Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules.

As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD).

Changes in metabolic overweight phenotypes over time and risk of nephrolithiasis: a cohort study.

Background: Overweight/obesity is considered an independent risk factor for nephrolithiasis, but little is known about its effect on nephrolithiasis according to metabolic health status.

Objectives: We aimed to investigate the association between various metabolic overweight phenotypes and the occurrence of nephrolithiasis. It also explores whether changes in these phenotypes over time influence the risk of nephrolithiasis.

Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development.

Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. Although there is much promise in this initiative, there are several challenges that need to be addressed, including multidimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long-term tolerability beyond dose-limiting toxicities, and the lack of reliable biomarkers for long-term efficacy.

Oncology Combination Dose-Finding Study Design for Targeted and Immuno-Oncology Therapies.

Combination therapies are often evaluated during the clinical development of oncology investigational agents. A new investigational agent may be combined with one or more approved agent(s) or investigational agent(s). As the initial step to test combination therapies, combination dose escalation of an investigational agent and an approved drug is generally conducted using one of the following designs: sequential design, parallel (staggered) design, healthy participant first-in-human prior to first-in-patient combination escalation, monotherapy lead-in (intra-patient "crossover"), and potentially combination escalation (no monotherapy component).

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development.

Exposure-response (E-R) analyses are an integral component in the development of oncology products. Characterizing the relationship between drug exposure metrics and response allows the sponsor to use modeling and simulation to address both internal and external drug development questions (e.g.

Association between serum uric acid/HDL-cholesterol ratio and chronic kidney disease: a cross-sectional study based on a health check-up population.

Objective: Evidence suggests that both serum uric acid (SUA) and high-density lipoprotein cholesterol (HDL-C) are risk factors for chronic kidney disease (CKD). The SUA-to-HDL-C ratio (UHR) has recently attracted attention as a new biomarker to evaluate the role between inflammatory and anti-inflammatory substances. Thus, we explored the association between UHR and CKD in a large Chinese population.

PK/PD model-informed dose selection for oncology phase I expansion: Case study based on PF-06939999, a PRMT5 inhibitor.

The optimal dose for targeted oncology therapeutics is often not the maximum tolerated dose. Pharmacokinetic/pharmacodynamic (PK/PD) modeling can be an effective tool to integrate clinical data to help identify the optimal dose. This case study shows the utility of population PK/PD modeling in selecting the recommended dose for expansion (RDE) for the first-in-patient (FIP) study of PF-06939999, a small-molecule inhibitor of protein arginine methyltransferase 5.

Oncology dose optimization paradigms: knowledge gained and extrapolated from approved oncology therapeutics.

There has been increasing attention to dose optimization in the development of targeted oncology therapeutics. The current report has analyzed the dose selection approaches for 116 new molecular entities (NMEs) approved for oncology indications by the US FDA from 2010 to August 2021, with the goal to extract learnings about the ways to select the optimal dose. The analysis showed that: (1) the initial label dose was lower than the maximum tolerated dose (MTD) or maximum studied dose (MSD) in Phase 1 for the majority of approved NMEs, and that the MTD approach is no longer the mainstay for dose selection; (2) there was no dose ranging or optimization beyond Phase 1 dose escalation for ~ 80% of the NMEs; (3) integrated dose/exposure-response analyses were commonly used to justify the dose selection; (4) lack of dose optimization led to dose-related PMRs/PMCs in 14% of cases, but 82% of these did not result in change of the initial label dose; and (5) depending on properties of the NME and specific benefit/risk considerations for the target patient population, there could be different dose selection paradigms leading to identification of the appropriate clinical dose.

Joint Disposition Properties and Comprehensive Pharmacokinetic Characterization of Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) comprise 3 distinct parts: a specific antibody carrier (mAb), a linker, and a cytotoxic payload. Typical pharmacokinetic (PK) characterization of ADCs remains fragmented using separate noncompartmental analyses (NCA) of individual analytes, offering little insight into the dynamic relationships among the ADC components, and the safety and efficacy implications. As a result, it is exceedingly difficult to compare ADCs in terms of favorable PK characteristics.

Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: learnings from a survey of FDA-approved drugs.

The ideal starting dose for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. A low starting dose combined with small dose increments could lead to a lengthy dose escalation and could expose patients unnecessarily to sub-therapeutic dosing. In the current analyses, we reviewed 59 approved small molecule oncology drugs (SMOD) with the overarching goals to assess the current approaches of FIP starting dose selection and dose escalation, and to identify potential opportunities for improving trial efficiency and minimizing number of patients receiving sub-therapeutic dose levels.

Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma.

Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m) and gemcitabine (1000 mg/m) administered on days 1, 8, and 15 of each 28-day cycle.

Correction to: Population pharmacokinetics of PF‑05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2‑positive metastatic breast cancer.

The article "Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer" written by Xiaoying Chen, Cheryl Li, Reginald Ewesuedo, Donghua Yin was originally published electronically on the publisher's internet portal (currently SpringerLink) on 3rd May 2019 without open access.

Population pharmacokinetics of PF-06438179/GP1111 (an infliximab biosimilar) and reference infliximab in patients with moderately to severely active rheumatoid arthritis.

: PF-06438179/GP1111 (PF-SZ-IFX) is an infliximab (IFX) biosimilar. Pharmacokinetic (PK) similarity of PF-SZ-IFX and reference IFX authorized in the European Union (ref-IFX-EU) and in the US (ref-IFX-US) was demonstrated in healthy subjects. Safety and efficacy of PF-SZ-IFX were investigated in a multinational, double-blind, randomized study in rheumatoid arthritis (RA) patients.

Time trend of cardiometabolic risk factors over a 10-year period in the office-working population in China.

Objectives: Recent dramatic increases in cardiovascular disease mortality in China can be mostly explained by adverse changes in hypertension, dyslipidaemia, diabetes and obesity, known as cardiometabolic risk factors. Our study aimed to assess the trend of these four signatures by a 10-year lag in Nanjing, China.

Methods: 8017 subjects attended the routine health examination in 2008, and 9379 subjects in 2017, from multiple work units of Nanjing, were included in the present study.

Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer.

Purpose: PF-05280014 is a biosimilar to trastuzumab (Herceptin). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.

Methods: Population PK of PF-05280014 and trastuzumab-EU was evaluated.

PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study.

Background: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer.

Methods: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33.

A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01).

Background: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US.

Methods: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively.

Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab.

Aims: To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586.

Methods: A randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments.

Evaluating imbalances of adverse events during biosimilar development.

Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety.

A phase I pharmacokinetics trial comparing PF-05280586 (a potential biosimilar) and rituximab in patients with active rheumatoid arthritis.

Aims: Pharmacokinetic (PK) similarity was assessed among PF-05280586 (a proposed biosimilar) vs. rituximab sourced from the European Union (rituximab-EU) and the United States (rituximab-US). Pharmacodynamics (PD), overall safety and immunogenicity were also evaluated.