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Why cancer drug programs need human mass balance studies

Historically, drug programs for oncology and other rapidly fatal diseases didn’t include mass balance studies in the clinical pharmacology package. This omission stems from the ICH S9 on nonclinical evaluation for anticancer pharmaceuticals (S9 ich.org). This guidance outlined a lighter preclinical package for these conditions. It was also more flexible regarding the non-clinical qualification of metabolites.

Labeling of oncology products approved during this period could be based on very sparse elimination information and the enzyme contribution was solely based on in vitro information. Thus, the drug labels could often be misleading. The clinical situations of over- and under-exposure of the oncology drug could not be fully foreseen.

Data from the mass balance study helps create a model of drug disposition in the human body.
Figure 1. Data from the mass balance study helps explain drug disposition in humans. Source: https://www.ema.europa.eu/en/assessment-templates-guidance#day-80-and-day-120-assessment-report-templates-containing-guidance-8164

What are human mass balance studies, and why must drug developers do them?

The human mass balance, or absorption, metabolism, and excretion (AME) study is central to the Clinical Pharmacology development program. In mass balance studies, subjects are administered radiolabeled drugs. Then, researchers collect as much of the radiolabeled drug as possible from excreta (urine, feces, etc.). In addition, they monitor the exposure of radioactivity and the drug in whole blood and plasma. Excreta and plasma are analyzed for the parent drug, and metabolites are identified and quantified. The goal is for all prominent metabolites in plasma to be identified, and to understand the fate of the parent drug and any active metabolites in the body.

This study helps answer several research questions about an investigational drug:

  • What are its primary elimination pathways?
  • What in vivo DDI studies should be performed to identify enzymes and transporters involved in these pathways? This can be determined with or without an expanded, metabolite formation-focused, in vitro package.
  • What’s the likely impact of renal or hepatic impairment on drug pharmacokinetics/pharmacodynamics (PK/PD)?

Human major metabolite(s) refer to metabolites representing 10% of the AUC (area under the curve) of dose-related material exposure. In the limited oncology indications where metabolites in safety testing (MIST) apply, the preclinical species exposure to human major metabolite(s) is investigated. The goal is to evaluate whether human-specific or disproportionate metabolite(s) have been identified and appropriately addressed in the toxicology program.

For small-molecule drugs, Quantitative Whole-Body Autoradiography (QWBA) studies are conducted in rodents before the human mass balance study. These studies can also be performed in parallel to a human micro tracer study. QWBA studies enable dosimetry assessment and help determine a safe dose of radiolabeled drugs for humans. They also quantify the radiolabeled drug’s distribution and elimination routes throughout the rodent body.

From a clinical pharmacology perspective, the information from the hAME study supports further mechanistic extrapolation. This enables predicting the effect of many intrinsic and extrinsic factors including

  • victim drug interactions
  • patients with renal and hepatic impairment
  • pharmacogenetic subpopulations
  • 인종적 가교
  • pediatric patients, etc.

The mass balance study also characterizes the major human metabolite exposure data. This information determines if in vitro characterization of the DDI perpetrator effect is needed.

What if a mass balance study can’t be done?

In rare cases, conducting a human mass balance study isn’t possible. Thus, the information missing needs to be gained using other methods.

Characterizing elimination routes and their enzyme and transporter involvement may be cumbersome. Sometimes, drug elimination may be characterized by

  • performing DDI studies with selective enzyme inhibitors
  • quantifying renal clearance
  • metabolite profiling of unlabeled drug in plasma and excreta (“cold analysis”)
  • additional supportive nonclinical studies may help to refine the data package.

The recently finalized FDA guidance Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies | FDA states when a study can be waived. These include drugs for which mass balance study results can be obtained from literature or product labeling, small molecule drugs with near complete renal elimination, monoclonal antibodies, endogenous substances, and drugs with no or negligible systemic exposure.

Gradual increase in requirements for oncology drug development programs

For quite some time, regulators have been dissatisfied with the lack of knowledge about these life-saving, but potent, drugs. Thus, the EU developed Revision 4 of the EMA Guideline on the clinical evaluation of anti-cancer medicinal products (2012). This guideline recommended also performing the mass balance study for oncology drugs:

“In the past, human mass-balance studies (in vivo studies investigating the fate of a radiolabeled dose in plasma and excreta) have not been performed to the same extent for anticancer drugs as for other medicinal products. Due to the importance of the information gained in these studies for the understanding of the clinical pharmacology of the investigational drug, including the drug-drug interactions assessment, mass-balance studies are strongly recommended (CPMP/EWP/560/95/Rev. 1 Evaluation of anticancer medicinal products in man – Scientific guideline | European Medicines Agency (europa.eu)).”

The EU also published the Clinical Pharmacology requirements for a mass balance study (The Drug Interaction guideline CPMP/EWP/560/95/Rev. 1). The agencies started asking for mass balance studies in oncology applications.

The Certara clinical pharmacology team analyzed oncology drugs approved by the FDA and EMA to see what regulators seek regarding mass balance studies. Of the small molecule oncology drugs approved by the FDA between 2015-2023, only four lacked a human mass balance study. Two of these, rucaparib1 and selinexor2 were accelerated approvals. Studies to characterize elimination were set as post-marketing requirements and commitments. These studies were a victim DDI study with a strong CYP3A4 inhibitor for selinexor, and a mass-balance study for rucaparib.

The third case was a combination of tipracil and the PK booster trifluridine approved in 2015. Neither substance was a CYP substrate, but a cold analysis of urine and plasma was still performed.  Tipracil is metabolized by a thymidine phosphorylase, and trifluridine is renally excreted. 

The fourth case is ripretinib which the FDA approved in 2020.  Ripretinib formulation issues hindered performing a mass balance study. Therefore, cold analysis of excreta was performed for the parent drug, its active metabolite, and other potential metabolites. Based on the in vitro data and the clinical metabolite profiling, the sponsor performed a clinical DDI study. This study indicated that CYP3A4 and the efflux transporter P-glycoprotein contribute to about 50% of ripretinib oral clearance.3

The EMA assessment4 suggested but didn’t require an intravenous microdosing study. Small deficiencies in recovery, and hence some risk that minor metabolite(s) are missed, were considered justified. This was based on the indication of patients with advanced gastrointestinal stromal tumors who were previously treated with 3 or more kinase inhibitors.

Rucaparib and selinexor both had a conditional approval in the EU. EMA regulators requested similar assessments related to elimination as US regulators.5,6 The EU submission of tipracil/trifluridine included a mass-balance study.

Regulatory scrutiny of the study

Besides the absence of mass balance information, the study performance could also be criticized. From 2010 to 2019, EMA regulators raised AME-related questions for at least 6 oncology drug submissions in the initial European Public Assessment Report (EPAR).

For example, ibrutinib, approved in 2014, had an hAME study. The fraction of drug identified in plasma and excreta was rather low. However, DDI and pharmacogenomic information covered the elimination of ibrutinib. For neratinib and ibrutinib, issues were initially due to incomplete identification of metabolites or lack of understanding of the elimination pathways.

Neratinib gained approval in 2018. The sponsor had to perform an additional study to characterize the urinary and fecal recovery of total radioactivity. They also provided urine and fecal samples for metabolite profiling and identification. The EMA CHMP requested several in vitro and in vivo studies as post-authorization measures for ibrutinib to characterize the contribution of different enzymes to the drug metabolism, involvement of transporters in hepatic uptake, and to evaluate the potential DDI risk.

Where to find information on best practices for conducting mass balance studies

The EMA Drug Interaction guideline (Guideline on the investigation of drug interactions, CPMP/EWP/560/95/Rev. 1 Corr. 2**) outlines the EU’s mass-balance study performance requirements. The final mass balance study guideline (Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies Guidance for Industry, July 2024) describes the FDA’s requirements.

We can support your cancer drug program’s approach.

Our early drug development and clinical pharmacology regulatory strategy teams can help you design your human mass balance studies!

To learn more about the clinical pharmacology-related regulatory hurdles across regions that may lead to review issues and potential strategies to mitigate them, watch this webinar.

References

  1. NDA Multi-disciplinary Review for Rucaparib. FDA access database. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000MultiDisciplineR.pdf . Accessed 9월 12, 2024.
  2. NDA Multi-disciplinary Review for Selinexor. FDA access database https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212306Orig1s000MultidisciplineR.pdf . Accessed 9월 12, 2024.
  3. NDA Multi-disciplinary Review for Ripretinib. FDA access database. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213973Orig1s000MultidisciplineR.pdf. Accessed 9월 12, 2024.
  4. Public Assessment Report for Ripretinib. EMA database. https://www.ema.europa.eu/en/documents/assessment-report/qinlock-epar-public-assessment-report_en.pdf. Accessed 9월 12, 2024.
  5. Public Assessment Report for Nexpovio. EMA database. https://www.ema.europa.eu/en/documents/assessment-report/nexpovio-epar-public-assessment-report_en.pdf. Accessed 9월 12, 2024.
  6. Public Assessment Report for Rucaparir. EMA database. https://www.ema.europa.eu/en/documents/assessment-report/rubraca-epar-public-assessment-report_en.pdf. Accessed 9월 12, 2024.

About the authors

Eva Gil Berglund, PhD
By: Eva Gil Berglund, PhD

Dr Eva Gil Berglund joined Certara Drug Development Support in 2019 as Senior Director in Clinical Pharmacology and Regulatory Strategy. Eva supports companies in Clinical Pharmacology Regulatory Strategy. She has 20+ experience as Clin Pharm Reviewer and Senior Expert at the Swedish Medical Products Agency, and has been lead writer of several EU Clinical Pharmacology guidance documents including in DDIs, PBPK, Pediatrics and has been a member of the EMA Pharmacokinetics and Paediatrics EMA working parties.

By: Krista Greenwood, PhD
Paola Coppola, MSc
By: Paola Coppola, MSc
Paola is currently a Director of Clinical Pharmacology at Certara. She has 15+ years of clinical pharmacology and regulatory experience having worked as a Senior Pharmacokinetics Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), UK and in a number of roles in Industry such as Head of Clinical Pharmacokinetics and Marketed Products Clinical Pharmacology Lead at AstraZeneca, UK, and Pharmacokinetics Scientist in Angelini, Italy. She obtained her MSc in Biological Sciences from the University Federico II of Naples, Italy and a Post graduate Master from the Business School ISTUD, Italy.
Blaire Osborn, Ph.D.
By: Blaire Osborn, Ph.D.
Blaire has over 25 years of drug development experience in the areas of clinical pharmacology and pharmacokinetics. Before joining Certara, she was a reviewer in the Office of Clinical Pharmacology, US Food and Drug Administration, in the Division of Cancer Pharmacology, CDER where, she participated in the assessment of multiple dose justification submissions under Project Optimus. Dr. Osborn is holds a Ph.D. in Pharmacology from The George Washington University.
Nathalie Rioux
By: Nathalie Rioux

Dr. Rioux joined Certara in October 2018 and is now a Vice President of Integrated Drug Development. Nathalie obtained her Ph.D. in Pharmacy at Laval University, Quebec, Canada, where she studied lung cancer chemoprevention by non-steroidal anti-inflammatory drugs and lipoxygenase inhibitors.  Following graduate school, Nathalie completed an industrial post-doctoral fellowship in drug metabolism, sponsored by NSERC Canada/Biochem Pharma.

Nathalie has more than 15 years of experience in the pharmaceutical industry, in biotech, pharma, and CRO service.  After being a DMPK lab head & project leader for multiple antiviral drug development projects at Boehringher Ingelheim Canada, she moved to a principal scientist role at Epizyme, where she represented DMPK on multidisciplinary oncology discovery and nonclinical programs including alliances with GSK, Eisai, and Celgene.  Most recently, she built the DMPK, bioanalytical and clinical pharmacology group at H3 Biomedicine in Cambridge, MA, where she drove the strategic and tactical activities around ADME, PK/TK, bioanalysis, and modeling across the discovery and development space.  At H3, she acted as a member of the development leadership team, where she contributed to regular review of project strategy, selection of development candidate, and multiple due-diligence activities.  Nathalie has co-authored multiple regulatory documents and contributed to several development compounds in H3’s Phase 1/1b oncology program.

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