College of Our Lady of Mt. Carmel (Pampanga) Inc.

DEPARTMENT OF PHARMACY

City of San Fernando, Pampanga

PHARM121
Biopharmaceutics and
Pharmacokinetics

FINAL ASSIGNMENT
ARTICLE REVIEW – ZAPNOMETINIB

(1st Semester)
A.Y. 2023-2024

Submitted by:

KAREN A. ORTIZ
BSPH-3

Submitted to:

Symonett Beatriz De Leon, RPh

Instructor
TABLE OF CONTENTS

INTRODUCTION ………………………………………………………………………………1
Background Information, Purpose of the Article, Scope of the Review
PART I - SUMMARY OF THE ARTICLE …………………………………………………...2
Key Concepts, Main Findings, Methodology Overview
PART II - DIAGRAM OF THE ARTICLE ……………………………………………………3
Visual Representation of Key Concepts, Relationships and Connections
PART III - CRITICAL THINKING …………………………………………………………….4
Discussion and Views on the Article
How the Article Was Written
Interpretation of the Data and Results
Discussion of Issues/Problems Raised
Significance of the Study
Personal Recommendations
Personal Key Takeaways
CONCLUSION ………………………………………………………………………………….5
Summary of Critical Thinking
Overall Impressions of the Article
REFERENCES ………………………………………………………………………………….6
List of Citations and Sources Used
INTRODUCTION

Zapnometinib is a MEK1/2 inhibitor with the chemical name PD-0184264, also referred to as
ATR-002 (2-(2-Chloro-4-iodophenylamino)-3,4-difluorobenzoic acid). Initially developed as
CI-1040, zapnometinib is the active metabolite of CI-1040, a compound that was described
as a potent and highly selective inhibitor of MEK with a 50% inhibitory concentration (IC50)
of 17 nM. CI-1040 was developed for cancer treatment but had its development terminated
due to a lack of antitumor response and low bioavailability. Now repurposed for use in
infectious disease indications, zapnometinib (derived from CI-1040) is especially useful for
treating acute viral infections. The compound's ability to both suppress the spread of viruses
and alter the immune system is emphasized as a possible advantage in the treatment of
conditions with significant inflammatory components.

The study focuses on the pharmacokinetics of zapnometinib in rats. The investigation

specifically focuses on explaining the time-dependent plasma concentrations, excretion
rates, tissue distribution patterns, metabolite profiles, and the chemical characteristics of
metabolites following the administration of single oral doses of [14 C]-zapnometinib.

This study aims to provide insight into the pharmacokinetic characteristics of zapnometinib,
specifically focusing on its potential for clinical development. The purpose of the study is to
shed light on the compound's unique properties, such as its rapid yet restricted absorption,
high rates of excretion, wide dispersion throughout several tissues, and complex metabolic
processes.

The article's focus is on deciphering the complex pharmacokinetic behavior of zapnometinib

to provide insightful knowledge that may facilitate the drug's future development in clinical
settings. The study analyzes the compound's overall pharmacokinetic profile in addition to
offering a thorough understanding of these processes through an examination of the
compound's absorption, distribution, metabolism, and excretion in a rat model. Considering
the noted features—such as rapid absorption, high rates of excretion, and extensive tissue
distribution—the results could be significant for directing future clinical development
strategies. This comprehensive analysis of zapnometinib's pharmacokinetics provides a
basis for debating the drug's viability and appropriateness for more clinical research as well
as possible therapeutic uses.
I. SUMMARY OF THE ARTICLE

The article delves into a comprehensive exploration of the pharmacokinetics of

Zapnometinib - a MEK inhibitor - in rats to support pharmacology and toxicology studies in
animals and clinical studies in man. Pharmacokinetics involves studying how a drug is
absorbed, distributed, metabolized, and excreted in the body. In this study, the researchers
administered a single oral dose of zapnometinib to rats and meticulously examined its
journey through various physiological processes.

The investigation unveils several key aspects of Zapnometinib's pharmacokinetics. Firstly,

the drug exhibits low absorption from the gastrointestinal tract which implies that a
substantial portion of the administered dose may not be taken up into the bloodstream,
potentially influencing the drug's efficacy. Secondly, the compound demonstrates rapid and
widespread distribution in the body tissues, indicating its ability to reach various organs and
tissues quickly. This characteristic could be advantageous in targeting specific areas affected
by the condition for which zapnometinib is intended.

Furthermore, the predominant excretion of zapnometinib via feces highlights the importance
of the gastrointestinal route in eliminating the drug from the body. Understanding the primary
excretion pathway is crucial for determining the appropriate dosing regimen and potential
accumulation risks.

The article also sheds light on the metabolic pathways of zapnometinib. The drug undergoes
metabolism primarily through oxidative reactions and glucuronidation. Oxidative reactions
and glucuronidation are common processes in drug metabolism, where the drug is
chemically modified to facilitate its elimination from the body. The study also notes minor
gender-dependent pharmacokinetic differences, indicating that the drug may be processed
differently in male and female rats.

The significance of this research lies in the valuable insights it provides for the development
and safety assessment of zapnometinib. By elucidating the drug's pharmacokinetic profile,
the study contributes essential information for designing effective dosing regimens and
understanding potential safety concerns. The clear and detailed presentation of the data
enhances the robustness of the findings, making them reliable for informing further
preclinical and clinical development of zapnometinib laying the groundwork for its
advancement in therapeutic applications.
II. DIAGRAM OF THE ARTICLE
III. CRITICAL THINKING

Discussion and Views on the Article

The scientific and technical article discussing the pharmacokinetics of the MEK inhibitor
zapnometinib in rats presents a thorough examination of the compound's absorption,
distribution, metabolism, and excretion after a single oral dose. The article employs
analytical data to provide a comprehensive analysis of both the pharmacokinetics and
pharmacodynamics of the drug. Supported by clinical evidence, laboratory samples, and
reliable references, the study delves into the drug's pharmacokinetics, offering novel insights
that challenge existing theories and open avenues for further research. Notably, the research
sheds light on potential effects of zapnometinib on infectious disease indications, adding
valuable contributions to the ongoing exploration of its pharmacological properties.

Interpretation of the Data and Results

The data and results indicate low absorption, rapid distribution, and predominant excretion
via feces, with metabolism mainly through oxidative reactions and glucuronidation. Gender-
dependent pharmacokinetic differences were minor. The research investigated how
zapnometinib is processed and removed from the bodies of both male and female rats. It
was discovered that the peak levels of the drug in the bloodstream happened a few hours
after administration(4hrs in males & 2.67hrs in females), and its presence gradually
diminished over time. The study also pinpointed particular byproducts and showed that the
majority of the drug and its derivatives were expelled through feces within the initial 24
hours. These insights are essential for comprehending how the drug behaves within the
body and are vital for ensuring its safety in ongoing development.

Discussion of Issues/Problems Raised

In my perspective, the study lacks any notable concerns or issues. It was thorough and
meticulous, and the results demonstrated precision in alignment with the study's procedures
and objectives. The presentation of materials and methods, including test design, test animal
and husbandry, and research design, is clear and straightforward. The progression of the
research study is easily understandable, and the practical implications of the article's
findings are thoroughly elucidated and apparent.

Significance of the Study

The significance of this research lies in its provision of valuable insights crucial for the
development and safety assessment of zapnometinib. This is achieved through a
comprehensive examination of the drug's pharmacokinetics in rats following single oral
doses. The findings not only support the groundwork for upcoming clinical trials in humans
but also offer indispensable information regarding various aspects such as plasma
radioactivity concentrations, excretion rates, tissue distribution, metabolite profiles, and the
chemical nature of metabolites.
One noteworthy outcome of the study is the identification of gender-dependent
pharmacokinetic differences and the rapid absorption of zapnometinib in both male and
female rats, adding variation to our understanding of the drug's behavior. These insights also
carry significance beyond the immediate scope of the study, potentially impacting the
broader field of pharmacology.
Importantly, the research extends its relevance to public health by contributing to our
understanding of the drug's potential therapeutic effects. This includes its implications in the
treatment of severe viral diseases, such as COVID-19 and influenza. By shedding light on
how zapnometinib behaves in the body and its gender-specific variations, the study paves
the way for further exploration and optimization of the drug's efficacy in combating infectious
diseases. Overall, these multifaceted findings not only advance the understanding of
zapnometinib but also hold promise for its future application in clinical settings, particularly in
the context of viral infections.

Personal Recommendations and Insights

All aspects of zapnometinib's pharmacokinetics and pharmacodynamics have been

extensively examined in both animal models and humans. Koch-Heier et al.'s study has
already proven the sustained MEK inhibition post zapnometinib elimination from plasma.
Additionally, the compound has undergone comprehensive assessment in a phase 1 clinical
trial, revealing favorable pharmacokinetic profiles, safety, and toxicology results.
Furthermore, the successful implementation of a phase 2 clinical trial for severe COVID-19
treatment in hospitalized patients further reinforces the compound's effectiveness.
Given the strong groundwork laid by prior research endeavors, encompassing both phase 1
and phase 2 clinical trials, and the methodical exploration of various pharmacokinetic
parameters in the ongoing study, it seems that all pertinent aspects concerning zapnometinib
have been thoroughly addressed. Therefore, at this stage, no additional recommendations
are considered necessary, as the existing body of evidence is thorough and all-
encompassing.

CONCLUSION

The article explores the pharmacokinetics of the MEK inhibitor zapnometinib in rats,
providing a detailed analysis of absorption, distribution, metabolism, and excretion after a
single oral dose. Supported by clinical evidence and laboratory samples, the study
challenges existing theories and suggests potential effects on infectious disease indications.
The data reveals low absorption, rapid distribution, and predominant fecal excretion, with
minor gender-dependent differences. The research highlights the drug's behavior in the
body, its safety, and potential therapeutic effects, particularly in treating infectious diseases
like COVID-19. The study's significance lies in providing valuable insights for the drug's
development and safety assessment, with implications for clinical trials and broader
pharmacological understanding. No significant concerns are raised in the study, and its
comprehensive findings contribute to the promising future application of zapnometinib in
clinical settings.
Overall, the article on the pharmacokinetics of the MEK inhibitor zapnometinib in rats leaves
a positive impression. The research is thorough and detailed, examining various aspects of
the study challenging existing theories, and introducing potential implications for infectious
disease indications, adding valuable contributions to the field. The data and results are also
well-interpreted.

REFERENCES

Füll, Y., Wallasch, C., Hilton, A., & Planz, O. (2022). Pharmacokinetics, absorption,
distribution, metabolism and excretion of the MEK inhibitor zapnometinib in rats. Frontiers in
pharmacology, 13, 1050193. https://doi.org/10.3389/fphar.2022.1050193

Koch-Heier, J., Schönsiegel, A., Waidele, L. M., Volk, J., Füll, Y., Wallasch, C., Canisius, S.,
Burnet, M., & Planz, O. (2022). Pharmacokinetics, pharmacodynamics and antiviral efficacy
of the MEK inhibitor zapnometinib in animal models and in humans. Frontiers in
Pharmacology, 13. https://doi.org/10.3389/fphar.2022.893635