1. INTRODUCTION:

Personalized medicine or precision medicine is a pharmaceutical standard with medical decision that separates people into different groups, practices, interventions and products are being made to measure to the individual patient based on their conclude response or risk of disease¹.

The terms personalized medicine or the precision medicine are utilized to depict this idea however a few creators and associations utilize these expressions independently to show particular nuances. Personalized medicine is fitting of medical therapy to the individual attributes of each medicine². The treatment should me safe and effective. The research for PM is increasing in our ability to predict which type of medical treatments will be safe and effective to each patients and which one’s will not be Genomics in a lowering costs and by facilitate each victim to accept earlier diagnoses, danger estimate, and excellent medication, personalized medicine holds obligation for developing well-being responsibility³. The affiliation of all subject with a certain circumstance, common dosage from that is ‘one size fits all’ approach to the therapy and to one which it uses a new approaches to accomplish the conquer conclusion in the authority of a victim disease and manage the patients health target therapies⁴. The Promise of Personalized Medicine, “therapy with the right drug at the right dose in the right patient” is a description of how personalized medicine will affect the prospect analysis⁵. Personalized medicine has improved in recent years, on basis of it provides the variation in human genome to efficacy in drug treatment, to the affected persons a form of medicine that custom the data about the person’s genes, proteins, ADME and habitat to inhibit, diagnose⁶. In inter-individual genetic variability the calculating of the individual gene has exposed that while human kind gene make-up is 99.1% are exact, where the other 0.9% is non-identical. The concept of personalized health care is increasing in acceptance to treat on individual response.

2.HISTORY:

The personalized medicine is initally came in the year 1999. The concepts have been in existence since 1960’s. The new technology has now bulit personalized medicine in more phenomenon and welfare to the patients to provide the drug in proper dosage form for the effective treatment and also to provide the drug in cheaper cost.⁷

The two discover keys are:

· Single nucleotide polymorphism:

SNP’s are single nucleotide changes in the DNA sequences that are to be frequent in the population that contributes about 90% of all known polymorphisms. SNP’s are proven to be an invaluable tool in segregating patients in clinical trials.

· Microarray biochip:

The ability to analyze and store the patient’s genome; it also helps in conducting the SNP genotype(8).

3. INTRODUCTION TO DRUGS:

3.1 FLUTICASONE:

Fluticasone is a synthetic glucocorticoid which is worn in some people to treat nasal syndrome. It is a normal efficacy corticosteroid worn to relax inflammatory and pruritic syndrome and also used to treat allergic and non-allergic rhinitis and orally for the cure of asthma.

3.1.1. DOSAGE

Adult: Initially 2 sprays one by one nostril once often.

Maximum of overall doses 2 sprays in each nostril of 200mcg/day.

Children:

First 1 spray in particular nostril once regularly, it may raise to 2 sprays in each nostril once daily Maximum of total dose in each nostril of 200mcg/day⁹

Table 1 Use and adverse effect

Use	Adverse Effect
Fluticasone is a corticosteroid that prevents substances from the body that cause inflammation. Used in treatment of asthma	Throat infection, nasal irritation, menstrual problems, sneezing, cough, nausea, headache, vomiting, back pain, sore throat.

3.2 CYCLOPHOSPHAMIDE:

Cyclophosphamide is determined for the treatment of malignant lymphomas, various myeloma, leukemias, mycosis fungoides, neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also recorded for the regimen of biopsy-proven minimal change nephrotic syndrome in pediatric patients.

3.2.1 DOSAGE:

Adult and Pediatric:

Powder injection: 500mg, 1g, 2g.

Tablet: 25mg, 50mg.

Table 2 Use and adverse effect

Uses	Adverse Effect
Cyclophosphamide is used for the different type of tumor therapy. It is a chemotherapy drug that works by block or retard the cell growth, erasing your immune system's return to many diseases.	Nausea and vomiting, bone marrow suppression, stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia changes in color and texture of the hair and lethargy.

4. SCOPE AND NEEDS:

Each human being has a one of a kind variation in their human genome. Albeit a large portion of the gene variation in humans has no impact on health, a person's energy stems from genetic variation with the practices and impacts from nature (10).

Present day propels in customized medication has improved in innovation that affirms a subject major biology, deoxyribonucleic acid, ribonucleic acid, or protein, which at last prompts affirming infection

As quoted from the article Pharmacogenomics: The Pledge of Personalized Medicine, “therapy with the right drug at the right dose in the right patient” is a description of how personalized medicine will affect the destiny of medication¹¹

Personalized medicine might be viewed as an augmentation of customary ways to deal with understanding and treating the disease yet with more prominent accuracy¹². A contour of a subject heredity variations can deal with the selection of drugs or treatment conventions to doctors that will confine the destructive reactions or certification the more useful outcome. Personalized medicine can also hint an specific sensitivity to certain diseases before they become disclosed, allowing physicians and patients to design a plan for monitoring and prevention of diseases¹³. Physicians can now go beyond the one-size-fits-all to “therapy with the right drug at the right dose in the right patient” model of prescribing to make more effective clinical decisions for each patient.

The need for personalized medicine is not only improved in drugs it also improved in device manufactures, it’s used to reduce the cost of drug and device manufactures and also to easily applicable to all patients at a right dose to improve the public health¹⁴.

5. PROS AND CONS:

5.1 PROS:

a) Decrease the cost of drugs

b) Improve quality of life

c) It customizes the disease prevention.

d) Less adverse drug reactions to patients.¹⁵

5.2 CONS:

a) Base Requirements

b) Legitimate Problems

c) Important data

d) Cost of healthcare(16)

6. FACTORS STRIVES TOWARDS: PERSONALIZED MEDICINE:

1. Patients as customer

2. The Shift to Value-established responsibility

3. Option of High-performance, memorial Computing

4. One Size DOES NOT Fit All (17)

7. DATABASE DEVELOPMENT OF FLUTICASONE:

7.1 POPULATION PHARMAOKINETICS OF FLUTICASONE:

Based upon the population pharmacokinetic data the possible parameters of personalized medicine on various populations that have the significant changes to pass on the track of personalized medicine. To pass on the track some factors are to be categorized¹⁸

The tests are conducted in different countries like China, USA, Canada, and Germany.

Table 3 Population and Factors

Sl. No	Population	Factors
1.	China	Genetic polymorphism, Alcohol consumption, Weight, Height, Age, Smoking.
2.	USA	Genetic polymorphism.
3.	Canada	Genetic polymorphism.
4.	Germany	Gender.

7.1.1 IMPACT OF GENETIC POLYMORPHISM FLUTICASONE:

7.1.2 ABCB1:

The genotype and allele frequencies of the ABCB1 rs1045642C>T polymorphic arrangement were accordingly particular between the active group and the non-active group. Haplotype analysis of ABCB1 determined that CTA (rs1045642C– rs1128503T–rs1202184A) haplotype frequencies in the effective group were significantly decreased than the ineffective group (p=0.022), but TCG (rs1045642T– rs1128503C–rs1202184G) haplotype frequencies in the effective group were significantly higher than the ineffective group (p=0.048). CTA/TCG haplotypes are the genetic sequences have the variation in the serine molecules. The constancy of TCG haplotype in the viable gathering are less, hence more examinations on haplotype analysis are expected to growth a superior awareness of SFC therapy reactions in COPD subjects. This genetic polymorphism variation has happened in Chinese population.^19,20,21

7.1.3 CYP3A4:

The nearness of CYP3A4*22 which is related with diminished hepatic CYP3A4 articulation and movement, was accomplished by improved asthma control in the FP-treated children. Diminished of CYP3A4 movement may improve the asthma control with breathed in FP (Fluticasone propionate). This genetic polymorphism variety has happened in USA and Canada population.

7.2 IMPACT OF CIGARETTE SMOKING IN FLUTICASONE:

Another interesting factor was found to be outcome in COPD patients in the involve SFC therapy²². it is a noteworthy hazard factor for COPD and expanded danger of respiratory side effects like lung damage, and higher COPD death rates²³. In this manner, in view of our outcomes, we recommend that transpire might be allied with suffering SFC therapy results in Chronic obstructive pulmonary disease patients because of its extreme effect on the general wellbeing status²⁴

7.3 IMPACT OF GENDER IN FLUTICASONE:

Gender was found to be a significant variation on clearance, when compared to the men’s women’s have the higher clearance on the Germany population, in Chinese population there is about 0.610 of regression coefficient²⁵.

7.4 IMPACT OF BODY WEIGHT IN FLUTICASONE:

The weight has varied in people and it has the significant variation of about 0.014 of regression coefficient in the Chinese population. If the body weight is raises it affects the significant clearance and the variation is differed²⁶.

7.5 IMPACT OF HEIGHT IN FLUTICASONE:

The height has varied in people and it has peoples have the significant variation of about 0.027 of regression coefficient in Chinese population²⁷.

7.6 IMPACT OF ALCOHOL CONSUMPTION IN FLUTICASONE:

Another factor is considered to be the alcohol consumption peoples have the significant variation of about 0.819 of regression coefficient in Chinese population²⁸.

7.7 IMPACT OF AGE FACTOR IN FLUTICASONE:

Another factor is considered to be the age, the age factor being varied in people and it have the significant variation of about 0.013 of regression coefficient in Chinese population²⁹.

8. CYCLOPHOSPHAMIDE:

8.1. POPULATION PHARMACOKINETICS IN CYCLOPHOSPHAMIDE:

The tests are conducted in different countries like India, Germany, Paris, China, Bangladesh, and Canada

Table 4 Population and Factors

S. No	Population	Factors
1.	India	Genetic polymorphism, Age, Body weight.
2.	Germany	Genetic polymorphism,
3.	China	Genetic polymorphism.
4.	Canada	Genetic polymorphism.
5.	Bangladesh	Genetic polymorphism.
6.	Paris	Age, Body weight.
7.	General considerations	Liver dysfunction

8.1.1 IMPACT OF GENETIC POLYMORHISM IN CYCLOPHOSPHAMIDE:

8.1.1.1 CYP2B6:

A large interindividual change was noticed in the area under the curve ratio of cyclophosphamide computed as the metabolic ratio. They verified that leukocytopenia and neutropenia were significantly (P<0.01) resulted to the area under the curve of 4-hydroxycyclophosphamide (31). It was proven to be that the homozygotes of CYP2B6*6 (Q172H and K262R) showed significantly (P<0.05) greater clearance and shorter half-life of cyclophosphamide than heterozygotes and homozygotes of CYP2B6*1. The narrow pattern size, however, the collide(32)(33).On the other hand, it was certainly establish that the victim acquire the single nucleotide polymorphisms of the CYP2B6 gene, g.-2320T>C, g.-750T>C (5'-flanking region), g.15582C>T, or g.18492T>C had significantly lower AUC ratios of 4-cyclophosphamide,pinpoint a weaken cyclophosphamide 4-hydroxylation. Of precise concern was the data that leukocytopenia was significantly related to the single nucleotide polymorphisms g.-2320T>C, g.-750T>C, and g.18492T>C in CYP2B6 gene, which are greatly linked. No relationship was detected between the pharmacokinetics of cyclophosphamide or 4 -hydroxycyclophosphamide and genetic polymorphisms of the other enzymes. They analyze that the single nucleotide polymorphisms is the promoter region in the CYP2B6 change the efficacy of cyclophosphamide stimulation to 4-hydroxycyclophosphamide. This type of genetic polymorphism has occurred in Japanese population (34)(35)(36).

8.1.1.2 GSTP1:

The enzyme GSTP1 (Glutothione- S- Transferase Pi1) is associated to produce toxicity if the expression of GSTP1is higher in patients. This type of genetic polymorphism has occurred in India, China, Bangladesh, Canada population (37)(38).

8.1.2. IMPACT OF AGE AND BODY WEIGHT IN CYCLOPHOSPHAMIDE:

Age and body weight of patients directly related to the cyclophosphamide drug efficacy in patients. It clearly shows that children and adult patients showed the variation in action and biotransformation of the drug. Hence the children showed the increased onset of action and biotransformation of the drug when compared to the adults. This type of age and body weight factor has occurred in India, Paris population(39)(40)(41).

8.1.3 IMPACT OF LIVER DYSFUNCTION IN CYCLOPHOSPHAMIDE:

Liver dysfunction in cancer patients may have a chance of decreased effect of cyclophosphamide within patients. This is due to polymorphism in liver ALDH1A1*2 alleles. The liver dysfunction is the general considerations among the patients.

8.3 NEW APPLICATION:

If a new dose of available drug molecule is prepared for clinical use that can either be increasing or decreasing in dose that should be filled under New Drug Application (NDA) by proving the safety and efficacy of the drug.

8.4 FUTURE OF REGULATORY TOWARDS PERSONALIZED MEDICINE:

The research towards personalized medicine is recently increasing nowadays. The regulations of personalized medicine are in budding stage and in countries like US and UK have started implementing the use of personalized medicine regulations. Since we are in budding stage on developing the personalized medicine research, it may take some more years to implement a strong guideline about personalized medicine in India

9. CONCLUSION:

There should be a strong co-ordination between manufacturer, researcher and clinicians for real-time implementation of personalized medicine. So that the research will strive from bench to bed-side for the maximized therapeutic benefit of population with minimal expenses and side effects. Based on this, the review of genetic polymorphism and population pharmacokinetics of Fluticasone and Cyclophosphamide towards Personalized medicine and its regulatory feasibility have carried out and completed successfully.

10. ACKNOWLEDGEMENT:

The authors are thankful for Department of science and technology-Fund for Improvement of science and Technology Infrastructure in Higher Educational institutions (DST-FIST) for providing the laboratory facility to carry out the research work.

11. CONFLICT OF INTEREST:

The authors have no conflict of interest.

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Received on 26.11.2019 Modified on 09.02.2020

Research J. Pharm. and Tech. 2021; 14(1):179-184.

DOI: 10.5958/0974-360X.2021.00031.7