VijithRoy
☆    

India,
2020-07-22 07:34
(13 d 05:55 ago)

Posting: # 21770
Views: 232
 

 Pre-clinical PK/PD Parameters [PK / PD]

Hello all,

When i was going through the PK parameters of an antibacterial drug, i got stuck up at one point with the background concept behind.

So basically, the three parameters are, Concentration/MIC, Time>MIC, AUC/MIC - These are the Gold standard for evaluating Antibiotic PK-PD & Dosage regimen.

My question is,
1. How the drugs(Antibiotics) are classified under one of these parameters ?
E.g - Aminoglycoside - it comes under Concentration dependent killing (i.e, Conc/MIC).
why can't this come under time/MIC ?? :confused:


Please kindly help me out.

Thanks in Advance !!
dshah
☆    

India,
2020-07-30 13:09
(5 d 00:20 ago)

@ VijithRoy
Posting: # 21804
Views: 143
 

 Pre-clinical PK/PD Parameters

Dear VijithRoy!

The primary measure of antibiotic activity is the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitro. While the MIC is a good indicator of the potency of an antibiotic, it indicates nothing about the time course of antimicrobial activity.

» Integrating the PK parameters with the MIC gives us three PK/PD parameters which quantify the activity of an antibiotic: the Peak/MIC ratio, the T>MIC, and the 24h-AUC/MIC ratio. The Peak/MIC ratio is simply the Cpmax divided by the MIC. The T>MIC (time above MIC) is the percentage of a dosage interval in which the serum level exceeds the MIC. The 24h-AUC/MIC ratio is determined by dividing the 24-hour-AUC by the MIC.

The three pharmacodyamic properties of antibiotics that best describe killing activity are time-dependence, concentration-dependence, and persistent effects. The rate of killing is determined by either the length of time necessary to kill (time-dependent), or the effect of increasing concentrations (concentration-dependent). Persistent effects include the Post-Antibiotic Effect (PAE). PAE is the persistant suppression of bacterial growth following antibiotic exposure.

For Type I antibiotics (AG's, fluoroquinolones, daptomycin and the ketolides), the ideal dosing regimen would maximize concentration, because the higher the concentration, the more extensive and the faster is the degree of killing. Therefore, the Peak/MIC ratio is the important predictors of antibiotic efficacy. For aminoglycosides, it is best to have a Peak/MIC ratio of at least 8-10 to prevent resistence.

Type II antibiotics (beta-lactams, clindamycin, erythromcyin, and linezolid) demonstrate the complete opposite properties. The ideal dosing regimen for these antibiotics maximizes the duration of exposure. The T>MIC is the parameter that best correlates with efficacy. For beta-lactams and erythromycin, maximum killing is seen when the time above MIC is at least 70% of the dosing interval.

Type III antibiotics (vancomycin, tetracyclines, azithromycin, and the dalfopristin-quinupristin combination) have mixed properties, they have time-dependent killing and moderate persistent effects. The ideal dosing regimen for these antibiotics maximizes the amount of drug received. Therefore, the 24h-AUC/MIC ratio is the parameter that correlates with efficacy. For vancomycin, a 24h-AUC/MIC ratio of at least 400 is necessary for MRSA.

[image]

Regards,
Dshah
Helmut
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Vienna, Austria,
2020-07-30 13:41
(4 d 23:48 ago)

@ dshah
Posting: # 21805
Views: 125
 

 MIC: in vitro…

Hi Dshah,

of course, all what you wrote is correct. I performed studies for an originator (new formulation), where t≥MIC* was the only confirmatory PK metric (see also this post). Studies accepted.

[image]However, we must not forget one important point: The MIC is based on in vitro data. Generally we have more than one MIC (dependent on the bacteria / strain). Everybody (myself included) compared the in vivo concentrations of the PK study with the in vitro MIC. That’s not the same thing… Is there a 1:1 relationship? I strongly doubt it.
Can/should we really do that? Well, cough… :lookaround:

BTW, we have a similar mix-up of PK with PD in the so-called “Therapeutic Occupancy Time” based on the misconception that Cmax is directly (‼) related to safety (toxicity) and Cmin to a potential lack of efficacy. See also this post.


  • t≥MIC, if you don’t mind. T is the [image] SI abbreviation for the absolute temperature and t for time. Hence, tmax, tmin, tlag, t½ as well. Forget what you find in the FDA’s guidances.

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VijithRoy
☆    

India,
2020-07-31 08:18
(4 d 05:11 ago)

@ dshah
Posting: # 21812
Views: 92
 

 Pre-clinical PK/PD Parameters

Dear Dshah,
Thank you for you valuable reply,

» The three pharmacodyamic properties of antibiotics that best describe killing activity are time-dependence, concentration-dependence, and persistent effects. The rate of killing is determined by either the length of time necessary to kill (time-dependent), or the effect of increasing concentrations (concentration-dependent). Persistent effects include the Post-Antibiotic Effect (PAE). PAE is the persistant suppression of bacterial growth following antibiotic exposure.

Consider a new antimicrobial drug, to determine their killing activity (Which would be anyone one of the 3 parameter)., We have to undergo all the 3 invitro PD parameter(PeaK/MIC, Time/MIC, 24AUC/MIC ) and determine which parameter the drug best suits ??
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