Dear Shivraj Vhanale

In general your dosing interval, number of doses, dose level etc should follow to safety endpoints, PK, potency and efficacy of the molecule. It very complex question but from my point of few few regulatory documents and excellent presentation by Bruno Boutouyrie-Dumont solve more questions around this topic:

Guideline for Industry Dose-Response Information to Support Drug Registration

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073115.pdf

Guidance for Industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072109.pdf

Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease Guidance for Industry

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM588884.pdf

Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antimicrobial medicinal products

https://www.ema.europa.eu/documents/scientific-guideline/guideline-use-pharmacokinetics-pharmacodynamics-development-antimicrobial-medicinal-products_en.pdf

Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2)

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf

Dose selection based on Minimal Anticipated Biological Effect Level (MABEL) for biologicals and high risk small molecules: case studies & discussion

http://www.eufemed.eu/wp-content/uploads/Bruno-Boutouyrie-Dumont.pdf

Best regards,

Tomasz

I believe Tomasz Grabowski gave you an extensive list of resources to find out the answer to a complex question. I think the very key point to your question is the half-life of the drug itself and the turnover time (i.e. half-life) of the drug target. These two parameters will help you estimate the time to reach steady state and the time to reach the full effect of the drug. Along these parameters, you are assessing for toxicity to ensure the safety and efficacy of the drug.

An example include the anti-coagulant drug warfarin. Though warfarin is dosed once daily to inhibit certain clotting factors, the time it takes to see the full effect of the dose on inhibiting those clotting factors only seen at 3-5 days later. Along this process, we measure INR as a monitoring parameter of efficacy and toxicity, which is also an assessment of the bleeding risk.

Another example of the duration of therapy is a drug called toradol. This drug is a strong NSAID used for acute moderately server pain. This drug could be given every 4-6 hours as needed for pain, but the duration of therapy should not exceed more than 5 days due to the increased GI bleeding. I think these are two simple answers to a complex question but I hope they get the point across.

The duration and interval in drug treatment according .

1. Pharmaco kinetics of drug including t half protein binding,metabolism and excretion. Narrow therapeutic index or not.

2.Therapeutic condition is acute or chronic, age ,underlying disease, renal and hepatic function and does of drug is calculated accordingly.

Thanks a lot Tomasz Grabowski , Youssef M Roman and Ahmed Kareem Hussein for your valuable suggestion.

By reading articles and your suggestion, I think that the half life, protein binding, metabolism and excretion, narrow therapeutic index are important parameters for evaluation of dosing interval.

But still I want more information wrt. evaluation of total duration of treatment ( Ex: 12, 24 hours drug administration- for 1, 2. 7. 12. 24 days) of NCE's in clinical research.

Thanks....

Dear,

As expert in Early Phase clinical development, I just advice you to answer first to some questions, which will help you further to obtain the answer for doses frequency!

- Do you have enough and especially long-term animal study results (toxicology and PK)?

- Do you know well the PD mechanisms of your molecule?

- Do you want to do a first in human study in HVs or in patients?

- Do you want to start directly with a multiple administration of your drug in human or single dosing in healthy volunteers (HV) can preceed?

- Do you aim to reach a steady state of plasma concentration by multiple dosing?

- Is it a biological or small compound?

- Do you know its elimination mechanism?

- Do you have modeling&simulation involved in your molecule development?

- Loading dose and maintenence dose regimen is suitable or not?

.....

When you have all answers, you need to collaborate with a clinical pharmacologist to define the dose and frequency. It is not an easy question, even if the main properties to consider are PK, but other variables should be taken into account.

Best.

Nariné

Thanks Narine Baririan.