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I have few question regarding the PK studies to evaluate sublingual bioavailability in a rabbit model for certain established drugs. These questions have been bothering me for quite some time and I have not found the exact answer for the same.The questions are:
1. What criteria should I keep in mind while deciding the dose for preclinical studies in rabbits for drugs I intend to administer sublingually?
I searched and found a means in which I can convert the recommended dose for a certain animal species to the dose for rabbit. It employs allometric scaling. I was wondering if I can use this method to calculate the dose for PK studies in rabbit.
The other method I could think of is:
I was looking at the guidance 'Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers' by FDA. In this particular guidance one can calculate dose for humans from animal studies using the formula 'HED = animal dose in mg/kg x (animal weight in kg/human weight in kg)^0.33'. I was wondering if I can use the same formula for calculating animal dose from the recommended human dose available. For eg. if the recommended dose for a drug for human use is 100 mg/day, then using this formula I can calculate dose for the animal studies.
BUT if I can use this formula, then in case of sublingual delivery, do I need to use human dose recommended for sublingual delivery only or can I use the dose recommended for oral delivery also.
2. The second query which I have is that how can I approximately calculate (theoretically) that how much of the drug will reach systemic circulation after the administration of a particular dose of the drug. This is basically to estimate how much my LOQ should be in analysis method.
This is the main question which has been bothering me as success of my experiments would totally depend on that.
Is there a formula to calculate that approximately.
Thanking you in anticipation,
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You are right these are two different methods to determine Human dose from preclinical data. You can also determine animal dose utilizing these methods.
The first method is allometric method and here first you have to predict pharmacokinetic parameter preferably clearance in the species of interest. After determination of predicted clearance in Rabbit you can determine the dose. There are many different approach to predict the clearance in animal, i.e. Three or more species method (Simple allometric approach, MLP approach, Brain weight approach & Rule of exponent), Two species method & One species method. Please note that here there is no need to consider Safety Factor.
The second method is guidance 'Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers' by FDA. You rightly mentioned that the formula HED = animal dose in mg/kg x (animal weight in kg/human weight in kg)^0.33' can be used to determine the animal dose, i.e. Rabbit. But here you have to consider Safety Factor which was used to determine MRSD (Maximum Recommended Starting Dose) or established dose for human use. And I am sure that you will not get this information because use of safety factor is arbitrary without any scientific justification and each investigator selects it depending upon their comfort zone.
Md. Tarique Imam (M. Pharm)
Clinsys Clinical Research Limited, Noida
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