From bench to bedside: 64Cu/177Lu 1C1m-Fc anti TEM-1: mice-to-human dosimetry extrapolations for future theranostic applications.

The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64Cu/177Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [64Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [177Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5-10 GBq and 25-30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [64Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [177Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals' models such as dogs before moving into the clinic.

Approaches for the setting of occupational exposure limits (OELs) for carcinogens.

This article addresses issues of importance for occupational exposure limits (OELs) and chemical carcinogens with a focus on non-threshold carcinogens. It comprises scientific as well as regulatory issues. It is an overview, not a comprehensive review. A central topic is mechanistic research and insights, and its implications for cancer risk assessment. Alongside scientific advancements, the approaches of hazard identification and qualitative and quantitative risk assessment have developed over the years. The key steps in a quantitative risk assessment are outlined, with special attention given to the dose-response assessment and the derivation of an OEL using risk calculations or default assessment factors. The work procedures of several bodies performing cancer hazard identifications and quantitative risk assessments, as well as regulatory procedures to derive OELs for non-threshold carcinogens, are presented. Non-threshold carcinogens for which the European Union (EU) introduced binding OELs in 2017-2019 serve as illustrations together with some currently used strategies in the EU and elsewhere. Available knowledge supports the derivation of health-based OELs (Hb-OELs) for non-threshold carcinogens, and the use of a risk-based approach with low-dose linear extrapolation (linear non-threshold, LNT) as the default for non-threshold carcinogens. However, there is a need to develop methods that allow recent years' advances in cancer research to be used for improving risk estimates. It is recommended that defined risk levels (terminology and numerical values) are harmonised, and that both collective and individual risks are considered and clearly communicated. Socioeconomic aspects should be dealt with transparently and separated from the scientific health risk assessment.

ADME, Pharmacokinetic Scaling, Pharmacodynamic and Prediction of Human Dose and Regimen of Novel Antiviral Drugs.

The search for new drugs is an extremely time-consuming and expensive endeavour. Much of that time and money go into generating predictive human pharmacokinetic profiles from preclinical efficacy and safety animal data. These pharmacokinetic profiles are used to prioritize or minimize the attrition at later stages of the drug discovery process. In the area of antiviral drug research, these pharmacokinetic profiles are equally important for the optimization, estimation of half-life, determination of effective dose, and dosing regimen, in humans. In this article we have highlighted three important aspects of these profiles. First, the impact of plasma protein binding on two primary pharmacokinetic parameters-volume of distribution and clearance. Second, interdependence of primary parameters on unbound fraction of the drug. Third, the ability to extrapolate human pharmacokinetic parameters and concentration time profiles from animal profiles.

Extrapolation of pharmacokinetics and pharmacodynamics of sunitinib in children with gastrointestinal stromal tumors.

PURPOSE: The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors. METHODS: Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure-response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored. RESULTS: Two-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure. CONCLUSION: Based on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.

Risk-based principles and incompleteness theorems for linear dose-response extrapolation for carcinogenic chemicals.

To conduct better health risk assessments, this study introduced two risk-based principles and a series of line-lognormal-intersection theorems that helped derive the safe ranges of the cancer slope factors (CSFs) for 708 carcinogenic chemicals. The extrapolated linear dose-response relationships presented in this study can ensure safety with respect to both static and dose-based instantaneous risks compared to the lognormal dose-response model. The theorems proved that the maximum static and dose-based hazard risk ratios of a lognormal curve and a linear model are independent of a chemical's toxicity (the effect dose that corresponds to a 50% response, or ED50), where the selected linear extrapolation (m value) and the individual variability (σ) of the responses to carcinogenic chemicals are two determining factors. The theorems also indicated that individual variability determines the range of m if the acceptable risk ratios were regulated. When σ was 1.36 (i.e., the 50th percentile of the individual variability's lognormal distribution), the safe range of m was derived as [11.22, 21.46] (i.e., from ED11.22 to ED21.46); if the 95th percentile of the σ lognormal distribution was used, the safe range of m was [1.13, 4.57] (i.e., from ED1.13 to ED4.57). This study also showed that for a relatively homogenous population (i.e., σ is relatively small) that has similar characteristics, the linear dose-response extrapolation method might not be completely effective due to the shape shift of the lognormal curve that draws the static risk of the extrapolated linear model away from the lognormal model.

Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1).

PURPOSE: Endosialin/tumor endothelial marker-1 (TEM1) is an attractive theranostic target expressed by the microenvironment of a wide range of tumors, as well as by sarcoma and neuroblastoma cells. We report on the radiolabeling and preclinical evaluation of the scFv78-Fc, a fully human TEM1-targeting antibody fragment cross-reactive with mouse TEM1. PROCEDURES: The scFv78-Fc was conjugated with the chelator p-SCN-Bn-CHX-A"-DTPA, followed by labeling with indium-111. The number of chelators per molecule was estimated by mass spectrometry. A conventional saturation assay, extrapolated to infinite antigen concentration, was used to determine the immunoreactive fraction of the radioimmunoconjugate. The radiopharmaceutical biodistribution was assessed in immunodeficient mice grafted with Ewing's sarcoma RD-ES and neuroblastoma SK-N-AS human TEM1-positive tumors. The full biodistribution studies were preceded by a dose-escalation experiment based on the simultaneous administration of the radiopharmaceutical with increasing amounts of unlabeled scFv78-Fc. Radiation dosimetry extrapolations to human adults were obtained from mouse biodistribution data according to established methodologies and additional assumptions concerning the impact of the tumor antigenic sink in the cross-species translation. RESULTS: [111In]CHX-DTPA-scFv78-Fc was obtained with a radiochemical purity > 98 % after 1 h incubation at 42 °C and ultrafiltration. It showed good stability in human serum and > 70 % immunoreactive fraction. Biodistribution data acquired in tumor-bearing mice confirmed fast blood clearance and specific tumor targeting in both xenograft models. The radiopharmaceutical off-target uptake was predominantly abdominal. After a theoretical injection of [111In]CHX-DTPA-scFv78-Fc to the reference person, the organs receiving the highest absorbed dose would be the spleen (0.876 mGy/MBq), the liver (0.570 mGy/MBq) and the kidneys (0.298 mGy/MBq). The total body dose and the effective dose would be 0.058 mGy/MBq and 0.116 mSv/MBq, respectively. CONCLUSIONS: [111In]CHX-DTPA-scFv78-Fc binds specifically to endosialin/TEM1 in vitro and in vivo. Dosimetry estimates are in the range of other monoclonal antibodies radiolabeled with indium-111. [111In]CHX-DTPA-scFv78-Fc could be potentially translated into clinic.

Extrapolation of Oligonucleotide Dose Levels Used in Nonclinical Toxicity Studies to Selection of Safe Starting Dose Levels in Human Clinical Trials.

One of the key questions for nearly all oligonucleotide therapeutic programs is how to properly extrapolate no-observed adverse effect levels (NOAELs) identified in nonclinical (animal) toxicity studies to the human equivalent dose to enable selection of an appropriate safe starting dose level in normal subjects or patients. There is a strong historical precedent, mainly driven by a guidance document issued from the U.S. Food and Drug Administration, for converting NOAELs expressed as milligram per kilogram body weight (mg/kg) to an NOAEL based on body surface area (BSA), often referred to as allometric scaling. This conversion imparts an additional safety factor of variable magnitude, depending on the species from which the NOAEL has been characterized. The primary impetus for the application of BSA-based dose extrapolation across species derives from cross-species comparisons of the sensitivity to small-molecule anticancer agents and other small-molecule drugs, for which poor predictivity of human sensitivity was obtained with direct extrapolation of mg/kg dose levels and for which much better predictivity was obtained when doses were converted to BSA (mg/m2). The primary question that is raised in the discussion presented herein is whether that widely used allometric scaling paradigm is broadly applicable to all oligonucleotide therapeutics and whether the adherence to this paradigm might result in the unnecessary administration of subpharmacologic doses to initial patient cohorts with life-threatening or severe disease conditions.

Mice-to-men comparison of inhaled drug-aerosol deposition and clearance.

Part of the effective prediction of the pharmacokinetics of drugs (or toxic particles) requires extrapolation of experimental data sets from animal studies to humans. As the respiratory tracts of rodents and humans are anatomically very different, there is a need to study airflow and drug-aerosol deposition patterns in lung airways of these laboratory animals and compare them to those of human lungs. As a first step, interspecies computational comparison modeling of inhaled nano-to-micron size drugs (50 nm < d<15µm) was performed using mouse and human upper airway models under realistic breathing conditions. Critical species-specific differences in lung physiology of the upper airways and subsequently in local drug deposition were simulated and analyzed. In addition, a hybrid modeling methodology, combining Computational Fluid-Particle Dynamics (CF-PD) simulations with deterministic lung deposition models, was developed and predicted total and regional drug-aerosol depositions in lung airways of both mouse and man were compared, accounting for the geometric, kinematic and dynamic differences. Interestingly, our results indicate that the total particle deposition fractions, especially for submicron particles, are comparable in rodent and human respiratory models for corresponding breathing conditions. However, care must be taken when extrapolating a given dosage as considerable differences were noted in the regional particle deposition pattern. Combined with the deposition model, the particle retention and clearance kinetics of deposited nanoparticles indicates that the clearance rate from the mouse lung is higher than that in the human lung. In summary, the presented computer simulation models provide detailed fluid-particle dynamics results for upper lung airways of representative human and mouse models with a comparative analysis of particle lung deposition data, including a novel mice-to-men correlation as well as a particle-clearance analysis both useful for pharmacokinetic and toxicokinetic studies.

Evidence for dose and dose rate effects in human and animal radiation studies.

For stochastic effects such as cancer, linear-quadratic models of dose are often used to extrapolate from the experience of the Japanese atomic bomb survivors to estimate risks from low doses and low dose rates. The low dose extrapolation factor (LDEF), which consists of the ratio of the low dose slope (as derived via fitting a linear-quadratic model) to the slope of the straight line fitted to a specific dose range, is used to derive the degree of overestimation (if LDEF > 1) or underestimation (if LDEF < 1) of low dose risk by linear extrapolation from effects at higher doses. Likewise, a dose rate extrapolation factor (DREF) can be defined, consisting of the ratio of the low dose slopes at high and low dose rates. This paper reviews a variety of human and animal data for cancer and non-cancer endpoints to assess evidence for curvature in the dose response (i.e. LDEF) and modifications of the dose response by dose rate (i.e. DREF). The JANUS mouse data imply that LDEF is approximately 0.2-0.8 and DREF is approximately 1.2-2.3 for many tumours following gamma exposure, with corresponding figures of approximately 0.1-0.9 and 0.0-0.2 following neutron exposure. This paper also cursorily reviews human data which allow direct estimates of low dose and low dose rate risk.

Dose and dose rate extrapolation factors for malignant and non-malignant health endpoints after exposure to gamma and neutron radiation.

Murine experiments were conducted at the JANUS reactor in Argonne National Laboratory from 1970 to 1992 to study the effect of acute and protracted radiation dose from gamma rays and fission neutron whole body exposure. The present study reports the reanalysis of the JANUS data on 36,718 mice, of which 16,973 mice were irradiated with neutrons, 13,638 were irradiated with gamma rays, and 6107 were controls. Mice were mostly Mus musculus, but one experiment used Peromyscus leucopus. For both types of radiation exposure, a Cox proportional hazards model was used, using age as timescale, and stratifying on sex and experiment. The optimal model was one with linear and quadratic terms in cumulative lagged dose, with adjustments to both linear and quadratic dose terms for low-dose rate irradiation (<5 mGy/h) and with adjustments to the dose for age at exposure and sex. After gamma ray exposure there is significant non-linearity (generally with upward curvature) for all tumours, lymphoreticular, respiratory, connective tissue and gastrointestinal tumours, also for all non-tumour, other non-tumour, non-malignant pulmonary and non-malignant renal diseases (p < 0.001). Associated with this the low-dose extrapolation factor, measuring the overestimation in low-dose risk resulting from linear extrapolation is significantly elevated for lymphoreticular tumours 1.16 (95% CI 1.06, 1.31), elevated also for a number of non-malignant endpoints, specifically all non-tumour diseases, 1.63 (95% CI 1.43, 2.00), non-malignant pulmonary disease, 1.70 (95% CI 1.17, 2.76) and other non-tumour diseases, 1.47 (95% CI 1.29, 1.82). However, for a rather larger group of malignant endpoints the low-dose extrapolation factor is significantly less than 1 (implying downward curvature), with central estimates generally ranging from 0.2 to 0.8, in particular for tumours of the respiratory system, vasculature, ovary, kidney/urinary bladder and testis. For neutron exposure most endpoints, malignant and non-malignant, show downward curvature in the dose response, and for most endpoints this is statistically significant (p < 0.05). Associated with this, the low-dose extrapolation factor associated with neutron exposure is generally statistically significantly less than 1 for most malignant and non-malignant endpoints, with central estimates mostly in the range 0.1-0.9. In contrast to the situation at higher dose rates, there are statistically non-significant decreases of risk per unit dose at gamma dose rates of less than or equal to 5 mGy/h for most malignant endpoints, and generally non-significant increases in risk per unit dose at gamma dose rates ≤5 mGy/h for most non-malignant endpoints. Associated with this, the dose-rate extrapolation factor, the ratio of high dose-rate to low dose-rate (≤5 mGy/h) gamma dose response slopes, for many tumour sites is in the range 1.2-2.3, albeit not statistically significantly elevated from 1, while for most non-malignant endpoints the gamma dose-rate extrapolation factor is less than 1, with most estimates in the range 0.2-0.8. After neutron exposure there are non-significant indications of lower risk per unit dose at dose rates ≤5 mGy/h compared to higher dose rates for most malignant endpoints, and for all tumours (p = 0.001), and respiratory tumours (p = 0.007) this reduction is conventionally statistically significant; for most non-malignant outcomes risks per unit dose non-significantly increase at lower dose rates. Associated with this, the neutron dose-rate extrapolation factor is less than 1 for most malignant and non-malignant endpoints, in many cases statistically significantly so, with central estimates mostly in the range 0.0-0.2.

Extreme sensitivity and the practical implications of risk assessment thresholds.

Traditional risk-assessment theory assumes the existence of a threshold for non-cancer health effects. However, a recent trend in environmental regulation rejects this assumption in favor of non-threshold linearity for these endpoints. This trend is driven largely by two related concepts: (1) a theoretical assumption of wide-ranging human sensitivity, and (2) inability to detect thresholds in epidemiologic models. Wide-ranging sensitivity assumes a subpopulation with extreme background vulnerability, so that even trivial environmental exposures are hazardous to someone somewhere. We use examples from the real world of clinical medicine to show that this theoretical assumption is inconsistent with the biology of mammalian systems and the realities of patient care. Using examples from particulate-matter air-pollution research, we further show that failure to reject linearity is usually driven by statistical rather than biological considerations, and that nonlinear/threshold models often have a similar or better fit than their linear counterparts. This evidence suggests the existence of practical, real-world thresholds for most chemical exposures.

State-of-the-science workshop report: issues and approaches in low-dose-response extrapolation for environmental health risk assessment.

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on 23-24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.