Pharmacokinetic models for first-in-human dose selection of immune-activating products in oncology.

Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using clearance for scaling was acceptable for dose estimation, FIH(SPM) doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BWh, a clearance exponent of 0.75, and a targeted plasma concentration based on relevant and/or sensitive activity assays was an acceptable approach for FIH dose selection; use of 0.85 as the scaling factor is questionable at this time as it resulted in a FIH dose that was too close to the AHD for one product (7%). Immune activating mAbs were not sensitive to changes in the clearance exponent (0.75-0.85) or body weight (60-70 kg). For PD-1/PD-L1 mAbs, using products' in vitro EC50 in the model resulted in suboptimal FIH doses and clinical data of closely related products informed FIH dose selection. PK models submitted by sponsors were diverse in methods, assumptions, and variables, and the resulting FIH doses were not always optimal.

MaBEL1 regulates banana fruit ripening by activating cell wall and starch degradation-related genes.

Banana is a typical subtropical fruit, sensitive to chilling injuries and prone to softening disorder. However, the underlying regulatory mechanisms of the softening disorder caused by cold stress remain obscure. Herein, we found that BEL1-LIKE HOMEODOMAIN transcription factor 1 (MaBEL1) and its associated proteins regulate the fruit softening and ripening process. The transcript and protein levels of MaBEL1 were up-regulated with fruit ripening but severely repressed by the chilling stress. Moreover, the MaBEL1 protein interacted directly with the promoters of the cell wall and starch degradation-related genes, such as MaAMY3, MaXYL32, and MaEXP-A8. The transient overexpression of MaBEL1 alleviated fruit chilling injury and ripening disorder caused by cold stress and promoted fruit softening and ripening of "Fenjiao" banana by inducing ethylene production and starch and cell wall degradation. The accelerated ripening was also validated by the ectopic overexpression in tomatoes. Conversely, MaBEL1-silencing aggravated the chilling injury and ripening disorder and repressed fruit softening and ripening by inhibiting ethylene production and starch and cell wall degradation. MaABI5-like and MaEBF1, the two positive regulators of the fruit softening process, interacted with MaBEL1 to enhance the promoter activity of the starch and cell wall degradation-related genes. Moreover, the F-box protein MaEBF1 does not modulate the degradation of MaBEL1, which regulates the transcription of MaABI5-like protein. Overall, we report a novel MaBEL1-MaEBF1-MaABI5-like complex system that mediates the fruit softening and ripening disorder in "Fenjiao" bananas caused by cold stress.

First-in-human dose: current status review for better future perspectives.

AIM: The aim of this article is to understand the pros and cons of various methods involved in first-in-human (FIH) dose calculation and act decisively in dose escalations when calculating the maximum tolerated dose. SUBJECTS AND METHODS: We reviewed early phase clinical trials for methods of FIH dose and dose-escalation steps and discuss them in line with existing guidelines. We also reviewed the clinical trial registry to recognize trends in trial registration in recent years and after a massive failure in a few trials. RESULTS: Phase 1 trials of TGN 1412 and BIA10-2474 would always be remembered as catastrophes for pharmaceutical development plans. Quite often than not, healthy human volunteers are the guinea pigs in this stage of drug development. And, the most important aspect of designing an early phase study is deciding upon the dose to be started with, apart from the selection of cohort and escalation steps. The common principles used for FIH dose calculation include no observed adverse effect level, minimum anticipated biological effect level, pharmacologically active dose, pharmacokinetic/pharmacodynamic approach, and similar drug comparison approach. CONCLUSION: Early phase clinical trials are basically foundation stones on which lies the entire onus of the later stages of development. Deciding FIH dose is a crucial step that necessitates the incorporation of detailed data from the preclinical stages and application of the most conservative approach for the safety/benefit of the volunteers in these studies.

What factors affect physicians' labour supply: Comparing structural discrete choice and reduced-form approaches.

Little is known about the response of physicians to changes in compensation: Do increases in compensation increase or decrease labour supply? In this paper, we estimate wage elasticities for physicians. We apply both a structural discrete choice approach and a reduced-form approach to examine how these different approaches affect wage elasticities at the intensive margin. Using uniquely rich data collected from a large sample of general practitioners (GPs) and specialists in Australia, we estimate 3 alternative utility specifications (quadratic, translog, and box-cox utility functions) in the structural approach, as well as a reduced-form specification, separately for men and women. Australian data is particularly suited for this analysis due to a lack of regulation of physicians' fees leading to variation in earnings. All models predict small negative wage elasticities for male and female GPs and specialists passing several sensitivity checks. For this high-income and long-working-hours population, the translog and box-cox utility functions outperform the quadratic utility function. Simulating the effects of 5% and 10% wage increases at the intensive margin slightly reduces the full-time equivalent supply of male GPs, and to a lesser extent of male specialists and female GPs.

Hours worked by general practitioners and waiting times for primary care.

The decline in the working hours of general practitioners (GPs) is a key factor influencing access to health care in many countries. We investigate the effect of changes in hours worked by GPs on waiting times in primary care using the Medicine in Australia: Balancing Employment and Life longitudinal survey of Australian doctors. We estimate GP fixed effects models for waiting time and use family circumstances to instrument for GP's hours worked. We find that a 10% reduction in hours worked increases average patient waiting time by 12%. Our findings highlight the importance of GPs' labor supply at the intensive margin in determining the length of time patients must wait to see their doctor.

Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges.

Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell-dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species.

Do Financial Incentives Influence GPs' Decisions to Do After-hours Work? A Discrete Choice Labour Supply Model.

This paper analyses doctors' supply of after-hours care (AHC), and how it is affected by personal and family circumstances as well as the earnings structure. We use detailed survey data from a large sample of Australian General Practitioners (GPs) to estimate a structural, discrete choice model of labour supply and AHC. This allows us to jointly model GPs' decisions on the number of daytime-weekday working hours and the probability of providing AHC. We simulate GPs' labour supply responses to an increase in hourly earnings, both in a daytime-weekday setting and for AHC. GPs increase their daytime-weekday working hours if their hourly earnings in this setting increase, but only to a very small extent. GPs are somewhat more likely to provide AHC if their hourly earnings in that setting increase, but again, the effect is very small and only evident in some subgroups. Moreover, higher earnings in weekday-daytime practice reduce the probability of providing AHC, particularly for men. Increasing GPs' earnings appears to be at best relatively ineffective in encouraging increased provision of AHC and may even prove harmful if incentives are not well targeted. Copyright © 2017 John Wiley & Sons, Ltd.

An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe.

An FDA oncology analysis of immune activating products and first-in-human dose selection.

As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products.

A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis.

CD3-bispecific antibodies are a new class of immunotherapeutic drugs against cancer. The pharmacological activity of CD3-bispecifics is typically assessed through in vitro assays of cancer cell lines co-cultured with human peripheral blood mononuclear cells (PBMCs). Assay results depend on experimental conditions such as incubation time and the effector-to-target cell ratio, which can hinder robust quantification of pharmacological activity. In order to overcome these limitations, we developed a new, holistic approach for quantification of the in vitro dose-response relationship. Our experimental design integrates a time-independent analysis of the dose-response across different time points as an alternative to the static, "snap-shot" analysis based on a single time point commonly used in dose-response assays. We show that the potency values derived from static in vitro experiments depend on the incubation time, which leads to inconsistent results across multiple assays and compounds. We compared the potency values from the time-independent analysis with a model-based approach. We find comparably accurate potency estimates from the model-based and time-independent analyses and that the time-independent analysis provides a robust quantification of pharmacological activity. This approach may allow for an improved head-to-head comparison of different compounds and test systems and may prove useful for supporting first-in-human dose selection.

Impact of rural workforce incentives on access to GP services in underserved areas: Evidence from a natural experiment.

Financial incentives are often used to improve recruitment and retention of physicians in rural and remote areas. In 2010, the General Practice Rural Incentive Program (GPRIP) was introduced in Australia, causing an exogenous change in the eligibility for rural incentives for some geographical areas. This study investigates the effect of this policy reform on waiting times for a non-urgent GP appointment using panel data (2008-2014) on 2058 GPs. Using difference-in-difference methodology, results show that the number of GPs in practices in newly eligible areas increased. However, no evidence is found that this reduces waiting times for existing patients, and only weak evidence is found that waiting times for new patients fell, by around 16%. Our results suggest that financial incentives may only play a limited role in improving access to primary care and should not be the only solution to address medical workforce shortages in underserved areas.

Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody: A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study.

E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double-blind, placebo-controlled single-ascending-dose study of intravenous administration of E6011 (0.0006-10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x-rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti-E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 µg/mL, identified as the minimum concentration needed to saturate the target-mediated elimination pathway. Model-based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.

In vitro assays supporting the safety assessment of immunomodulatory monoclonal antibodies.

Many monoclonal antibodies (mAbs) licensed for human use or in clinical development for cancer and autoimmune disease directly interact with the immune system. These immunomodulatory mAbs have an inherent risk of adverse immune-mediated drug reactions, including infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the potential for immunotoxicity of a mAb is required to support administration to humans. This review will highlight the key role of in vitro assays in defining the immunopharmacology, immunotoxicity and immunogenicity of mAbs. A wide range of in vitro tests with multiple formats of different complexity can be utilized to characterize i) the antibody-binding domains of the mAb, such as on-target binding and downstream pharmacological effects (e.g. immunosuppression, immune activation, cytokine release) in both humans and animal species used for toxicology studies and off-target binding; ii) Fc-dependent effects such as Fc-mediated cellular activation (e.g. of leukocytes, platelets) and cytokine release, complement activation; and iii) product-related factors (sequence, physical-chemical properties and impurities) that can impact both pharmacological activity and immunogenicity potential of a mAb. These assays can be crucial to the selection of mAbs with an optimum balance of safety and efficacy, in defining whether a mAb is a high risk molecule, and together with animal data, can inform human safe starting doses and escalation schemes.

Inland and Near Shore Water Profiles Derived from the High Altitude Multiple Altimeter Beam Experimental Lidar (MABEL).

The Advanced Topographic Laser Altimeter System (ATLAS) on the Ice, Cloud, and Land Elevation Satellite (ICESat-2) mission is a six beam, low energy, high repetition rate, 532 nm laser transmitter with photon counting detectors. Although designed primarily for detecting height changes in icecaps, sea ice and vegetation, the polar-orbital satellite will observe global surface water during its designed three year life span, including inland water bodies, coasts, and open oceans. In preparation for the mission, an ICESat-2 prototype or the Multiple Altimeter Beam Experimental Lidar (MABEL), was built and flown on high altitude aircraft experiments over a range of inland and near-shore targets. The purpose was to test the ATLAS concept and to provide a database for developing an algorithm that detects along track surface water height and light penetration under a range of atmospheric and water conditions. The current analysis examines the datasets of three MABEL transects observed from 20 km above ground of coastal and inland waters conducted in 2012 and 2013. Transects ranged from about 2 to 12 km in length and included the middle Chesapeake Bay, the near shore Atlantic coast at Virginia Beach, and Lake Mead. Results indicate MABEL's high capability for retrieving surface water height statistics with a mean height precision of approximately 5-7 cm per 100m segment length. Profiles of attenuated subsurface backscatter, characterized using a Signal to Background Ratio written in Log10 base, or LSBR 0 , were observed over a range of 1.3 to 9.3 meters depending on water clarity and atmospheric background. Results indicate that observable penetration depth, although primarily dependent on water properties, was greatest when solar background rate was low. Near shore bottom reflectance was detected only at the Lake Mead site down to maximum of 10 m under a clear night sky and low turbidity of approximately 1.6 Nephelometric Turbidity Units (NTU). The overall results suggest that the feasibility of retrieving operational surface water height statistics from space-based photon counting systems such as ATLAS is very high for resolutions down to about 100m, even in partly cloudy conditions. The capability to observe subsurface backscatter profiles is achievable but requires much longer transects of several hundreds of meters.

Changes in Doctors' Working Hours: A Longitudinal Analysis.

The study examined changes in doctors' working hours and satisfaction with working hours over five time points and explored the influence of personal characteristics on these outcomes. Latent growth curve modeling was applied to Medicine in Australia: Balancing Employment and Life data, collected from 2008 to 2012. Findings showed that working hours significantly declined over time, with a greater decrease among males, older doctors, and doctors with fewer children. Satisfaction increased faster over time among specialists, doctors with poorer health, those whose partners did not work full-time, and those with older children. The more hours the doctors worked initially, the lower satisfaction reported, and the greater the increase in satisfaction. Findings are consistent with a culture change in the medical profession, whereby long working hours are no longer seen as synonymous with professionalism. This is important to take into account in projecting future workforce supply.

Tools for predicting the PK/PD of therapeutic proteins.

INTRODUCTION: Assessments of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics are an integral part in the development of novel therapeutic agents. Compared with traditional small molecule drugs, therapeutic proteins possess many distinct PK/PD features that necessitate the application of modified or separate approaches for assessing their PK/PD relationships. AREAS COVERED: In this review, the authors discuss tools that are utilized to describe and predict the PK/PD features of therapeutic proteins and that are valuable additions in the armamentarium of drug development approaches to facilitate and accelerate their successful preclinical and clinical development. EXPERT OPINION: A variety of state-of-the-art PK/PD tools is currently being applied and has been adjusted to support the development of proteins as therapeutics, including allometric scaling approaches, target-mediated disposition models, first-in-man dose calculations, physiologically based PK models and empirical and semi-mechanistic PK/PD modeling. With the advent of the next generation of biologics including bioengineered antibody constructs being developed, these tools will need to be further refined and adapted to ensure their applicability and successful facilitation of the drug development process for these novel scaffolds.