Monoclonal Antibodies vs Small Molecules - Essay Example

Introduction Undertaking early human exploratory development of therapeutic drug or compound of any kind, the outcomes that will be achieved are always different depending on the compound or drug in question. In this essay, the emphasis is placed on two major forms of molecules that may be considered for therapeutic treatments. These are monoclonal antibody and small molecules. The pharmacology of these two molecules are compared for any significant clinical differences. To ascertain the exact differences in these two molecules when it comes to early human exploratory development, their different characteristics, clinical trial design, choice of study population, study design guidelines, estimation of the first dose, study design guidelines, and regulatory agencies shall all be investigated. A conclusion will thus be drawn. Early human exploratory development Given the risky and fatal impact of failed drug production in humans, the need to be comprehensively certain of the efficacy, function and overall pharmacological outcomes of a clinical drug is very important. It is against this backdrop that early human exploratory development has been used over the years as the first part of any clinical development phase of a novel compound or clinical drug where the compound or drug is assessed for tolerability, pharmacodynamics, and pharmacokinetics in humans (Jefferis, 2007). Differential characteristics of monoclonal antibody and small molecules There are number of ways in which mAbs have been noted to be different from conventional small molecule drugs. First, Telling (2004) indicated that there is a major interspecies variation between the use of the two molecule forms. What is more, mAbs exhibit less homogenous biological production process when compared to small molecules. Directly related to the action of the biological production is the fact that the mAb is able to achieve specificity of action during drug development but no such specificity of action is achieved for small molecules (Vorberg et al., 2000). Again, the target toxicity for mAbs have been found to be unspecific as there could be on and off target toxicity, accompanied with a highly complex PK:PD relationship. In terms of the field research that have been performed for these two molecule forms, Treon et al. (2005) argued that mAb has seen a relatively youthful research field, most of which have showed outcomes of rare to no linear dose response. What is more, there is an unpredictable effect on the immune system complex when mAb is used. among other factors, there is poor oral bioavailability, long half-life, and complex non-linear kinetics in mAb when in actual fact none of these exist for small molecules (Shantha and Raju, 2010). The table highlights the main characteristics, which have been noted to have significant clinical implications. Characteristic mAb Small molecule Weight of organic compound 150,000 200-500 Dalton Production process Heterogeneous biological production process Homogeneous chemical production process Selectivity There is high species selectivity Overall selectivity is low Toxicity Toxicity is on target and requires exaggerated pharmacology Off target mediated exaggerated pharmacology Target binding Exhibits a multi-functional target binding There is single target binding Clearance Very slow rate of clearance leading to long half-life in days Rapid rate of clearance leading to short half-life in hours Effect of target on PK behaviour Target can affect PK behaviour Target has non-linearity from saturation of metabolic pathways Drug-drug interaction Few known examples which are mostly PD related Many known examples, which could be either metabolic or PD related Immunogenicity Yes. Sometimes observed Rarely observed (Lloyd, 2014) Clinical Trial design The clinical trial deigns used for monoclonal antibodies and small molecules in drug development in general and early human exploratory developments to be specific are very relevant in determining the outcome of the trial. This is because such clinical trial design aim to directly solve specifically identified clinical defects. As far as clinical trials of mAbs are concerned, the use of primary purpose treatment has been identified as being ideal for both phase I and phase II studies (Chadd & Chamow, 2001). Choice of study population When undertaking an early human exploratory development with the use of mAb and small molecules, there are some critical points that need to be considered when it comes to the choice of study population. In the first place, both cases of monoclonal antibodies and small molecules have been noted to come with no expectation of achieving therapeutic benefits in human trials (Kohrt et al., 2012). To this end, phase I trial for small molecules may be undertaken with the use of healthy volunteers who have fewer confounding factors, less variability, and come with minimal risk to the study (Weiner, 2010). For mAb, the choice of population should be with the aim of confirming clinical efficacy. Where there are healthy volunteers for small molecules, it is important that fewer confounding factors that make risk minimal will be used (Jefferis, 1993). Moreover, it should be in cases when information such as PK, PD and tolerability will be needed that healthy volunteers must be considered (Kohrt et al., 2012). This means that where there may be any uncertainties about study, the use of healthy volunteers must be discouraged. Where patients are used for mAb, continuation of treatment should be encouraged only when drug is found to be effective (Chadd & Chamow, 2001). It is therefore important that an inclusion and exclusion criteria be used to clearly know candidates who are suitable and those who are not. Clinical trial designs and Study design guidelines Liebdert et al. (2007) performed a study with the aim of finding the safety of phase I clinical trials of mAbs in Germany for the aftermath of the TGN1412 disaster. The study was found to have several effects on participants’, including organ dysfunction and other adverse events. To prevent similar situations in the UK, there has been the need to having regulations that guide the performance of early human exploratory developments with mAbs. The Committee for Medicinal Products for Human Use (CHMP) has since 2007 given out guidelines that are used for study designs with the aim of identifying and mitigating risks for early human exploratory developments involving small molecules and monoclonal antibodies. As part of the guidelines, it is strongly recommended that provisions should be made on how to identify risks even before they begin, and once they begin, how to put in place mitigation plans in place to minimise their effects. Some of the areas where researchers are admonished in the guidelines to take particular precaution include the study population as extensively discussed above. There are also guidelines on the trial sites, where maximum safety precautions are expected to be practiced by the researcher in protecting both life and property (Kohrt et al., 2012). The first dose is another of the most important areas where precaution is needed to minimise any forms of risks. The guidelines particularly relate the following observations to the first dose, so as to minimise risk. They include, route and rate of administration, cohort, sentinel groups, sequence of dosage, dose escalation increments, and stopping rules (Jefferis, 2007). When it comes to administration of drugs, it is strongly recommended that for the study design, the predicted period of highest risk of adverse effects should be the duration between each cohort at a specified dose level (Bai, 2011). Again, it is very important that sufficient time will be left between each cohort that will be used for gathering results that are clinically relevant for understanding associated risks (Rathore and Winkle, 2009). What is more, before dose escalation, it is important that 3 or 4 subjects will be made to receive a specified dose. Dosing and estimation of first dose Before deciding on dose to use, it is strongly recommended that additional approach to dose calculation be employed when risk factors have been associated with investigational medicinal products (Beckman, Roemeling and Scott, 2011). Such additional information could be ascertained through the use of PD which gives guidance for dose selection. In terms of approach, minimum anticipated or acceptable biological effect level (MABEL) is recommended for mAb. When using the MABEL approach, Jefferis (1993) advises that both in vitro and in vivo information that have been gathered from PD and PK data including target binding receptor occupancy studies, concentration-response curves, and exposures at pharmacological doses should all be itemised as part of estimation of dose. To make an accurate choice of first dose, the use of NOAEL is strongly recommended for small molecules. With this said, it is important to consider any forms of severities that are recorded as part of exaggerated pharmacology in both cases of MABEL and NOAEL approaches (Bai, 2011). Other factors that must be considered in making choice of first dose are preference for intravenous infusions, a minimum of 1 hour of infusion duration, retention of subjects in study unit for a minimum of 24 hours after dosing, and admission of drug to only one subject on day one (Chadd & Chamow, 2001). The determination and administration of dose may well not serve as the last activity as there should be between-dose review. In-between dose, it is very important that three major information will be obtained, which are effect on subjects, exposure to subjects, and safety from previous human dose (Rathore and Winkle, 2009). Such other information as adverse effects, attributability, laboratory data, vital signs, PD, and PK are all very important reviews that need to be made before proceeding (Bai, 2011). Finally, decision needs to be taken on the dose at which no more administration will be continued. For this, it is important to ensure that whenever safety of subjects is compromised, dose will be stopped. It is also important that the stopping rules that have been given in protocol and as agreed upon before the experiment will be used (Rathore and Winkle, 2009). What is more, cases of poor tolerability and the reaching of maximum planed dose, as well as unfavourable PK must all be reasons that should ensure that dose will not be continued any longer. Adverse Events The American Cancer Society outlines a number of adverse events that the use of monoclonal antibodies may carry in early human exploratory development. Some of these include fever, chills, weakness, headache, nausea, vomiting, diarrhoea, low blood pressure, and rashes (Jefferis, 1993). When Aducanumab was tried for the first time in humans for Alzheimer’s disease, Imal and Takaoka (2006) reports that as Aducanumab is a type of therapeutic mAb the major cause of adverse events was by the immunugenesity characteristics. In small molecules, the adverse events associated have been found to be generally mild. Such adverse effects such rash, acne, dry skin and pruritus, as well as gastrointestinal events including diarrhoea, nausea, vomiting and anorexia may all be recorded (Jefferis, 1993). It is against this background that the use of MABEL and NOAEL criteria for risk assessments are strongly recommended in first human trials of monoclonal antibodies and small molecules respectively. This risk assessment form ensures that while developing drug, all precautionary measures and mitigation plans to minimise the possible effects that participants and eventual users of the drug may experience are minimised. Regulatory Agencies Due to the sensitivity of both monoclonal antibodies and small molecules, there are regulatory agencies responsible for its non-clinical trial, clinical trial, and product usage. For example, for traditional small molecule early human exploratory developments, the Association of the British Pharmaceutical Industry (ABPI) has guidelines which are used alongside those of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). First human trails by the Research Institute of Molecular Pathology (IMP) also have strong input from the Expert Scientific Group (ESG) on phase I clinical trials. There are other regulatory inputs from Medicines and Healthcare products Regulatory Agency (MHRA). As an executive agency of the Department of Health, the MHRA and similar agencies as it regulates the safety, quality, effectiveness and performance of medicines and medical devices (Vorberg et al., 2000). On the whole, it can therefore be said that the MHRA ensures that precautionary measures for all mAb FIH clinical trial applications are duly observed (MHRA, 2014). It has oversight duties at all levels of development of drug including the very early stages when early human exploratory development is being performed. It is important that all guidelines given by the MHRA and other regulatory agencies be followed extensively when performing early human trials. Conclusion Monoclonal antibodies are mainly for diseases such as cancer, rhematology and immunology. Small molecules for all types of diseases. It is however critical that for any of these to be used very effectively, the right form of characteristics clinical features that makes them unique be identified. This was the rationale for this paper which differentiated the two types of molecules. On the whole, it can be concluded that safety is the ultimate and most important outcome that can be expected with the use of both monoclonal antibodies and small molecules. When it comes to structural and characteristic features of the two types of molecules, it has been seen that the differences between the two molecules are very vast. Some important concluding recommendations that will be made is that there should be an increase in the number of early human studies so that enough evidence can be gathered for decisions making. Whiles experimenters engage in their roles, they ought to consider volunteer populations as individuals, each of who shares a unique case of identity that must be considered in the clinical design. Finally, experimenters must always make use of the competent authority by speaking to these when the need arises. References Bai J.P.F. (2011) Monoclonal antibodies: from benchtop to bedside. Therapeutic Delivery Vol. 2 No. 3, 329-331. Beckman, R. 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