Change in Dose Selection: FDA Perspective

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Change in Dose Selection: FDA Perspective IDSA/ISAP/FDA Workshop April 16, 2004 Jenny J Zheng, Ph.D. Pharmacometrician DPEIII/OCPB/CDER/FDA

Objectives To examine the reviews to bolster dosage choice To talk about a model based quantitative way to deal with guide measurements determination To talk about ways to deal with further propel the utilization of PK/PD for measurement choice

Dose Selection Efficacy Safety Resistance

Studies to Support Dose Selection 1. Microbiology/in vitro information Susceptibility information for pathogens important to the sign Protein restricting Post anti-infection impact (PAE) 2. Pre-clinical information PK/PD thinks about in different creature/in vitro models Efficacy considers in different helpful disease models PK examines in the creatures utilized as a part of restorative contamination models

Studies to Support the Dose Selection 3. Stage 1 pharmacokinetic examines PK considers in solid subjects Phase 2 contemplates Efficacy Safety

Time to Communicate with FDA Early correspondence is supported. Before stage 2/3 examines

How to Select Dose Rationale for measurements choice in antimicrobial medication applications is variable. All the time the measurement is chosen in view of mean PK profile in connection to MIC for pertinent pathogens. The PK inconstancy of medication is not considered. The relationship between a focus time profile and a MIC is not generally clear. A quantitative approach is suggested.

Quantitative Approach What is quantitative approach? Utilize displaying and recreation instruments to quantitatively anticipate the result. Favorable position of quantitative approach Quantitative (prescient) Decision is more consistent and straightforward Objective

Quantitative Approach Can pathogen be murdered at measurement X? A PK/PD list can be acquired from pre-clinical reviews and be utilized to foresee the bacterial slaughtering/restraint impact . In the event that the PK/PD record for the unbound medication in the subject is over the PK\PD list got from pre-center: YES. Something else: NO Dose X PK Protein restricting Pathogen

The Goal To foresee the rate of patients who could come to a PK/PD focus at a scope of measurements . Dosage/measurements can be resolved for clinical trials: Phase 3 (settled measurement): dominant part of subjects would come to the PK/PD target. Stage 2 measurement extending contemplates: the dosages ought to be chosen so it is differentiable with respect the percent of subjects who could come to the PK/PD focus among the measurements.

The Method PK information PK show (parameters and its inconstancy) PK profiles at measurements even not contemplated.

The Method Distribution of PK/PD file at dosage X 77%

The Method X4 X3 X2 MIC 90 =2 m g/mL X1 MIC 90 =1 m g/mL MIC 90 =0.5 m g/mL

Antimicrobial Model Successful treatment of contamination includes the cooperations of host, medication and microorganisms Pharmacokinetics Tissue entrance  ? Have Drug ? Weakness of pathogens PK/PD relationship PAE Killing rate Other measurements  ? Safe framework ? Microorganisms s The variables not being considered may speak to potential impediments.

PK/PD Studies in Human The consistency of PK/PD relationship in creatures for treatment of contaminations in human is not clear. The PK/PD relationship for the greater part of medications was built up just in creatures. To enhance understanding the PK/PD relationship in human: Phase 2/3 examines

Summary A model based quantitative approach is instructive for measurement determination. With the potential constraints, the measurements ought to be chosen in view of the totality of accessible information. Measurements determination: Microbiology Pre-center Phase 1 Phase 2 Phase 3

Future Well planned dosage going stage 2 contemplates in suitable diseases. PK/PD relationship in human Safety Improvement of the model utilized as a part of quantitative approach. Viability + Safety + Resistance Evaluation of records other than AUC/MIC, C max/MIC, and T>MIC. Advancement of ideal length of treatment.