. Encorafenib exposures significantly increased in hepatic as compared to renal impairment because of reduced CYP3A4 levels. Hepatic impairment caused changes in inhibition and induction DDI's, when compared to healthy population. Renal impairment did not cause significant changes in DDIs except for itraconazole. P-gp, CYP2C19 inhibitors did not result in altered DDI's. The DDI's were found to have insignificant correlation with relative exposure increase of perpetrators in case of impairment. Overall, this work signifies use of PBPK modelling for DDI's evaluations in hepatic and renal impairment populations. [ABSTRACT FROM AUTHOR]

Use of direct oral anticoagulants (DOACs) in patients with cancer on active chemotherapy is challenging due to changes in renal or hepatic function, thrombocytopenia, chemotherapy-induced nausea and vomiting (CINV), and drug-drug interactions (DDIs) attributed to disease or treatment. The purpose of this retrospective cohort analysis was to characterize DOAC management through various interventions and evaluate the efficacy and safety of DOAC use in this patient population. A total of 58 patients with 97 unique index periods in which a patient was concomitantly on a DOAC and chemotherapy were identified. Several instances were observed in which an intervention should be made based on manufacturer guidance or clinical judgment. Of 37 instances attributed to changes in renal function, the following interventions were employed: dose adjustments (10/37), holding DOAC therapy until renal function improved (held 3/37, restarted 4/37), changing to an alternative anticoagulant (5/37), DOAC discontinuation (2/37), or no change (13/37). One change was made in response to decreased hepatic function (1/15). DOACs were held in the setting of platelet counts below 50 K/mm3 (8/20) and restarted when platelets improved above this threshold (5/20). In patients with CINV, DOAC therapy was continued (26/32) with few changes made. To manage DOAC-chemotherapy DDIs, changes in DOAC agents (4/6) and dose reductions in chemotherapy agents (2/6) were made. Thrombotic and bleeding events did not strongly correlate with renal or hepatic impairment, thrombocytopenia, CINV, or DDIs. Further guidance regarding the use of these agents in this patient population is warranted to address management strategies, efficacy, and safety. Use of direct oral anticoagulants (DOACs) in patients with cancer on active chemotherapy is challenging due to changes in renal or hepatic function, thrombocytopenia, chemotherapy-induced nausea and vomiting (CINV), and drug-drug interactions (DDIs) attributed to disease or treatment. The purpose of this retrospective cohort analysis was to characterize DOAC management and evaluate the efficacy and safety of DOAC use in this patient population. A total of 58 patients with 97 unique index periods in which a patient was concomitantly on a DOAC and chemotherapy were identified. Several instances were observed in which an intervention should be made based on manufacturer guidance or clinical judgment. Interventions employed are summarized graphically. Thrombotic and bleeding events did not strongly correlate with renal or hepatic impairment, thrombocytopenia, CINV, or DDIs. CINV chemotherapy-induced nausea and vomiting, DDIs drug-drug interactions, DOAC direct oral anticoagulant, OAC oral anticoagulant [ABSTRACT FROM AUTHOR]

Background The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486.Research design and methods This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min.Results In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS).Conclusions Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment.Trial registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.