Background
Pfi-Pharma, a major pharmaceutical company holds the recently expired patent for Brand X®, a cDMARD formulated as a modified-release preparation in the management of Rheumatoid Arthritis. Brand X® is delivered orally at a dose of 200mg once daily.
Originally Brand X® was formulated as an immediate release formulation, this was quickly identified as being rapidly absorbed through the gastrointestinal mucosa, requiring multiple daily dosing and having a broad side-effect profile (Abdominal pain; decreased appetite; diarrhoea; emotional lability; headache; nausea; skin reactions; vision disorders; vomiting, photosensitivity reactions, psychosis and hepatoxicity). Subsequently, it was formulated as a modified-release formulation. Brand X is weakly basic, with a molecular weight of 98.82 (g/mol) and a water solubility of 1.56g/L.
Brand X is believed to be pharmacologically akin to hydroxychloroquine and is a weak inhibitor of CYP3A4, CYP3A5 and CYP2J2 enzymes. The drug is also observed to have a narrow therapeutic index.
Three separate smaller companies, 420-Pharma, Nakli-Pharmaceuticals and Shoda-Ceuticals, have recently started pilot studies in a bid to manufacture three separate generic formulations Generic A, Generic B and Generic C respectively, all the same type of modified release.
You are provided with the plasma concentrations of the novel cDMARD at 30-minute intervals over a 36-hour period for each brand, from volunteers who have taken each brand (Table 1).
Table 1. Plasma concentrations from individuals following administration of each of the Brands developed
Time (Hrs) Plasma concentration (mcg/ml)
Brand X Generic A Generic B Generic C
0.00 0.00 0.00 0.00 0.00
0.50 14.07 18.07 0.00 30.07
1.00 22.44 26.44 3.44 39.92
1.50 33.98 37.98 14.98 49.98
2.00 43.22 47.22 24.22 71.88
2.50 51.21 55.21 32.21 79.94
3.00 58.98 62.98 39.98 80.21
3.50 62.89 66.89 43.89 80.23
4.00 64.99 68.99 45.99 78.33
4.50 65.89 69.89 46.89 77.22
5.00 67.22 71.22 48.22 75.45
5.50 68.22 72.22 49.22 72.01
6.00 69.50 73.50 50.50 70.99
6.50 69.54 73.54 50.54 67.33
7.00 67.33 71.33 48.33 66.78
7.50 65.22 69.22 46.22 66.06
8.00 63.21 67.21 45.32 65.22
8.50 62.25 66.25 44.32 64.55
9.00 61.05 65.05 42.87 62.22
9.50 59.05 63.05 41.98 61.22
10.00 57.22 61.22 41.55 59.12
10.50 55.05 59.05 39.05 57.21
11.00 54.33 58.33 38.33 55.22
11.50 53.78 57.78 37.78 54.01
12.00 53.06 57.06 37.06 52.77
12.50 52.22 56.22 36.22 51.01
13.00 51.55 55.55 35.55 49.99
13.50 49.22 53.22 33.22 48.23
14.00 48.22 52.22 32.22 46.21
14.50 46.12 50.12 30.12 44.97
15.00 44.21 48.21 28.21 42.98
15.50 42.22 46.22 26.22 39.01
16.00 41.01 45.01 25.01 37.88
16.50 39.77 43.77 23.77 36.32
17.00 38.01 42.01 22.01 35.99
17.50 36.99 40.99 20.99 35.22
18.00 35.23 39.23 19.23 34.22
18.50 33.21 37.21 17.21 33.50
19.00 31.97 35.97 15.97 31.22
19.50 29.98 33.98 15.66 29.23
20.00 27.88 31.88 15.30 28.01
20.50 26.77 30.77 14.97 26.59
21.00 24.01 28.01 14.97 25.01
21.50 22.01 26.01 14.97 23.77
22.00 20.33 24.33 14.97 21.51
22.50 19.22 23.22 14.97 19.86
23.00 18.50 22.50 14.97 17.77
23.50 18.21 22.21 14.97 14.98
24.00 18.21 22.21 14.97 13.28
24.50 18.21 22.21 14.97 12.21
25.00 18.21 22.21 14.97 10.00
25.50 18.21 22.21 14.97 10.00
26.00 18.21 22.21 14.97 10.00
26.50 18.21 22.21 14.97 10.00
27.00 18.21 22.21 14.97 10.00
27.50 18.21 22.21 14.97 10.00
28.00 18.21 22.21 14.97 10.00
28.50 18.21 22.21 14.97 10.00
29.00 18.21 22.21 14.97 10.00
29.50 18.21 22.21 14.97 10.00
30.00 18.21 22.21 14.97 10.00
30.50 18.21 22.21 14.97 10.00
31.00 18.21 22.21 14.97 10.00
31.50 18.21 22.21 14.97 10.00
32.00 18.21 22.21 14.97 10.00
32.50 18.21 22.21 14.97 10.00
33.00 18.21 22.21 14.97 10.00
33.50 18.21 22.21 14.97 10.00
34.00 18.21 22.21 14.97 10.00
34.50 18.21 22.21 14.97 10.00
35.00 18.21 22.21 14.97 10.00
35.50 18.21 22.21 14.97 10.00
36.00 18.21 22.21 14.97 10.00
The total word count for this assignment is 1000 ± 10% words. References will not be included as part of the word count
Activity 1: 500 + 10% words allocated
You are to write a report for the MHRA (Medicines & Healthcare products Regulatory Agency) of 500 words + 10% words, which should consider the following points:
10% marks- Plot the data provided for all four products (i.e. x-axis time, y-axis plasma concentration). From this Identify the type of modified release formulation from the plotted data.
40% marks- Upon interpretation of the data, discuss the suitability of the type of modified release and the impact of the patterns/differences in drug release between each formulation upon the patient, in terms of; potential therapeutic effect and clinical outcomes (e.g. how would the patients management of condition be affected and also potential side-effect exposure).
When considering the suitability of the formulation, consider the physiochemical properties of the drug e.g. solubility, therapeutic index, in addition to patient challenges in managing long term conditions.
Potential clinical implications should be considered in-depth
40% marks- Discuss the influence of excipients upon drug release, comparing the modified-release formulation identified and immediate release formulations.
For example, using examples, what impact would polymer type have upon the release characteristics?
10% marks- You should reach a rational conclusion on which of the formulations Brand X, Generic A, Generic B or Generic C is expected to produce the best clinical outcome (i.e. which formulation would you recommend and why?).
Activity 2: 500 + 10% words allocated
You are to design a patient information leaflet of 500 words + 10% words for an appropriate dosage form for the formulation that you have chosen in the previous question. You are expected to provide a rational explanation on the science underpinning the information included in the patient information leaflet. Considerations should include; the effect of food, interaction with co-administered drugs, interchangeability of brand, storage conditions, packaging etc. Marks will be allocated as follows:
50% Marks- Patient relevant information (e.g. how and when to take, considerations for specific patient groups, warnings and precautions etc.)
50% Marks- Interpretation of formulation and drug specific characteristics (e.g. side-effects, storage conditions, considerations relating to administration etc.)
10% Marks- Overall presentation
