# Presentation: 716587

## Augmentin® ES Suspension Summary of PK/PD Data

- He Sun, Ph.D.
- Frank Pelsor, Pharm.D.
- Pharmacometrics Specialist
- Review Team Leader
- Office of Clinical Pharmacology
- FDA

- Antiinfectives AC Meeting, 1/30/2001

## Overview

- There were two Clinical Pharmacology studies, Study 382 and Study 446.
- Time above MIC (T>MIC) was used as the PD marker, and
- T>MIC greater than 40% of dose interval was used for efficacy prediction.

- Antiinfectives AC Meeting, 1/30/2001

## PK/PD Study 382 

- 25000/382
- N = 5 patients - aged 1 month to 12 years
- Augmentin®  (7:1) 45/6.4 mg/Kg/day  *q12h*
- Results:
- All had full C-T profiles
- Amoxicillin half-life = 1.2 hours
- T>MIC Estimation:
- Plasma Amoxicillin concentrations were doubled for estimating T>MIC for the 14:1 formulation.
- The estimated T>MIC was 41%.

- Antiinfectives AC Meeting, 1/30/2001

## PK/PD Study 446

- 25000/446
- N = 19 patients - aged 3 months to 12 years
- Augmentin® ES (14:1) 90/6.4 mg/Kg/day  *q12h*
- Results:
- Patients (n=17) each provided 1 blood and 1 MEF samples.
- T>MIC Estimation:
- Plasma Amoxicillin concentrations after 3 hours post dose were extrapolated using the amoxicillin t1/2 obtained in Study 382.
- The estimated T>MIC was 38%.

- Antiinfectives AC Meeting, 1/30/2001

## Slide 5

- Antiinfectives AC Meeting, 1/30/2001

## Comparison of Studies 382 and 446:Mean (CV%) amoxicillin concentrations

- Time	       Predicted	      Observed
- (hour)		  (mcg/ml)	             (mcg/ml)
-   Study 382	              Study 446
- 	_(Plasma)__	__    Plasma              MEF    ._      _ _
- 1			     18		 8 (71%)   5.0(69%)
- 2			     20		16 (39%)  5.2(52%)
- 3			     12		13 (56%)  6.4 (28%)

- Antiinfectives AC Meeting, 1/30/2001

## The Importance of Variability

- Same mean T>MIC will not predict same probability of efficacy:
- Say, at a given MIC, it is known that requires 41% TMIC over 12 hours: 5 hours
- Data 1:  TMICs: 4.3, 5, 5, 6.2, mean = 5.13 hrs. CV=15%;  75% efficacy
- Data 2:  TMICs: 3, 4.5, 4.7, 8.3, mean= 5.13 hrs. CV=43%;  25% efficacy

- Antiinfectives AC Meeting, 1/30/2001

## The Importance of Variability:

- Inter-subject variability characteristics of T>MIC, in the population of interest, is  a critical component of PK/PD information.
- Mean T>MIC alone will not provide adequate prediction in efficacy
- Although limited, the submitted amoxicillin data show large inter-subject variability in concentrations.
- There is inadequate data to obtain a true estimate of T>MIC and/or  its inter-subject variability in children.

- Antiinfectives AC Meeting, 1/30/2001

## Summary

- The 7:1 formulation (Study 382)
- Full concentration-time profile (**n=5**)
- T>MIC was estimated by doubling the observed concentrations
- The estimated T>MIC is 41%.
- The 14:1 formulation (Study 446)
- Samples were collected at 1, 2, or 3 hours post dose
- Single observation per patient (**n=17**)
- T>MIC was estimated based on extrapolated mean concentrations
- The estimated T>MIC is 38%.

- Antiinfectives AC Meeting, 1/30/2001

## Conclusions

- The predicted and observed concentrations from the two studies are not in agreement.
- Reliable amoxicillin concentration-time curves from Augmentin ES (14:1) to allow accurate estimation of T>MIC is not available.
- Information on variability characteristics of T>MIC, a PK/PD measure, is not available.

- Antiinfectives AC Meeting, 1/30/2001