The Importance of the Human Mass Balance Study in Regulatory Submissions

Coppola, Paola; Andersson, Anita; Cole, Susan

doi:10.1002/psp4.12466

Cited by 37 publications

(53 citation statements)

References 10 publications

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“…However, of the many clinical pharmacology studies conducted during the development of new medicines, the radiolabeled absorption-distribution-metabolism-excretion (ADME) study offers the richest dataset to understand how the human body handles the drug. 1 ADME studies are generally conducted for drugs under development that are organic xenobiotics, whereas for drug candidates that are biological macromolecules containing no xenobiotic elements, radiolabeled ADME studies are often not done. An exception to a required ADME study for small organic molecule drug candidates is when the entire dose can be accounted for as unchanged drug in the urine, and, in such a case, the need for the radiolabeled ADME study is obviated.…”

Section: Importance Of the Human Adme Studymentioning

confidence: 99%

Mini‐Review: Comprehensive Drug Disposition Knowledge Generated in the Modern Human Radiolabeled ADME Study

Spracklin

Chen

Bergman

et al. 2020

CPT Pharmacom & Syst Pharma

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The human radiolabeled absorption, distribution, metabolism, and excretion (ADME) study offers a quantitative and comprehensive overall picture of the disposition of a drug, including excretion pattern and metabolite profiles in circulation and excreta. The data gathered from the ADME study are highly informative for developing a cohesive strategy for clinical pharmacology studies. Elements of standard ADME study designs are described. An exciting new development in human ADME studies is the application of accelerator mass spectrometry (AMS) as the detection technique for carbon‐14, in replacement of radioactivity measurements. This technology permits administration of 100‐fold to 1,000‐fold lower amounts of carbon‐14, and thus opens the door to the application of new study designs. A new ADME study design, termed the AMS‐Enabled Human ADME study, is described. In this design, both oral and intravenous administration are assessed in a single clinical study with a two‐period crossover. In addition to all of the standard ADME study end points (e.g., mass balance and quantitative metabolite profiles), the AMS‐Enabled ADME study can provide the fundamental pharmacokinetic parameters of clearance, volume of distribution, absolute oral bioavailability, and even estimates of the fraction of the dose absorbed. Thus, we have entered a new era of human ADME study design that can yield vastly more informative and complete data sets enabling a superior understanding of overall drug disposition.

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Section: Importance Of the Human Adme Studymentioning

confidence: 99%

Mini‐Review: Comprehensive Drug Disposition Knowledge Generated in the Modern Human Radiolabeled ADME Study

Spracklin

Chen

Bergman

et al. 2020

CPT Pharmacom & Syst Pharma

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“…In the context of use in pregnancy, an extensive understanding of the absorption and elimination processes is essential, and parameters describing this should be reliable. A drug disposition diagram ( 15 , 16 ) is recommended for the drugs of interest ( Figure 1 ). The quantitative contribution of all enzymes and transporters involved in the absorption and elimination should be adequately captured in the model, and any uncertainties should be explored with a sensitivity analysis.…”

Section: Evaluation Of the Pregnancy Physiologically Based Pharmacokinetics Modelmentioning

confidence: 99%

Physiologically Based Pharmacokinetics Model in Pregnancy: A Regulatory Perspective on Model Evaluation

Coppola¹,

Kerwash²,

Cole³

2021

Front. Pediatr.

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Physiologically based pharmacokinetics (PBPK) modelling is widely used in medicine development and regulatory submissions. The lack of clinical pharmacokinetic data in pregnancy is widely acknowledged; therefore, one area of current interest is in the use of PBPK modelling to describe the potential impact of anatomical and physiological changes during pregnancy on the medicine's pharmacokinetics. PBPK modelling could possibly represent a predictive tool to support the medicine benefit–risk decision and inform dose adjustment in this population and also to investigate medicine levels in the foetus to support the risk assessment to the foetus. In the context of regulatory application, there are, however, a number of considerations around model evaluation, and this should be tailored to the model purpose, in order to inform the confidence in the model for the intended application. A number of gestational age-related physiological changes are expected to alter the pharmacokinetics of medicines during pregnancy, and there are uncertainties on some parameters; therefore, well-qualified models are needed to improve assurance in the model prediction before this approach can be used to inform with confidence high-impact decisions as part of regulatory submissions.

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“…The characterization of human absorption, distribution, metabolism and excretion (hADME) and pharmacokinetics (PK) plays an important role during drug development and the approval process (Coppola et al, 2019). Data from hADME studies are critical in the understanding of rates and routes of excretion, metabolic pathways, and the identification, quantification, and exposure to metabolites, as well as in designing appropriate clinical drug-drug interaction studies (Coppola et al, 2019). These data can also be used to evaluate the presence of metabolites in humans that would also need to be confirmed present in animals used in preclinical safety testing (Coppola et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Data from hADME studies are critical in the understanding of rates and routes of excretion, metabolic pathways, and the identification, quantification, and exposure to metabolites, as well as in designing appropriate clinical drug-drug interaction studies (Coppola et al, 2019). These data can also be used to evaluate the presence of metabolites in humans that would also need to be confirmed present in animals used in preclinical safety testing (Coppola et al, 2019). hADME studies are most commonly performed using drug labeled with a radioactive isotope, most often hydrogen-3 (tritium; 3 H) or carbon-14 ( 14 C), and by the intended clinical route.…”

Section: Introductionmentioning

confidence: 99%

“…hADME studies are most commonly performed using drug labeled with a radioactive isotope, most often hydrogen-3 (tritium; 3 H) or carbon-14 ( 14 C), and by the intended clinical route. After administration, the recovery of radioactivity is determined in excreta, and the metabolites and quantitative radio-chromatographic metabolite profiles are recorded in plasma and excreta (Coppola et al, 2019). However, for compounds intended to be administered via inhalation, there are both technical and ethical complications associated with administering a radioisotope (Beaumont et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of Velsecorat Using an Intravenous Microtracer Combined with an Inhaled Dose in Healthy Subjects

et al. 2021

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This open-label, single-period study describes the human absorption, distribution, metabolism, excretion, and pharmacokinetics of velsecorat (AZD7594). Healthy subjects received inhaled velsecorat (non-radiolabeled; 720 mg) followed by intravenous infusion of carbon 14 ( 14 C)-velsecorat (30 mg). Plasma, urine, and feces were collected up to 168 hours post-dose. Objectives included identification and quantification of velsecorat and its metabolites (i.e., drug-related material) in plasma and excreta, and determining the elimination pathways of velsecorat by measuring the rate and route of excretion, plasma half-life (t 1/2 ), clearance, volume of distribution and mean recovery of radioactivity. On average, 76.0% of administered 14 C dose was recovered by the end of the sampling period (urine 5 24.4%; feces 5 51.6%), with no unchanged compound recovered in excreta, suggesting that biliary excretion is the main elimination route. Compared with intravenous 14 C-velsecorat, inhaled velsecorat had a longer t 1/2 (27 versus 2 hours), confirming that plasma elimination is absorption-rate-limited from the lungs. Following intravenous administration, t 1/2 of 14 C-drug-related material was longer than for unchanged velsecorat, and 20% of the 14 C plasma content was related to unchanged velsecorat. The geometric mean plasma clearance of velsecorat was high (70.7 l/h) and the geometric mean volume of distribution at steady state was 113 l. Velsecorat was substantially metabolized via O-dealkylation of the indazole ether followed by sulfate conjugation, forming the M1 metabolite, the major metabolite in plasma. There were 15 minor metabolites. Velsecorat was well tolerated, and these results support the progression of velsecorat to phase 3 studies. SIGNIFICANCE STATEMENTThis study describes the human pharmacokinetics and metabolism of velsecorat, a selective glucocorticoid receptor modulator, evaluated via co-administration of a radiolabeled intravenous microtracer dose and a non-radiolabeled inhaled dose. This study provides a comprehensive assessment of the disposition of velsecorat in humans. It also highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion for velsecorat, related to the inhaled route, the high metabolic clearance, sequential metabolite formation and the low intravenous dose.

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The Importance of the Human Mass Balance Study in Regulatory Submissions

Cited by 37 publications

References 10 publications

Mini‐Review: Comprehensive Drug Disposition Knowledge Generated in the Modern Human Radiolabeled ADME Study

Mini‐Review: Comprehensive Drug Disposition Knowledge Generated in the Modern Human Radiolabeled ADME Study

Physiologically Based Pharmacokinetics Model in Pregnancy: A Regulatory Perspective on Model Evaluation

Characterization of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of Velsecorat Using an Intravenous Microtracer Combined with an Inhaled Dose in Healthy Subjects

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