1. Modeling and simulation (M&S) was employed to recommend doses for human Phase I studies of a direct Factor Xa (FXa) inhibitor, CS-3030. Predicted human pharmacokinetics (PK), biomarker responses (PD), and clinical outcomes were obtained using appropriate projection methods and PK/PD data from cynomolgus monkey, together with literature data. Models were developed for anti-FXa activity and fold-increase in prothrombin time (PT) compared to baseline using the following criteria to determine the target dose range: (1) anti-FXa activity within 0.5-0.8 IU/mL range (based on enoxaparin) and (2) 2- to 3-fold increase in PT (based on warfarin). PK/PD for a range of CS-3030 doses (10 to 320 mg), regimens (single dose, once daily (QD) and twice daily (BID)) and bioavailability fractions (4.5 to 50%) were simulated. The ranges of doses and bioavailability fractions were intended to compensate for any misspecification due to projection method or underlying assumptions. Influences of patient demographics and laboratory values were investigated on response to CS-3030. No one dose met the dual criteria of anti-FXa activity and PT response. Rather, target levels were achieved only partially over the dosing interval. If a single criterion was used, e.g. anti-FXa activity only, then a dose of 40 mg provided 50% time within the targeted range. Renal impairment was expected to influence drug exposure, and the effect was smaller for PT response than anti-FXa activity. Appropriate dose adjustment is thus possible for different populations. Human projections from animal FXa activity suggest doses up to 40 mg/day CS-3030 may provide similar efficacy (prevention of deep vein thrombosis) and safety (risk of bleeding) profiles to that of enoxaparin doses up to 100 mg/day following hip and knees surgeries. In conclusion, M&S led to identification of key elements to be studied earlier than usual, i.e., bioavailability and the effect of renal clearance, and the FIM study could be designed accordingly. This illustrated the application of M&S to guide drug development and inform the design of clinical trials. What do we do now? ●We model the drug as part of analysis. ●We are reactive What should we do? ●Think prospectively ●Provide the context for evaluating New Chemical Entities (NCEs) ●Inform key multi-faceted development decisions ◦ Product profiles vs. key competitors ◦ Treatment opportunities (mono vs. combo, doses) ◦ Special populations and covariates ●Communicate uncertainty in these attributes to decision makers ●Support informed Go/No-Go decision-making ●Ideally, critical development decisions should leverage relevant public and proprietary data ●Make model the basis of developing drugs When do we start? ●As early as possible What types of models ●PK/PD ●Disease models ●Animal/human correlations ●Basically integration of Knowledge ABSTRACT CONCLUSIONS AND DISCUSSION MODEL SCHEMATICOBJECTIVES Model Based Development of a Direct Factor Xa Inhibitor S. Rohatagi 1, T. Ozeki-Ishizuka 2, Y. Nitsu 2, F. Ezzet 3, H. Kastrissios 3, T.J. Carrothers 3, S.J. Haworth 1 1 – Daiichi Sankyo Pharma Development, Edison, NJ; 2 – Daiichi Sankyo, Tokyo; 3 - Pharsight Corporation, Mountain View, CA Modeling and simulation (M&S) were employed to make dosage recommendations for human Phase 1 studies of CS-3030. Specific objectives were to: Predict human PK-PD of CS-3030 based on animal to human projections, Characterize sources of variability or safety concerns, and Simulate potential clinical outcomes as compared to other anticoagulants. MOTIVATION BACKGROUND METHODS Predicted human pharmacokinetics (PK), biomarker responses (PD), and clinical outcomes were obtained using appropriate projection methods and PK/PD data from cynomolgus monkey, relative potency data and literature data. Allometric scaling was used to predict human pharmacokinetics. Models were developed for anti-FXa activity and fold-increase (i.e., multiples of the baseline value) in PT using the following criteria to determine the target dose range: 1) anti-FXa activity within 0.5-0.8 IU/mL range (based on enoxaparin) 2) 2- to 3-fold increase in PT (based on warfarin) It was assumed that PK-PD relationships observed in cynomolgus monkeys apply to humans. PK/PD for a range of CS-3030 doses (10 to 320 mg), regimens (single dose, once daily (QD) and twice daily (BID)), and bioavailability fractions (4.5 to 50%) were simulated. Ranges of doses and bioavailability fractions were intended to compensate for any misspecification due to projection method or underlying assumptions. Influences of patient demographics and laboratory values were investigated on response to CS-3030. Comparison of clinical events was made using publicly available literature for three comparators: warfarin, enoxaparin sodium (Lovenox ® ) and fondaparinux sodium (Arixtra ® ). CS-3030 is an oral, direct Factor Xa (FXa) inhibitor in development for the management of thromboembolic diseases. In animal studies, CS-3030 is cleared largely by the kidney. It is not metabolized by CYP 450 isozymes and therefore is expected to have low potential for drug- drug interactions. An International Normalized Ratio (INR) of 2-3 fold is generally considered a safe and effective anticoagulant range, thereby serving as a practical guide to dose selection for clinical use. Prothrombin time (PT) prolongation is known to be mediated by FXa inhibition; therefore, determination of PT and anti-FXa activity during preclinical development provides a basis for driving the drug development process towards selection of doses associated with target anti-FXa activity and PT/INR range. RESULTS – PK/PD MODELING Simulated PK Profiles in Humans: Allometric Scaling from Monkey Data Simulated Biomarker Profiles in Humans: Anti-Factor Xa Activity and PT Simulated PK and Biomarker Profiles: Special Populations Relationship Between Dose and Event Probability None of the doses met the dual criteria of anti-FXa activity and PT response. Rather, target levels were achieved only partially over the dosing interval. Proportions of the anti-FXa and PT profiles within the targeted range were consistently larger for BID regimens as compared to QD regimens. If a single criterion was used, e.g. anti-FXa activity only, then a dose of 40 mg provided 50% time within the targetted range. Renal impairment was expected to influence drug exposure, and therefore PD. The effect was smaller for PT response than anti-FXa activity. For a subject with severe renal impairment, average anti-FXa activity was approximately double that a healthy subject. This may suggest that appropriate dose adjustment may be warranted if target anti-FXa activity were to be maintained close to target values. Human projections from animal FXa activity suggest doses up to 40 mg/day CS-3030 may provide similar efficacy (prevention of deep vein thrombosis) and safety (risk of bleeding) profiles to that of enoxaparin following hip and knees surgeries. However, doses of 10 – 80 mg show lower bioavailability and large intersubject variability. Integration of animal data and public literature allowed human PK-PD to be projected under certain plausible assumptions and scenarios. Human projections for CS-3030 identified dosing regimens which provided similar efficacy and safety profiles to that of comparators M&S was used to optimize the Phase 1 program to reduce uncertainty and test assumptions relating to bioavailability and variability, and further to provide a basis to: ●Estimate the likely quality of Phase 2 dose-response in Phase 1 planning. ●Quantify the effect of covariates, the magnitude and sources of uncertainty, and key assumptions. This example illustrates the application of M&S to guide drug development and inform the design of clinical trials. SUMMARY OF RESULTS PROJECTED COMPARISON Comparison across drugs shows favorable projected response profile for CS-3030, comparable to observed responses for comparator drugs. “Opportunity: The concept of model-based drug development, in which pharmaco-statistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers an important approach to improving drug development knowledge management and development decision making. Model-based drug development involves building mathematical and statistical characterizations of the time course of the disease and drug using available clinical data to design and validate the model. The relationship between drug dose, plasma concentration, biophase concentration (pharmacokinetics), and drug effect or side-effects (pharmacodynamics) is characterized, and relevant patient covariates are included in the model. Systematic application of this concept to drug development has the potential to significantly improve it. FDA scientists use, and are collaborating with others in the refinement of, quantitative clinical trial modeling using simulation software to improve trial design and to predict outcomes. It is likely that more powerful approaches can be built by completing, and then building on, specific predictive modules.” From: Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, FDA, March 2004. Page 24. Model Based Drug Development – a FDA Critical Path Initiative