Drug Discovery and Clinical Trials and Clinical Pharmacology

QUESTION 1
A）
Muromonab-CD3 is an example of biosimilars of monoclonal antibody (mAbs)therapy that targets and destroys antigens. The biosimilar was first commercialized in 1986 for the treatment of transplant rejection in humans. In Europe, infliximab was the first biosimilar mAb to be authorized in September 2013 and the US Food and Drug Administration approved Zarxio TM, filgrastim, -sndz, Sandoz in March 2015. Biosimilars represent various biological medicinal products containing versions of active substances of already authorized original biological medicinal products or reference medicinal products within the European Economic Area (EEA). These products are similar to reference medicinal products in terms of biological activities, quality characteristics, efficacy, and safety, and have no clinically important differences from reference products in terms of safety and efficacy. To date, the United States has not approved any biosimilar mAb for clinical use due to several challenges associated with biological medical products. For this reason, it is necessary for relevant pharmaceutical companies and the academic community to understand both the costs and stages associated with the processing of biosimilar mAbs.
Compared to other biosimilars such as biological and small molecules, monoclonal antibodies represent complex challenges due to their high molecular weight and have more complex structures. Examples of small molecular drugs as aspirin is comprised of about 21 atoms and 180 Daltons, while a typical mAb, which is a complex biopharmaceutical, has 20,000 atoms of 150,000 Daltons. The structure of small molecular drugs is also well defined but mAbs have more complex structures that are challenging to define. mAbs are highly complex molecules consisting of secondary and tertiary structures that are also subject to post-translational modifications such as glycosylation. While the molecular characterization of mAbs can be extremely precise, reproducible, and reliable, challenges in heterogeneity also exist that make physicochemical characterization a challenge. Pharmaceutical companies can produce small molecules at relatively lower prices without the need for extensive clinical trials. The complexity of biosimilar mAb therapies also introduces batch-to-batch variations, even in the originator molecules. Furthermore, characterization techniques used to reveal similarities in folded tertiary and quaternary structures such as x-ray crystallography and nuclear magnetic resonance are yet to become robust for industrial application.
Similar to biological molecules, biosimilars of mAb therapy may only be derived from living organisms as opposed to small molecules that can be chemically synthesized in the laboratory. In terms of development cost and time to market, biosimilars take longer, 7-8 years, and have a budget of $100-300 million, compared to generic products that take 2-3 years with a budget of $2-3 million. Compared with biologics, biosimilars have a shorter time to market and lower development cost with biologics costing 800 million and time to market of 8-10 years，note that the cost of developing biosimilars is significantly higher compared to their generic equivalents because of the higher cost of manufacturing and therapeutic equivalence trials. The cost of biosimilar mAbs has made the approval of these drugs a serious challenge with only 214 mAbs currently approved with about 1000 under development in various phases of development. Many of mAbs are withdrawn at human clinal trials or phase 1.
B)
mAbs are often complex biotherapeutics that require a comprehensive and stepwise development strategy that considers non-clinical, quality, and clinical aspects required for approval by both emerging and mature regulatory agencies. The development of biosimilar mAbs requires the identification and detection of biomarkers before generating mAbs in transgenic mice. The clones are then screened and selected before scaling up the cell culture. These first steps constitute protein engineering processes that must be carried out before development begins. The next stage involves purification and downstream processing and later formulation and stability testing. The candidate drug enters the preclinical study and clinical study (phase 1 to III) before it is manufactured and made available in the market. To ensure efficacy and safety of biosimilar mAbs, comparative clinical studies are conducted, where adverse events (AE), serious adverse events (SAE), and suspected unexpected serious adverse events (SUSAR) are assessed. Compared with other small-molecule generic drugs, biosimilar mAbs are evaluated through an abbreviated approval pathway. Unlike small-molecule generics, approval of biosimilar mAbs does not depend on the bioequivalence approach but is based on a stepwise comparability exercise with “Reference Biologic”, starting with the comprehensive characterization of biological and physicochemical characteristics. It is recommended that reference biological product is licensed with a full dossier with safety, quality, and efficacy details. In most regulatory agencies, reference production selection demands that the reference biological products be sourced from the same territory where the authorization of the biosimilar is requested. Traditionally, drugs must pass quality and safety assessment tests to understand their pharmacology and toxicology profiles.
The safety and efficacy of drug products, including biosimilar mAbs require pharmaceutical quality studies, non-clinical studies, clinical studies, and risk management plans. However, biosimilar mAbs must undergo additional and unique steps such as comparative quality studies that other drug products do not go through. Comparative non-clinical studies and comparative clinical studies to test safety and efficacy, immunogenicity, and pharmacokinetics/pharmacodynamics (PK/PD) are also necessary steps for biosimilars. Besides, biosimilars have unique risk management plans as compared to generic drugs. this plan constitutes immunogenicity assessment to collect additional information as early as possible and characterize the risk profile and whether the drugs are safe and effective to be used for clinical purposes. The European Medical Agency (EMA) has recommended that there should be a comprehensive pharmacovigilance plan that should be submitted alongside the original approval application and this plan should consider the immunogenicity risks during product development and other future risks. The process of risk management plan involved in biosimilars is conducted by a multidisciplinary team and includes pre-authorization and post-authorization testing. Furthermore, there is a need for post-marketing safety studies for long-term clinical usages of biosimilars that may demand the use of targeted questionnaires, registries, special follow-up plans, and phase IV studies. All these steps must be carried out to ensure the efficacy and safety of the drugs compared with the usual development process involved in producing traditional generic drugs.
QUESTION 2
A)
During phase III clinical trials, JM/B-2022 has been shown to vary significantly in terms of plasma concentration and efficacy when taken with other medications. This observation shows possible drug interactions or a change in the effects of one drug by the presence of a different drug, drink, food, or an environmental chemical agent. Drug-to-drug interactions are classified as either pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions are mainly caused by the interaction of drugs in absorption, distribution, metabolism, and excretion. The consequences of drug interaction include expected, inconsequential, and adverse, of which the insignificant accounts for the vast majority. Pharmacokinetically, drug interaction results in altered gastric absorption, drug displacement or protein binding, drug metabolism or biotransformation, and changes and excretion. Drug-drug interaction may also potentiate toxicity, cause antagonism, alter transport mechanisms, or change electrolyte levels based on pharmacodynamic assessments. Kinase inhibitors can be divided into three categories according to their binding sites: one is to act on ATP binding sites, which is the first type of kinase inhibitors; One is acting on the regulatory region, which is the second type of kinase inhibitor; The third type of kinase inhibitors, also known as allosteric inhibitors, target hydrophobic pockets away from ATP binding sites, but can regulate kinase activity by causing conformational changes in ATP binding pockets.
The possible mechanism of drug-drug interactions of kinase inhibitors with JM/B-2022 is a reduction in protein binding, which may result in a 5-fold increase in unbound drugs. This decline in protein binding inhibits the action of the drug as well as its metabolism and excretion. Therefore, understanding the mechanism of drug interaction with JM/B is critical to determine the type of drugs that may be inhibited or potentiated if co-administered. JM/B-2022 belongs to a class of drugs known as kinase inhibitors such as dasatinib, erlotinib, and imatinib, which are both tyrosine kinase inhibitors. These drugs may present a direct effect on glycemic control instead of improving leukaemia. Among patients with diabetes, these drugs need to be monitored as they alter glucose metabolism. Nilotinib has also been found to cause hyperglycaemia and may result in the need to increase levels of insulin among diabetic patients. Besides, tyrosine kinase inhibitors may also cause hypothyroidism among patients on levothyroxine, and is it important to understand these drug-drug interactions when managing patients with challenges in thyroid function. Most of the interactions that involve tyrosine kinase inhibitors are due to altered bioavailability due to the metabolism of cytochrome P450 isoenzymes, altered stomach pH, and prolongation of the QTc interval. Tyrosine kinase inhibitors are metabolized by cytochrome P450 enzymes with activities characterized by high interindividual variability. Some of these inhibitors may also act as either inhibitors or substances of drug transporters such as P-glycoproteins such as organic cation transporter 1 (hOCT1; SLC22A1 and Breast Cancer Resistance Protein (BCRP; ABCG2). This means that a standard treatment may produce very different circulating and cell concentration profiles among different patients. Safe use of JM/B-2022, therefore, requires the drugs review for individual patients. Examples of drugs that are likely to interact with JM/B-2022 include omeprazole which inhibits Pgp, esomeprazole which also inhibits Pgp and increases imatinib exposure.
B)
It is always expected that the same drug dose should have the same levels of plasma concentrations among all patients. However, due to variabilities, these levels change and may be due to drug-drug interactions. The impact of JM/B-2022 interactions could be monitored through therapeutic drug monitoring (TDM) where patients are monitored clinically to confirm the clinical picture of toxicity and assess the apparent cause of treatment failure. The rationale for TDM is to reduce chances of toxicity and have a greater chance of optimal control of treatment. TDM will also assess possibilities of malabsorption or drugs that could impair absorption such as antacids, and enteral feeds. Some drugs such as omeprazole and esomeprazole also work to increase exposure to some tyrosine kinase inhibitors such as imatinib and thus alter serum levels of the drug. If any of these changes are confirmed, it is necessary to consider TDM when changing treatment and recommend dose change, avoiding interacting drugs, or changing formulations or preparations. TDM involves the use of drug serum or plasma concentrations, pharmacodynamics, and pharmacokinetics in individualizing and optimizing the responses of patients to treatment. Through TDM, it is possible to offer optimum drug treatment by maintaining serum concentration within the expected therapeutic range. TDM can be conducted by taking a sample of systemic drug concentration through blood sampling or taking the patient’s saliva. For blood samples, an assay can be done with plasma or blood to measure both the bound and unbound drug. Drug assays such as automated immunoassays high-performance liquid chromatography (HPLC) and gas-liquid chromatography (GLC) can be conducted as TDM criteria. In most cases, pharmacokinetic variabilities during treatment may be caused by the age difference, variabilities in compliance, physiology, disease factors, drug interaction, and genetic polymorphism.
Safety assurance will involve studying drug interaction through absorption, distribution, metabolism, and excretion of drugs, which are critical processes in pharmacokinetics and pharmacodynamics. TDM is always recommended for drugs with narrow therapeutic ranges. For drugs that are difficult to make clinical interpretation or account for toxic responses, it is necessary to conduct TDM. Testing drug safety and efficacy are important steps in any drug discovery and before JM/B-2022 is ready to market, these stages must be confirmed as the drug advances from phase I to phase IV of clinical trials. Pre-clinical trials involve in vitro, in silico, or whole animal testing, while clinical trials will involve human subjects beginning with phase 0 to phase IV. Ph...