Pharmacological Studies During Drug Development Process (Essay Sample)

PHARMACOLOGICAL STUDIES DURING DRUG DEVELOPMENT PROCESS
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Introduction
Hypertension is a serious medical condition that results in heart failure or stroke. The primary aim of treating hypertension is to lower the pressure of the blood in the blood vessel to prevent damage to other vital organs such as the kidneys and the brain. Several oral and injectable drugs are available for the treatment of hypertension. These drugs act by relaxing and vasodilating the blood vessels, thus, reducing the pressure of blood. However, most medications for hypersensitivity are associated with several side effects such as a headache, fatigue, diarrhea and erectile dysfunction in men (Mayo clinic, 2017). Development of a new medication for hypertension is essential since the adverse side effects associated with the use of other drugs can be minimized. The new drug is a class of Angiotensin II receptor blockers (ARBs) with a molecular weight of 500. This paper analyzes the pharmacological and toxicological evidence required for the development and marketing of the new drug.
Pharmacological Evidence to Justify Clinical Development
Pharmacodynamics evidence
Pharmacodynamics is the study of what the new drug will do to the body. ARBs act by blocking the activities of Angiotensin II receptors (ATR1) in the body. The new drug should demonstrate the ability to attach to the right receptors and induce the desired response. Therefore, for clinical development, a suitable ARB drug should demonstrate the ability to selectively bind to (ATR1 ) in several regions of the body such as the kidney, adrenal gland, and the heart, preventing the receptors from increasing the level of aldosterone hormone and inducing the relaxation of smooth muscles. The result of the inhibitory actions of the new ARB drug should be a reduction the plasma volume through the increase in the excretion of salt and water from the body (Al Sabbah, Mansoor & Kaul, 2013, p.464). The drug should be able to lower blood pressure a few hours after its administration and the duration of action should be long. The pharmacodynamic studies should also demonstrate that the new drug cannot affect the activities of other receptors, transport channels, organs or tissue apart from the desired (ATR1) receptors in various organs (Colucci, 2016).
Pharmacokinetic evidence
The new drug should be well absorbed and distributed in the body. The metabolism and clearance of the body should also be efficient. The administration of the drug should be easy preferably by oral means. It should be absorbed rapidly through the gastrointestinal tract, achieving a plasma peak levels within four hours after its administration. Bioavailability of the drug should be approximately 80% with the volume of distribution of around 500 L to ensure that the drug reaches the target site in adequate concentrations without accumulating in undesired regions (Al Sabbah, Mansoor & and Kaul, 2013, p.465).
The candidate drug should demonstrate high plasma binding abilities of up to 90% and its metabolism should not extensively be in the liver. Like most ARBs, the primary route of elimination should be hepatic with a small amount of unchanged drug eliminated through the urine and the stool. This can make it suitable for patients with impaired renal functions by reducing the chanced of drug accumulating in the body. Pharmacokinetic studies should also demonstrate that the new drug can interact well with other medications. It should not suppress or stimulate the action of other drugs in the body (Al Sabbah, Mansoor & and Kaul, 2013, p.465).
Safety evidence
Safety studies should be conducted to ensure that the new drug cannot produce toxic byproducts which can poison or cause injuries to the cardiovascular, central nervous, and the respiratory systems. Cardiac function tests such as heart rate, systolic, diastolic pressure, electrocardiograph parameters and the morphology of the heart should be assessed. For the respiratory system, the test conducted should include measuring the respiration rate and the concentration of oxygen in the hemoglobin. These tests should be performed periodically to determine the condition of the organs and the effectiveness or toxicity of the drug. Follow up tests are recommended in cases where toxic effects are noticed (Abraham, C. White, & W. White, 2015, pp.35-38).
Animal models can be used to study the pharmacological activities of the new drug. Hypertension can be induced in a rat, mouse, hamster or a dog by giving it excess salt or increasing the actions of the renin-angiotensin-aldosterone system (RAAS).The animal model should demonstrate the exact condition that occurs naturally in humans for the results to be accurate and reliable. The new drug can then be administered after which the animal is monitored and studied to determine the efficacy and toxicity of the drug. (Leong, Ng & Jaarin, 2015, p.3).
Toxicological Studies
A single ascending dose clinical study
Single dose studies are conducted to check whether the new drug is safe and can be well tolerated by humans. The new ARB is administered at varying doses to different groups of volunteers to determine the dosage in which the drug can be useful and the dosage where adverse effects can occur (Lynch, 2016, p.3). The maximum level the drug can be administered is picked from the No Observable Adverse Event Level (NOAEL). In this experiment, the most sensitive animal is a dog. Hence the NOAEL is 10 mg/kg which is equivalent to 0.54mg/kg in human subjects. Before administering the drug to human subjects, it should first be two groups of rodent and no-rodent species (Andrade et al., 2016, 4-7).Studies conducted during this phase are:
Repeated dose study –This study is performed to determine the levels in which the drug is safe. This can be done by exposing two mammalian animals to repeated doses of the drug for a period of 30 to 90 days. The animals are then monitored and assessed for changes in their body weight, eating habits, histological, hematological and biochemical behaviors. The doses in which toxic effects are noticed and the levels in which their animal does not demonstrate harmful effects are recorded. The mechanism that results in toxicity such as increased plasma concentration, toxic build up or unidentified metabolite should be well understood before administering the drugs to human subjects (Andrade et al., 2016).
Multiple Ascending Dose (MAD) Clinical Study:
MAD studies are performed to assess pharmacological effects that can occur when various doses of the drug are administered starting with the lowest dose which should be smaller than 1/50th of 0.54 mg/kg for human subjects. Different groups of subjects are administered with multiple doses of the new drug from lowest dose to maximum tolerable dose (Quanticate, 2016, para 4).
A 6-month phase 2 study
Studies to determine the chronic toxicity of the doses are conducted in two species of animals that are biologically similar to human beings for six months. Toxicity of the genetic materials and the reproductive system are also studied using in vivo and in vitro models.
Genotoxicity study – This study is conducted to determine whether the new drug can induce the alteration of the genetic material by damaging the DNA. The study should be done both in vivo and in vitro. Genotoxicity tests include the assessment of mutation in the gene of a bacteria such as Salmonella typhimurium TA98. The damage to the chromosome can be tested by the in vitro cytogenetic analysis of mammalian cells and in vivo analysis of the hemopoietic cells of a rodent (Andrade et al., 2016).
Reproductive toxicity–Reproductive toxicology tests are conducted to assess the effect of the drug on fertility, development of the embryo and the fetus, pre- and post-natal development. The fertility test involved the administration of the drug to male and female subjects before mating followed by the analysis of the semen and the percentage of the implanted embryo. The embryonic and fetal studies are conducted on rats, mice, and rabbits by administering the drug to the female during the beginning of pregnancy. The offsprings are monitored for abnormalities during their stages of development to assess the sexual behavior and the secondary offsprings (Andrade et al., 2016).
Two one-year phase 3 studies
For one-year phase 3 clinical trials, additional repeat dose toxicity, reproductive toxicity carcinogenicity and immunotoxicology studies are conducted for twenty-four weeks in rodents and thirty-six weeks in non-rodent mammals. The immunotoxicology studies are essential in determining the effects of the drugs has on the immune system functions such as such as anaphylaxis, allergies, hypersensitivity, and suppression of the immunity. Assessment of immunological studies can involve the analysis of biomarkers such as the concertation of the immunoglobulins, hematological and histopathological evaluation. Carcinogenicity studies are essential in assessing the potential ability of the drug to induce the development of tumors. The rats or mice are treated with the medication for an extended period, followed by the analysis of carcinogenic markers and histological studies. The Carcinogenicity studies should be performed for two years in mice and six months in transgenic mice (Andrade et al., 2016).
Toxicological studies to support Marketing Approval
To support marketing approval, more extended periods of clinical studies are required. The repeat-dose toxicity studies should be conducted for six months in rats and nine months in dogs. Other studies to support marketing approval are safety, efficacy, reproductive toxicology...