Effect of Hepatic Impairment on Trilaciclib Pharmacokinetics.

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.

Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [C], area under the curve [AUC] and AUC) and secondary PK parameters (AUC, apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [T], and half-life [T]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non‑compartmental analysis.

Pharmacokinetics of Oral Nirmatrelvir/Ritonavir, a Protease Inhibitor for Treatment of COVID-19, in Subjects With Renal Impairment.

Nirmatrelvir coadministered with ritonavir is highly efficacious in reducing the risk of coronavirus disease 2019 (COVID-19) adverse outcomes among patients at increased risk of progression to severe disease, including patients with chronic kidney disease. Because nirmatrelvir is eliminated by the kidneys when given with ritonavir, this phase I study evaluated the effects of renal impairment on pharmacokinetics, safety, and tolerability of nirmatrelvir/ritonavir. Participants with normal renal function (n = 10) or mild, moderate, or severe renal impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose with 100 mg ritonavir given 12 hours before, together with and 12 and 24 hours after the nirmatrelvir dose.

Characterization of Potassium-Induced Natriuresis in Hypertensive Postmenopausal Women During Both Low and High Sodium Intake.

Background: Potassium-induced natriuresis may contribute to the beneficial effects of potassium on blood pressure but has not been well-characterized in human postmenopausal hypertension. We determined the time course and magnitude of potassium-induced natriuresis and kaliuresis compared with hydrochlorothiazide in 19 hypertensive Hispanic postmenopausal women. We also determined the modulating effects of sodium intake, sodium-sensitivity, and activity of the thiazide-sensitive NCC (sodium-chloride cotransporter).

Evaluation of the Pharmacokinetics and Safety of a Single Dose of Acalabrutinib in Subjects With Hepatic Impairment.

Acalabrutinib received approval for the treatment of adult patients with mantle cell lymphoma who received at least 1 prior therapy and adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study investigated the impact of hepatic impairment (HI) on acalabrutinib pharmacokinetics (PK) and safety at a single 50-mg dose in fasted subjects. This study was divided into 2 parts: study 1, an open-label, parallel-group study in Child-Pugh class A or B subjects and healthy subjects; and study 2, an open-label, parallel-group study in Child-Pugh class C subjects and healthy subjects.

Pharmacokinetics of Gepotidacin in Subjects With Normal Hepatic Function and Hepatic Impairment.

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.

Thiazide-Sensitive NCC (Sodium-Chloride Cotransporter) in Human Metabolic Syndrome: Sodium Sensitivity and Potassium-Induced Natriuresis.

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome.

Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment.

Two open-label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m ) and 8 healthy age-, sex-, and body mass index-matched controls were administered a single oral dose of voxelotor 900 mg.

Pharmacokinetics of Gepotidacin in Renal Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. In this phase 1, nonrandomized, open-label, parallel-group, multicenter, multipart study, the pharmacokinetics, safety, and tolerability of a single intravenous (IV) dose of gepotidacin 750 mg over 2 hours were evaluated in subjects with normal renal function, in those with moderate and severe renal impairment, and in end-stage renal disease (ESRD) on and not on dialysis. Administration of IV gepotidacin 750 mg was safe and generally tolerated in the study subjects.

A phase 1, open-label, single-dose study of the pharmacokinetics of zanubrutinib in subjects with varying degrees of hepatic impairment.

The pharmacokinetics and safety of single-dose zanubrutinib (80 mg) were assessed in subjects with mild, moderate, and severe hepatic impairment ( = 6 each, Child-Pugh class A, B, and C) relative to healthy controls ( = 11). Zanubrutinib median was 1.25-2.

Single-Center Investigation of the Pharmacokinetics of WCK 4282 (Cefepime-Tazobactam Combination) in Renal Impairment.

WCK 4282 is a combination product of cefepime (FEP) and tazobactam (TAZ) in a 1:1 ratio currently under development for the treatment of multidrug-resistant Gram-negative bacterial infections. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 4282 in 48 subjects with various degrees of renal function. Subjects were categorized on the basis of their Cockcroft-Gault equation-estimated creatinine clearance (CL).

Outcomes of minority patients with very severe hypertension (>220/>120 mmHg).

Objectives: Acute severe hypertension is a common problem among inner-city ethnic minority populations. Nevertheless, the effects of currently employed treatment regimens on blood pressure have not been determined in a clinical practice setting. We determined the SBP responses to acute antihypertensive drug protocols and the 2-year natural history of patients presenting with severe hypertension.

Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment.

WCK 5222 is a novel β-lactam-β-lactam-enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel β-lactam enhancer with a dual action of binding to Gram-negative penicillin-binding protein 2 (PBP2) and β-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogen infections.

Pharmacokinetics and safety of glecaprevir and pibrentasvir in HCV-negative subjects with hepatic impairment.

Purpose: This study characterized the effects of hepatic impairment on the pharmacokinetics and safety of glecaprevir and pibrentasvir, two direct-acting antivirals used for treatment of chronic HCV infection.

Methods: HCV-negative subjects with normal hepatic function, or with mild (Child-Pugh [CP]-A), moderate (CP-B), or severe (CP-C) hepatic impairment received single doses of pibrentasvir 120 mg alone or with glecaprevir 200 mg or 300 mg (n = 6/functional group/dose). Plasma pharmacokinetics and protein binding were evaluated.

Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed.

Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry.

The re-emergence of Zika virus (ZIKV) and Ebola virus (EBOV) poses serious and continued threats to the global public health. Effective therapeutics for these maladies is an unmet need. Here, we show that emetine, an anti-protozoal agent, potently inhibits ZIKV and EBOV infection with a low nanomolar half maximal inhibitory concentration (IC) in vitro and potent activity in vivo.

Effects of Renal Impairment and Hemodialysis on the Pharmacokinetics and Safety of the Glecaprevir and Pibrentasvir Combination in Hepatitis C Virus-Negative Subjects.

Hepatitis C virus (HCV) infection is an independent risk factor for developing chronic renal impairment and end-stage renal disease. Limited treatment options are available for HCV genotype 2, 3, 5, and 6 infections in patients with an estimated glomerular filtration rate (eGFR) of <30 ml/min. Glecaprevir and pibrentasvir are active against all six major HCV genotypes, are primarily excreted in the bile, and have minimal renal elimination.

Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment.

Background: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection.

Objective: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment.

Methods: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study.

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.

Introduction: Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.

Methods: These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.

Prehypertension is real and can be associated with target organ damage.

Prehypertension (systolic blood pressure 120-139 or diastolic blood pressure 80-89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors.

Single-Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment.

Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites.

Effects of Mild to Severe Hepatic Impairment on the Pharmacokinetics of Sonidegib: A Multicenter, Open-Label, Parallel-Group Study.

Background And Objective: Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function.

Methods: The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects.

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment.

Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram-positive, Gram-negative, atypical, and anaerobic bacteria, including methicillin-resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia. This was a phase 1, open-label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C, respectively) compared with matched healthy controls.

Pharmacokinetics and Tolerability of Anti-Hepatitis C Virus Treatment with Ombitasvir, Paritaprevir, Ritonavir, with or Without Dasabuvir, in Subjects with Renal Impairment.

Background: The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles.

Objective: The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens.