American Conference on Pharmacometics American Conference on Pharmacometics –San Diego, CA; April 3-6 2011–San Diego, CA; April 3-6 2011

Population PK modeling incorporating enzyme induction mechanism to Population PK modeling incorporating enzyme induction mechanism to guide the design of optimal dose regimen for an antiviral drugguide the design of optimal dose regimen for an antiviral drug

Jing YuJing Yu1, June Ke, June Ke2, Leo Kawai, Leo Kawai1 1M&S - Novartis Pharma, Cambridge, MA; M&S - Novartis Pharma, Cambridge, MA; 2DMPK – Novartis Pharma, East Hanover, NJDMPK – Novartis Pharma, East Hanover, NJ

Objectives: Respiratory Syncytial Virus (RSV) infection is the leading cause of serious respiratory tract infections in infants, young children, elderly, and immuno-compromised patients throughout the world. RSV604 is a benzodiazepine analog that inhibits RSV replication in vitro. In vitro and clinical studies indicate that RSV604 systemic exposure had potential for a narrow therapeutic concentration range. Therefore, selection of optimal dose regimen required a model which precisely profiles individual PK in the therapeutic range.

Methods: A linear three-compartment PK model with first-order absorption was built with Phase 1 study data including intravenous (IV; 10-200 mg) and oral (PO; 25-150 mg) doses, as population PK model with NONMEM. The linear model suggested a 450 mg loading dose followed by 150 mg BID to satisfy the therapeutic concentration range requirement. However, the highest dose group (200 mg) in the IV Phase 1 study and the 150 and 300 mg dose groups in a later conducted oral Phase 1 study showed the compound didn't accumulate after 5 days of dosing as projected from single dose data. As RSV604 was shown to moderately induce CYP3A4 by in vitro reporter gene assay, a clearance induction model, considering enzyme turn-over, was then examined, using in vitro enzyme induction parameters as initial estimations of in vivo model.

Results: The enzyme induction model fitted all the data from Phase 1 studies well and eliminated the gaps observed in the initial linear model. This model predicted a 600 mg loading dose followed by 300 mg BID would rapidly reach the desired Cmin of 2000 ng/mL but decrease the potential safety risk. The prediction of this enzyme induction model was further validated by the PK data from subsequent clinical studies.

Conclusions: Incorporation of an induction effect in the population PK model increased the accuracy in describing PK data from all Phase 1 studies and predicted an optimal dose regimen to be used in the next stage of drug development.

AbstractAbstract

IntroductionIntroduction

Evidence of enzyme inductionEvidence of enzyme induction

2101 study: exposure at MD (AUCss) vs. SD (AUCinf) tends to be low in high iv dose (200 mg); attenuated accumulation in higher dose

in vitro and animal data suggest CYP3A4 induction: in vitro EC50 =~2750ng/mL

Linear model over-predicts data from the oral Phase 1 study (2103) cohorts 1 & 2

Simulations (linear) vs. 2103 data

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2101: AUCss (MD) /AUC0-inf (SD) vs. Dose

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Concentration-dependent clearance:

dCLint /dt = Kreg *[1+ Emax *C/(EC50 +C) – CLint/ Clint,0], where C is concentration

When C<< EC50, it can be simplified to

dCLint /dt = Kreg *[1+ Ke *C – CLint/ Clint,0], where Ke = Emax / EC50

Estimated parameters

Kreg = 4.62 L/hr/hr;

Ke = 0.000427 /(ng/mL)Model building and validationModel building and validation

Simulations vs. Data

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2103 study cohorts 1 & 2 data for model fitting (left) and cohort 3 data for model validation (right) Estimated parameters

Clint,0 = 3.21 L/hr

Kreg = 4.62 L/hr/hr

Ke = 0.000427 /(ng/mL)Simulation (induction started from beginning) vs. Data

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New dose regimen for efficacy study New dose regimen for efficacy study

4.543.532.521.510.50

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Potentially efficacious dose regimen suggested by induction model: 600 mg loading dose followed by 300 mg bid

ConclusionConclusion

The enzyme induction model represents the available clinical data well, although the real mechanism of the nonlinear PK profile needs to be further evaluated. With this model, we have reached a higher level of confidence in designing an optimal dose regimen, 600 mg loading dose followed by 300 mg bid, for the efficacy study in the next stage of drug development.

AcknowledgementsAcknowledgements

The whole RSV604 Team, especially Kathryn Bracken (PJM), Jens Praestgaard (CIS), Russ Wada (M&S), Daniel Stein and Tom Evans (TME).

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for CYP

CYPEnzyme

CompoundConcentration

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SynthesisStimulate clearance pathway

Degradation Degradation

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