Clinical study design strategies to mitigate confounding effects of time-dependent clearance on dose optimization of therapeutic antibodies.

Time-dependent pharmacokinetics (TDPK) is a frequent confounding factor that misleads exposure-response (ER) analysis of therapeutic antibodies, where a decline in clearance results in increased drug exposure over time in patients who respond to therapy, causing a false-positive ER finding. The object of our simulation study was to explore the influence of clinical trial designs on the frequency of false-positive ER findings. Two previously published population PK models representative of slow- (pembrolizumab) and fast-onset (rituximab) TDPK were used to simulate virtual patient cohorts with time-dependent clearance and the frequency of false-positive ER findings.

Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT).

Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor.

Background And Objectives: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models.

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor).

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments.

Neutrophil elastase as a versatile cleavage enzyme for activation of αvβ3 integrin-targeted small molecule drug conjugates with different payload classes in the tumor microenvironment.

The development of bioconjugates for the targeted delivery of anticancer agents is gaining momentum after recent success of antibody drug conjugates (ADCs) in the clinic. Smaller format conjugates may have several advantages including better tumor penetration; however, cellular uptake and trafficking may be substantially different from ADCs. To fully leverage the potential of small molecule drug conjugates (SMDCs) with potent binding molecules mediating tumor homing, novel linker chemistries susceptible for efficient extracellular activation and payload release in the tumor microenvironment (TME) need to be explored.

Time-dependent clearance can confound exposure-response analysis of therapeutic antibodies: A comprehensive review of the current literature.

Exposure-response (ER) analysis is used to optimize dose and dose regimens during clinical development. Characterization of relationships between drug exposure and efficacy or safety outcomes can be utilized to make dose adjustments that improve patient response. Therapeutic antibodies typically show predictable pharmacokinetics (PK) but can exhibit clearance that decreases over time due to treatment.

Discovery of VIP236, an αvβ3-Targeted Small-Molecule-Drug Conjugate with Neutrophil Elastase-Mediated Activation of 7-Ethyl Camptothecin Payload for Treatment of Solid Tumors.

The emerging field of small-molecule-drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvβ3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor.

Chemically engineering the drug release rate of a PEG-paclitaxel conjugate using click and steric hindrance chemistries for optimal efficacy.

A small molecule drug with poor aqueous solubility can be conjugated to a hydrophilic polymer like poly(ethylene glycol) (PEG) to form an amphiphilic polymer-drug conjugate that self-assembles to form nanoparticles (NPs) with improved solubility and enhanced efficacy. This strategy has been extensively applied to improve the delivery of several small molecule drugs. However, very few reports have succeeded to tune the rate of drug release from these NPs.

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation.

The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at , , and , or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects.

Physiologically Based Pharmacokinetic Models Can Be Used to Predict the Unique Nonlinear Absorption Profiles of Vismodegib.

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult, since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans.

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 () are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD.

Endoscopic nodal staging in oligometastatic non-small cell lung cancer (NSCLC) being treated with stereotactic ablative radiotherapy (ENDO-SABR).

Background: Research in treatment of non-small cell lung cancer (NSCLC) has shown promising results with stereotactic ablative radiotherapy (SABR) of oligometastatic disease, wherein distant disease may be limited to one or a few distant organs by host factors. Traditionally, PET/CT has been used in detecting metastatic disease and avoiding futile surgical intervention, however, sensitivity and specificity is limited to only 81 and 79%, respectively. Mediastinal staging still identifies occult nodal disease in up to 20% of NSCLC patients initially thought to be operative candidates.

Trends in non-receipt of recommended COPD medication.

https://bit.ly/3IhK5Y4.

A Small Molecule-Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αß Binder for the Treatment of Multiple Cancer Types.

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule-drug conjugate consisting of an αβ integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models.

First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy.

Purpose: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor.

Patients And Methods: Adults with solid tumors or aggressive non-Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined.

Rational Clinical Dose Selection of Adeno-Associated Virus-Mediated Gene Therapy Based on Allometric Principles.

One of the challenges in translational medicine is to select first-in-human doses of investigational drugs based on findings in preclinical studies. Despite substantial progress in the optimization of recombinant adeno-associated virus (AAV) vectors of in vivo gene therapy for treating various diseases, there remain significant limitations to the use of preclinical data to guide dose selection in clinical trials. Here we introduce a novel concept of gene efficiency factor (GEF) to describe the efficiency of the gene transfer system and describe and apply the concept of GEF in AAV-mediated in vivo gene transfer systems.

Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity.

Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket.

Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool.

The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed.

Exposure-Effect Relationships in Established Rat Adjuvant-Induced and Collagen-Induced Arthritis: A Translational Pharmacokinetic-Pharmacodynamic Analysis.

The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis.

Evaluation of the predictive performance of physiologically based pharmacokinetic models for intramuscular injections of therapeutic proteins.

Several physiologically-based pharmacokinetic (PBPK) models have been reported for intravenous (IV) and subcutaneous (SC) injections, but there has been a paucity of work for intramuscular (IM) injections. The primary objective of this work was a wide-scale evaluation of the predictive performance of IM PBPK models of therapeutic proteins. PBPK models for all administration routes available in the literature have regarded muscle as the total muscle (TM) in the body; however, anatomically, the body is composed of discrete muscle groups.

Which Physicians Are Taking Care of People With COPD?

Background: There is limited knowledge on what proportions of patients with COPD receive ambulatory care from primary care physicians, pulmonologists, or other specialists. We evaluated the types and combinations of physicians who provide ambulatory care to patients with COPD.

Methods: We conducted a population-based cross-sectional study using health administrative datasets from Ontario, Canada between April 1, 2014 and March 31, 2015.

Cyclodextrin Reduces Intravenous Toxicity of a Model Compound.

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined.

Exploring a Kinetic Model Approach in Biopharmaceutics: Estimating the Fraction Absorbed of Orally Administered Drugs in Humans.

Increasing costs of research and development in the pharmaceutical industry has necessitated a growing interest in the early prediction of human pharmacokinetics of drug candidates. Of growing interest is the need to understand oral absorption, the most common route of small molecule drug administration. The fraction of dose absorbed (%Fa) is considered a critical yet challenging parameter to predict.