The fact that many drugs fail to come on the market due to poor pharmacokinetic profiles

The fact that many drugs fail to come on the market due to poor pharmacokinetic profiles, has necessitated the inclusion of pharmacokinetic considerations at earlier stages of drug discovery programs (Hodgson 2001; Navia and Chaturvedi 1996). This demands the exploration for lead compounds which can be easily orally absorbed, easily transported to their site of action, negligibly metabolised into noxious products prior to reaching the targeted site and easily removed from the body system before accumulating in enough quantities that might yield hostile adverse effects. Computer-based approaches have been used in the prediction of ADME characteristics of drug leads at primary stages of drug discovery. Such methods are becoming more and more popular (Lipinski et al. 1997; Lombardo et al. 2003; Gleeson et al. 2011). The rationale behind in silico methods are the relatively lesser cost and the time factor involved, when compared to standard experimental approaches for ADMET profiling (DiMasi et al. 2003; Darvas et al. 2002). As an example, it takes 60 seconds in an in-silico model to screen 20,000 molecules but takes 5 months in the “wet” laboratory to do the same thing (Hodgson 2001). An interesting example of an in-silico technique would be developing 3D structures of naturally occurring compounds within ConMedNP (a natural product library from Central African medicinal plants for drug discovery) (Ntie-Kang F et al 2013). Such a technique would be a good foundational point for pharmacophore-based virtual screening campaigns, thus rendering ConMedNP a great asset for a drug discovery team.
Pharmacokinetic (PK) and pharmacodynamic (PD) data attained from animal models may not always be predictive of human PKs/PDs. This makes the pre-clinical phase of drug development complicated, risky, and expensive: this chiefly determines whether a new molecular entity is “druggable,” i.e. how likely it can modulate a target (Owens J 2007). So, let’s discuss the next section of clinical trials (the clinical stage). The clinical phases of clinical trials start with phase zero trials and conclude with phase four trials. Phase zero trials (also known as exploratory investigational new drug studies) are the first clinical trials performed that involve human participants. Therefore, considering that MK 0966 (rofecoxib) was approved in 1999, it didn’t undergo this phase. This phase aims to ascertain how a drug is processed in the body and how it affects the body. Therefore, we can safely say that the aim of this phase is TARGET MODULATION. In these trials, a very small dose of a drug is given to approximately 15 people (US Food and Drug Administration 2006). Phase zero trials conduit the gap between traditional preclinical testing and clinical studies. They are intended to provide a better understanding of a new compound’s pharmacokinetics, pharmacodynamics and target localization before commencement of Phase one trials. This phase involves very limited dosing, done only to achieve target modulation. Therefore, there is less risk of toxicity. To put this in a nutshell, we can comprehend as Pharmacy students that phase zero studies are envisioned to offer flexibility in the drug development course, principally for drug and organic products intended to treat a serious or lethal illness. A notable merit of phase 0 studies is that one can perform studies combining molecularly targeted drugs and studies for clinical trials of molecular imaging agents. The opportunity to administer two or more investigational or US FDA-approved drugs while collecting suitable PK data can contribute significantly to a better understanding of the bioavailability of these agents! The potential to compare PK and PD data allows additional assessment and authentication of any synergistic activity with minimal risk to patients from combination toxicity (Marchetti S, Schellens JH 2007). In this regard, this phase has therefore been particularly useful for chemotherapeutic agents such as ABT 888 (veliparib). Preclinical data showed that tumor poly (ADP-ribose) polymerase (PARP) inhibition was the target of ABT-888 and a validated assay was available. Furthermore, at preclinical assessment, efficacy of ABT-888 was established at concentrations that inhibit tumour PARP but which do not markedly increase the agent’s toxicity. Thus, it was reasonable to conduct a Phase 0 study that would be designed to evaluate the mechanism of action at doses that posed negligible risk of toxicity to human subjects (Eliopoulos H et al 2008).
In phase 1 investigations, a small group of 2–100 healthy volunteers will be recruited. This phase is aimed at determining the dose and schedule of an investigational agent and/or drug (DeMets, D., Friedman, L., and Furberg, C. 2010). This evaluation also provides the initial explanation of adverse events accompanying agent administration in a dose-dependent fashion. The dose is determined using an assortment of dose-escalation approaches that target a toxicity rate below 33%. This target is attained by increasing the dose of the study drug until the toxicity rate reaches 33% (i.e. two of six participants). Investigators then drop back to the next lower dose level(s) to accrue additional patients at the recommended phase 2 dose (RP2D) and schedule also called the maximally tolerated dose (MTD) to further assess the adverse event profile of the study agent (Percy Ivy S et al 2010). When the pharmacokinetic characteristics of MK 0966 were scrutinised in healthy human participants, the peak concentration of the drug was doubtlessly accomplished in 9 hours with a half-life of ca. 17 hours. This study in the long run indicated that rofecoxib absorption varies with motility of the ileum. This could lead to high variability until the peak concentration is attained. (Halpin RA 2000).
When a dose or range of doses is determined, the next thing is to evaluate if the medicine has any biological activity or consequence. Phase II trials are done on bigger groups (100–400) and are tailored to assess how well the medication works, as well as to continue Phase I safety assessments in a larger collection of participants (De Mets et al 2010). A famous phase two study was done to determine whether treatment with MK 0966 (rofecoxib) or naproxen for one year will slow the rate of decline of cognitive function in patients with Alzheimer’s disease (AD) (National Institute on Aging 2000). 351 participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. This number were given MK 0966. An approximate other 2200 were enrolled on naproxen. This study indicated that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate Alzheimer’s disease (De Mets et al 2010).

Phase 3 is so often termed the “pre-marketing phase” since it measures consumer attitude to the drug. This phase can be done either pre or post approval. (De Mets et al 2010). 17 years ago, Merck began the APPROVe (Adenomatous Polyp PRevention On Vioxx) study. It was a 36-month trial on MK 0966 (rofecoxib) with the key aim of assessing the rofecoxib as prophylaxis therapy for colorectal polyps. A further aim of the study was to further assess the cardiovascular safety of MK 0966. The APPROVe study was interestingly ended early when the preliminary data from the study exhibited an increased relative risk of adverse thrombotic cardiovascular events (including stroke and myocardial infarction), starting after 72 weeks of rofecoxib. The findings from the first 72 weeks of the APPROVe study didn’t display an elevated comparative risk of adverse cardiovascular events. Besides, overall and cardiovascular mortality rates were alike between the placebo and rofecoxib participants. In a nutshell, the APPROVe study indicated that long-term rofecoxib use was associated with approximately twice the risk of suffering a myocardial infarction or stroke in comparison to participants getting a placebo (Bresalier et al 2005).

Compared to premarketing phase I–III trials, phase IV studies assess drug safety in a real-world situation, which can provide evidence to confirm or further refine the safety of approved drugs. The safety investigation in this phase endeavours to spot any rare or long-term adverse effects over a much bigger population of patients and longer period than was probable throughout the Phase I-III trials (American Cancer Society 2017). The least period compulsory for Phase IV clinical trials is 24 months (US Food and Drug Administration 2016). Owing results of the APPROVe study, Merck openly declared withdrawal of MK 0966 from the global market on September 30, 2004 (Merck.com: “Merck Announces Voluntary Worldwide Withdrawal of VIOXX” (PDF). Along with private findings, in September 2004, Merck seemingly received evidence about new FDA research supporting earlier discoveries of high risk of suffering a myocardial infarction among patients on MK 0966 (rofecoxib) (Grassley et al 2004). FDA officials believe that Vioxx is the cause of between 86,00 and 129,000 myocardial infarctions (among which 40% were possibly fatal), in the 60 months the medication was sold. Quite the scandal I imagine!! By mid-March 2006, approximately 10,000 court cases and 190 class actions were filed against the company due to adverse cardiovascular (CV) events linked heavily to rofecoxib and the inadequacy of Merck’s cautions to users (Petryna Adriana 2009).
REFERENCES
Bresalier, R.; Sandler, R.; Quan, H.; Bolognese, J.; Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton, D.; Lanas, A.; Konstam, M. A.; Baron, J. A.; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators (2005). “Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial”. The New England Journal of Medicine. 352 (11): 1092–1102. doi:10.1056/NEJMoa050493. PMID 15713943.

DeMets, D., Friedman, L., and Furberg, C. (2010). Fundamentals of Clinical Trials (4th ed.). Springer. ISBN 978-1-4419-1585-6.

Eliopoulos H, Giranda V, Carr R, Tiehen R, Leahy T, Gordon G. Phase 0 trials: an industry perspective. Clin Cancer Res. 2008;14(12): 3683–3688
Gleeson MP, Hersey A, Hannongbua S (2011) In-silico ADME models: a general assessment of their utility in drug discovery applications. Current Top Med Chem 11(4):358–381
Halpin, R. A.; Geer, L. A.; Zhang, K. E.; Marks, T. M.; Dean, D. C.; Jones, A. N.; Melillo, D; Doss, G; Vyas, K. P. (2000). “The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs”. Drug Metabolism and Disposition. 28 (10): 1244–54. PMID 10997947.

Hodgson J (2001) ADMET – turning chemicals into drugs. Nat Biotechnology 19:722–726
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 23:3–25
Lombardo F, Gifford E, Shalaeva MY (2003) In silico ADME prediction: data, models, facts and myths. Mini Rev Med Chem 3:861–875
Marchetti S, Schellens JH. The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials. Br J Cancer. 2007;97(5):577–581
Merck Announces Voluntary Worldwide Withdrawal of VIOXX” (PDF). Merck.com. Archived from the original (pdf) on 17 April 2012. Retrieved 4 January 2015.

National Institute on Aging 2000
Navia MA, Chaturvedi PR (1996) Design principles for orally bioavailable drugs. Drug Dev Today 1:179–189
Ntie-Kang F, Mbah JA, Mbaze LM, Lifongo LL, Scharfe M, Ngo Hanna J, Cho-Ngwa F, Amoa Onguéné P, Owono Owono LC, Megnassan E, Sippl W, Efange SMN (2013a): CamMedNP: Building the Cameroonian 3D structural natural products database for virtual screening. BMC Complement Alternative Med 13:88
Owens J. Determining druggability. Nat Rev Drug Discovery 2007; 6:187
Petryna, Adriana (2009). When Experiments Travel: Clinical Trials and the Global Search for Human Subjects. Princeton University Press. p. 272. ISBN 9780691126579.

Phases of clinical trials”. Canadian Cancer Society. 2017. Retrieved 1 February 2017.

S. Percy Ivy, Lillian L. Siu, Elizabeth Garrett-Mayer and Larry Rubinstein March 2010. Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee. DOI: 10.1158/1078-0432.CCR-09-1961 Published March 2010
Step 3. Clinical research”. US Food and Drug Administration. 14 October 2016. Retrieved 1 February 2017.

US Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry, Investigators, and Reviewers – Exploratory IND Studies. 2006. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf. Accessed September 24, 2013.

What Are the Phases of Clinical Trials?”. American Cancer Society. 2017. Retrieved 17 July 2017.