The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering: OCEAN(a)-DOSE Extension Period Results.

Background: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%.

Objectives: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety.

Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration.

A Phase I, Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Pharmacokinetics, Safety, and Tolerability of Etelcalcetide Administered Intravenously to Chinese Patients With Chronic Kidney Disease Undergoing Hemodialysis.

Purpose: This study reports data from the first evaluation of etelcalcetide treatment in Chinese adults with chronic kidney disease and secondary hyperparathyroidism.

Methods: This phase I, randomized study compared thrice-weekly etelcalcetide (5 mg per dose intravenously) and placebo in 33 Chinese adults (aged 18-70 years) receiving hemodialysis. Patients in both treatment groups received standard-of-care treatment with a total of 12 doses of the investigational product during a 4-week treatment period, followed by 4 weeks of washout and follow-up.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Amiodarone and Digoxin in Healthy Subjects.

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.

Evaluation of drug-drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically-based pharmacokinetic model.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Omeprazole, a Proton Pump Inhibitor, in Healthy Subjects.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure (HF) with reduced ejection fraction. OM is administered as a 25-, 37.5-, or 50-mg modified-release formulation in patients with HF.

Phase 1, single-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of etelcalcetide in pediatric patients with secondary hyperparathyroidism receiving hemodialysis.

Background: Data on the safety, efficacy of etelcalcetide in children with secondary hyperparathyroidism (sHPT) are limited.

Methods: This phase 1 study (NCT02833857) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) of single-dose etelcalcetide (0.035 mg/kg intravenously) in pediatric hemodialysis patients (two cohorts; 1: 12-< 18 years; 2: 2-< 12 years).

Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet.

Aims: The aims of this study were to develop a pharmacokinetic (PK) and PK-pharmacodynamic (PK/PD) model of cinacalcet in adults and paediatrics with secondary hyperparathyroidism (SHPT) on dialysis, to test covariates of interest, and to perform simulations to inform dosing in paediatrics with SHPT.

Methods: Cinacalcet PK, intact parathyroid hormone (iPTH) and corrected calcium (cCa) time courses following multiple daily oral doses (1-300 mg) were modelled using a nonlinear mixed effects modelling approach using data from eight clinical studies. Model-based trial simulations, using adult or paediatric titration schemas, predicted efficacy (iPTH change from baseline and proportion achieving iPTH decrease ≥30%) and safety (cCa change from baseline and proportion achieving cCa ≤8.

Correction to: An open-label, single-dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinacalcet in pediatric subjects aged 28 days to < 6 years with chronic kidney disease receiving dialysis.

The original version of this article unfortunately contained three mistakes. In Table 1, the last line under "Key Inclusion Criteria" should read "Normal or clinically acceptable ECGs at screening and at day - 1." In addition, the abbreviation "IP" in the legend to Table 1 stands for "investigational product.

An open-label, single-dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinacalcet in pediatric subjects aged 28 days to < 6 years with chronic kidney disease receiving dialysis.

Background: Calcimimetics, shown to control biochemical parameters of secondary hyperparathyroidism (SHPT), have well-established safety and pharmacokinetic profiles in adult end-stage renal disease subjects treated with dialysis; however, such studies are limited in pediatric subjects.

Methods: In this study, the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cinacalcet were evaluated in children with chronic kidney disease (CKD) and SHPT receiving dialysis. Twelve subjects received a single dose of cinacalcet (0.

Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis.

Objective: To evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN).

Methods: In this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement).

An open-label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners.

Aims: Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner.

Methods: An open-label, single-dose study in 12 healthy men was conducted over a 106-day period.

Blockade of interferon-γ normalizes interferon-regulated gene expression and serum CXCL10 levels in patients with systemic lupus erythematosus.

Objective: To assess the safety and immunologic impact of inhibiting interferon-γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).

Methods: Twenty-six patients with mild-to-moderate, stable SLE were administered placebo or a single dose of AMG 811, ranging from 2 mg to 180 mg subcutaneously or 60 mg intravenously.

Results: Similar to results previously reported following inhibition of type I IFNs, treatment of SLE patients with AMG 811 led to a dose-dependent modulation of the expression of genes associated with IFN signaling, as assessed by microarray analysis of the whole blood.

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors.

Denosumab (XGEVA®) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target-mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab.

Pharmacokinetic and pharmacodynamic relationship of AMG 811, an anti-IFN-γ IgG1 monoclonal antibody, in patients with systemic lupus erythematosus.

Purpose: To investigate the relationships between AMG 811 exposure, concentration changes in serum IFN-γ, and IFN-γ-induced protein 10 (CXCL10), and to identify important contributions of baseline covariates to these relationships.

Methods: A mechanism based pharmacokinetic (PK)-pharmacodynamic (PD) model was developed. A target mediated disposition model was used to describe AMG 811 and target IFN-γ interaction.

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review.

Aim: The objective of this systematic review was to characterize the pharmacokinetics and pharmacodynamics of denosumab (XGEVA®), a fully human IgG2 monoclonal antibody which binds to receptor activator of nuclear factor kappa-B ligand (RANKL), for the treatment of skeletal-related events (SREs) in patients with advanced cancer and bone metastases.

Methods: A total of 708 patients (116 healthy patients and 592 patients with solid tumours or multiple myeloma and bone metastases) included in seven clinical studies were evaluated for denosumab pharmacokinetics. Denosumab was administered as a single subcutaneous (s.

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours.

Background And Objective: Denosumab (XGEVA®; AMG 162) is a fully human IgG2 monoclonal antibody, which binds to the receptor activator of nuclear factor κ-B ligand (RANKL) and prevents terminal differentiation, activation and survival of osteoclasts. We aimed to characterize the population pharmacokinetics of denosumab in patients with advanced solid tumours and bone metastases.

Methods: A total of 14 228 free serum concentrations of denosumab from 1076 subjects (495 healthy subjects and 581 advanced cancer patients with solid tumours and bone metastases) included in 14 clinical studies were pooled.

Denosumab dose selection for patients with bone metastases from solid tumors.

Purpose: To quantitatively characterize the longitudinal dose exposure-response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors.

Experimental Design: Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis.

Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study.

Background: Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity. GCT is rich in osteoclast-like giant cells and contains mononuclear (stromal) cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. We investigated the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT.

Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.

Purpose: Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy.

Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases.

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL), suppresses bone resorption. This open-label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer-related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for > or = 141 days.