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Steps of drug development (cont'd...)

Four phases of clinical development

a. PhaseI of clinical trial

In previous steps the dose was estimated for animals. In this step, it should be administered in human. Therefore, a cautious dose calculation is required, made based on body weight and body surface area (BSA) of human and selected animal. Conversion methods, proposed by [Shin JW, 2010] is given as follows:

Table. 3. Representation of conversion of animal dose to human dose, based on BSA [Shin JW, 2010]

Species

Average body wt  (kg)

BSA (m2)

Km

Conversion factor

Human

Adult

60

1.6

37

1.00

Child

20

0.8

25

1.48

Baboon


12

0.6

20

1.85

Dog


10

0.5

20

1.85

Monkey


3

0.24

12

3.08

Rabbit


1.8

0.15

12

3.08

Guineapig


0.4

0.05

8

4.63

Rat


0.15

0.025

6

6.17

Hamster


0.08

0.02

5

7.40

Mouse


0.02

0.007

3

12.33


The experiment is performed on healthy volunteers or the patients, not responding to the existing therapy. First, experiment is started with three persons with the previous calculated dose. The motive is to find out the maximum tolerable dose (tolerability). In no remarkable toxic action is found on three persons, it is applied on further three persons and continued on 20-80 persons. Dose is lowered, if considerable toxicity is found in initial dose and stopped increasing the dose when toxicity found. The last dose, no toxic effect observed is considered as the maximum tolerable dose. This data is useful when if action of the drug will be dose dependent in future. The safety profile of the drug (any kind of toxicity to cardiovascular system, respiratory system, kidney or liver) and the pharmacokinetic and pharmacodynamic (action and the mechanism of action of the drug) properties (on human) are also evaluated in phase I trial [Friedman LM, 2010, Rang MP et. al., 2007].

b. Phase II of clinical trial

Usual sample volume for this study is 100-300. The main goal of this trial is to check the efficacy of the drug. It can be performed comparing the result of test with concurrent control (untreated) group, historical control group (received other treatment) or pre treatment status of the same group with post treatment status. The bioavailability of the drug (amount, present in plasma after a certain time), biological response (in human) and dose-response relationship (relation between plasma concentration and therapeutic effect) are found out in the experiment [Friedman LM, 2010, Rang MP et. al., 2007].

c. Phase III of clinical trial

The objective of this trial is to compare the efficacy of the new drug with the existing therapy. Therefore, the drug is applied on patients. The sample size varies between 1000-3000. It is a double blind randomized trial, that is both the doctor and patients are uninformed of the group of patients, receiving standard drug and test drug. If no significant difference of therapeutic outcomes revealed among the groups, the drug is allowed to be marketed, under the vigilance [Rang MP et. al., 2007].

Reference

Rang MP et. al., 2007] Rang HP, Dale MM, Ritter J M, Moore P K, Pharmacology, 5th Edition, Elsevier, 2-752, 2007.
[Shin JW, 2010] Shin JW, Seol IC, Son CG, Interpretation of animal dose and human equivalent dose for drug development, The Journal of Korean Oriental Medicine, vol. 31, issue 3, 1-7, 2010.
[Tripathi KD, 2004] Tripathi KD, Essential of Medical Pharmacology, 5th Edition, Jaypee Brothers Medical Publishers Limited, 3-123, 2004.

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