First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension.

Effect of CSL112 (apolipoprotein A-I [human]) on cholesterol efflux capacity in Japanese subjects: Findings from a phase I study and a cross-study comparison.

CSL112 (apolipoprotein A-I [apoA-I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring.

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first-in-human trial of the activated Factor XII inhibitor garadacimab (CSL312).

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa).

Pharmacometric analysis linking immunoglobulin exposure to clinical efficacy outcomes in chronic inflammatory demyelinating polyneuropathy.

The two main objectives of this analysis were to (i) characterize the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra ) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG pharmacokinetic (PK) parameters, including those from a previous population PK model, were used to predict individual IgG profile and exposure metrics. Treatment-related changes in Inflammatory Neuropathy Cause and Treatment (INCAT) scores were best described by a maximum effect (E ) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilization).

Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.

Aims: To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients.

Methods: A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations.

Pharmacometric modeling to explore 4F-PCC dosing strategies for VKA reversal in patients with INR below 2.

The indicated dose of 4-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with an international normalized ratio (INR) of 2 to 4 is 25 IU/kg, but there is no indicated dose for INR <2. We explored 4F-PCC dosing strategies for baseline INR <2. Clinical trial data were used to develop pharmacometric models for Factor X (FX) and FII, accounting for covariates including baseline INR.

Pharmacometric Analysis of IgPro10 in Japanese and Non-Japanese Patients With Primary Immunodeficiency.

Purpose: Immunoglobulin (Ig) G replacement therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is the standard treatment in patients with primary immunodeficiencies (PID). We aimed to characterize the pharmacokinetic (PK) characteristics of serum IgG following administration of IgPro10 every 3 or 4 weeks in Japanese patients with PID, and compare with PK in non-Japanese patients. A previously developed population PK (PPK) model was validated, and predicted parameters were compared with the results from the clinical study.

Pharmacokinetic properties of Privigen in Japanese patients with primary immunodeficiency.

This prospective, Phase 3, open-label, study (EudraCT: 2016-001631-12) evaluated pharmacokinetic (PK) characteristics of 3-/4-weekly Privigen (IgPro10, CSL Behring, King of Prussia, PA, USA) in Japanese patients with PID. PK parameters including serum trough immunoglobulin (IgG) level before next infusion during the wash-in/wash-out phase (), area under the concentration-time curve from time point zero to the last time point with quantifiable concentration (AUC), dose-adjusted AUC (dAUC), lowest and highest observed IgG levels (, ), time to reach (), and total clearance (CL) were analyzed for both regimens of Privigen (dose: 138-554 mg/kg body weight). Ten patients were included in this analysis (3-/4-weekly:  = 2/ = 8).

Pharmacokinetic Analysis of Weekly Versus Biweekly IgPro20 Dosing in Patients With Primary Immunodeficiency.

Flexible dosing of IgPro20 (Hizentra®, CSL Behring, King of Prussia, Pennsylvania) maintains normal serum immunoglobulin G (IgG) levels in patients with primary immunodeficiencies (PID). Until now, clinical trials testing the pharmacokinetic (PK) characteristics of serum IgG of weekly and biweekly subcutaneous IgG therapy were not published. This is the first study assessing PK characteristics following weekly and biweekly IgPro20 in patients with PID.

Population pharmacokinetic analysis of weekly and biweekly IgPro20 (Hizentra®) dosing in patients with primary immunodeficiency.

Background: IgPro20 (Hizentra®), a 20% subcutaneous immunoglobulin G (IgG), is an effective treatment for patients with primary immunodeficiencies with impaired IgG production. Flexible dosing regimens of IgPro20 have been supported by pharmacokinetic (PK) modeling and simulation. This study further describes the PK characteristics of serum IgG concentrations after weekly and biweekly administration of IgPro20 and compares predicted and actual serum IgG data using a previously-developed population PK (popPK) model.

Moderate Renal Impairment Does Not Impact the Ability of CSL112 (Apolipoprotein A-I [Human]) to Enhance Cholesterol Efflux Capacity.

CSL112 (apolipoprotein A-I [human]) is a novel intravenous formulation of plasma-derived apolipoprotein A-I (apoA-I) that enhances cholesterol efflux capacity. Renal impairment is a common comorbidity in acute myocardial infarction patients and is associated with impaired lipid metabolism. The aim of this phase 1 study was to assess the impact of moderate renal impairment on the pharmacokinetic and pharmacodynamic profile of CSL112.

Privigen® has similar pharmacokinetic properties in primary and secondary immune deficiency.

Purpose: Primary (PID) and secondary immune deficiencies (SID) represent diverse groups of diagnoses, yet both can be effectively treated with intravenous immunoglobulin (IVIG) replacement therapy. Guidelines for the use of IVIG in SID vary due to the paucity of data. The objective was to analyze available IVIG Privigen® (IgPro10, CSL Behring, Bern, Switzerland) data on Efficiency Index (EI) and pharmacokinetic (PK) parameters in patients with PID and SID.

Long-Term Efficacy and Safety of Hizentra® in Patients with Primary Immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials.

Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized.

Pharmacokinetics and Safety of CSL112 (Apolipoprotein A-I [Human]) in Adults With Moderate Renal Impairment and Normal Renal Function.

CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.

CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

Objective: CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease.

Exposure-Response Model of Subcutaneous C1-Inhibitor Concentrate to Estimate the Risk of Attacks in Patients With Hereditary Angioedema.

Subcutaneous C1-inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)-approved, highly concentrated formulation of a plasma-derived C1-esterase inhibitor (C1-INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low-Volume Subcutaneous C1-inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time-to-event model to characterize the timing and frequency of HAE attacks as a function of C1-INH activity, and then develop an exposure-response model to assess the relationship between C1-INH functional activity levels (C1-INH(f)) and the risk of an attack. The C1-INH(f) values of 33.

Quantitative disease progression model of α-1 proteinase inhibitor therapy on computed tomography lung density in patients with α-1 antitrypsin deficiency.

Aims: Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A -PI; 60 mg kg  week ) therapy completed to date, demonstrated for the first time that A -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE).

Background: Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT.

Methods: Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE).

Dosage Adjustments Related to Young or Old Age and Organ Impairment.

Differences in physiology related to young or old age and/or organ system impairment alter the absorption, distribution, metabolism, and excretion of many medications and consequently their effectiveness and toxicity. This module discusses common alterations in medication use and dosage that are required in the pediatric age group, in the elderly, and in patients with renal or hepatic disease.

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients.

Unlabelled: Calcineurin inhibitor-associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients.

Methods: This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus.

A pharmacodynamically guided dose selection of PF-00337210 in a phase I study in patients with advanced solid tumors.

Purpose: PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210.

Patients And Methods: Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses.

Axitinib plasma pharmacokinetics and ethnic differences.

Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians.

Effect of axitinib on the QT interval in healthy volunteers.

Purpose: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization.

Methods: The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily).