Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study.

Background: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours.

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels.

A quantitative systems pharmacology model for acute viral hepatitis B.

Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B.

Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent.

Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.

Background: Alterations in the gene encoding fibroblast growth factor receptor () are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with alterations.

Methods: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified alterations.

Immune network for viral hepatitis B: Topological representation.

The liver is a well-known immunotolerogenic environment, which provides the adequate setting for liver infectious pathogens persistence such as the hepatitis B virus (HBV). Consequently, HBV infection can derive in the development of chronic disease in a proportion of the patients. If this situation persists in time, chronic hepatitis B (CHB) would end in cirrhosis, hepatocellular carcinoma and eventually, the death of the patient.

Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer.

Background And Objectives: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure-PSA dynamics relationship in mCRPC.

Methods: Abiraterone pharmacokinetics-PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC.

Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors.

Purpose: JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493.

Patients And Methods: Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.

Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients.

Purpose: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA).

Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model.

Results: The effect of AA on PSA kinetics was significant (P < 0.

Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.

Background And Objectives: Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics.

The association between body composition and toxicities from the combination of Doxil and trabectedin in patients with advanced relapsed ovarian cancer.

Emerging research suggests that body composition can predict toxicity of certain chemotherapeutic agents. We used data from a clinical study to investigate associations between body composition and combined DOXIL (pegylated liposomal doxorubicin; PLD) and trabectedin (Yondelis) treatment, an effective treatment for ovarian cancer that shows high interpatient variation in toxicity profile. Patients (n = 74) participating in a phase III randomized trial of relapsed advanced ovarian cancer receiving PLD (30 mg/m(2)) and trabectedin (1.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes.

What Is Already Known About This Subject: • Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation.

What This Study Adds: • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290).

Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.

Background: Tapentadol is a new, centrally active analgesic agent with two modes of action--mu opioid receptor agonism and norepinephrine reuptake inhibition--and the immediate-release (IR) formulation is approved in the US for the relief of moderate to severe acute pain. The aims of this analysis were to develop a population pharmacokinetic model to facilitate the understanding of the pharmacokinetics of tapentadol IR in healthy subjects and patients following single and multiple dosing, and to identify covariates that might explain variability in exposure following oral administration.

Methods: The analysis included pooled data from 11,385 serum pharmacokinetic samples from 1827 healthy subjects and patients with moderate to severe pain.

Modeling the effectiveness of paliperidone ER and olanzapine in schizophrenia: meta-analysis of 3 randomized, controlled clinical trials.

The time course of Positive and Negative Syndrome Scale (PANSS) scores in adult schizophrenia patients was modeled, and the effectiveness of paliperidone extended-release tablets (paliperidone ER) and olanzapine was quantified. Data from 3 randomized, double-blind phase III studies were used. Patients received paliperidone ER (3, 6, 9, 12, or 15 mg), olanzapine 10 mg, or matched placebo once daily for 6 consecutive weeks.

Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic.

Objectives: To characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting palmitate ester at various doses and at two different injection sites (deltoid and gluteal muscle).

Methods: The retrospective analysis included pooled data from 1795 subjects from six phase I trials and five phase II and III trials. A total of 18 530 pharmacokinetic samples with valid concentration timepoints were available for this analysis.

Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment.

Purpose: Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients.

Patients And Methods: Trabectedin was administered to 711 patients as monotherapy (dose range: 0.

Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients.

Objective: To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis(R)) in cancer patients.

Methods: A total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.