Bioequivalence and Bioavailability Forum • T>MIC for Anti microbial is sufficient to show therapeutic efficacy

heritage
☆

India,
2018-02-17 08:32
(2404 d 07:57 ago)

Posting: # 18427
Views: 4,464

T>MIC for Anti microbial is sufficient to show therapeutic efficacy [Regulatives / Guidelines]

Hi all

I need one help.

My objective is to replace immediate release formulation one antimicrobial with sustained release formulation of the same antimicribial

Can pharmacodynamic end-point (T>MIC) of Sustained Release formulation establish therapeutic effect and hence waive need to do clinical study? or we have to do a clinical study of Sustained release formulation vs immediate release formulation?

ElMaestro
★★★

Denmark,
2018-02-17 13:11
(2404 d 03:18 ago)

@ heritage
Posting: # 18428
Views: 3,690

T>MIC for Anti microbial is sufficient to show therapeutic efficacy

Post reply

Hi Heritage,

❝ Can pharmacodynamic end-point (T>MIC) of Sustained Release formulation establish therapeutic effect and hence waive need to do clinical study? or we have to do a clinical study of Sustained release formulation vs immediate release formulation?

This is a strategy that works for some developers, but mainly in EU. It does require that you know a lot about the ref. product from publications or from PARs and that the regulators you talk to are friendly. It may vary from agency to agency.
I would seek sc.advice for a 10.3 submission in EU, or approach FDA for a dialogue (controlled corr.) for a prospective 505(b)(2) development.

T>MIC in plasma is a good guess, but depending on the ADME caracteristics it may be not-so-well correlated with efficacy. Look for example at Azitromycin. This is an area were the fine distinction between rate and extent of the API being absorbed vs rate and rate of the API becoming available at the site of action seems muy importante.

Seek regulatory dialogue. Lots of it.

—
Pass or fail!
ElMaestro

heritage ☆ India, 2018-02-17 15:26 (2404 d 01:03 ago) @ ElMaestro Posting: # 18429 Views: 3,759	T>MIC for Anti microbial is sufficient to show therapeutic efficacy Post reply
	Hi EIMaestro Thank you for valuable inputs. Do we evaluate T>MIC always in patients or it can be done in healthy vouln.? Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]

ElMaestro ★★★ Denmark, 2018-02-17 19:13 (2403 d 21:17 ago) @ heritage Posting: # 18430 Views: 3,655	T>MIC for Anti microbial is sufficient to show therapeutic efficacy Post reply
	Hi Heritage, ❝ Thank you for valuable inputs. Do we evaluate T>MIC always in patients or it can be done in healthy vouln.? You evaluate it in exactly the population that the regulator is asking for — Pass or fail! ElMaestro

Helmut
★★★

Vienna, Austria,
2018-02-17 22:27
(2403 d 18:02 ago)

@ heritage
Posting: # 18431
Views: 3,856

Therapeutic Occupancy Time

Post reply

Hi Heritage,

❝ Thank you for valuable inputs. Do we evaluate T>MIC always in patients or it can be done in healthy vouln.?

T>MIC (actually t≥MIC) is called “Therapeutic Occupancy Time” (see this post). That’s a PK metric, not a PD endpoint. We performed such a study (antibiotic, MR vs. IR) a while ago. Be aware that

MIC generally is an in vitro concentration. For most antibiotics in vivo MIC is based on a wacky calculation.
For ~~most~~ (all?) antibiotics there is more than one MIC (different strains of bacteria show different susceptibilities).

@ElMaestro: Forget patients. You will never find ones with the same grade of infection. Parallel design difficult. Crossover impossible.

We performed a crossover in healthy subjects where we had three MICs.

Confirmatory: One-sided test for the Occupancy Times (superiority).
Exploratory: AUC (two-sided).
Descriptive: C_max (no CI).

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

heritage ☆ India, 2018-02-18 08:19 (2403 d 08:11 ago) @ Helmut Posting: # 18432 Views: 3,610	Therapeutic Occupancy Time Post reply
	Hi Helmut Thank you for your reply I need to learn three points 1. What should be design and patient population of the study? I found many studies on clinical trials.gov wherein patient was taken. Can you advice any good articles to read wherein healthy were taken 2. T>MIC study can waive need to do clinical trial? 3. Is there any regulatory guidance available for T>MIC stud?