1. 1 The Role of Exposure-Response Evaluation in Drug Development and Regulatory Decisions Case Study: Rosuvastatin Hae-Young Ahn, Ph.D. Office of Clinical Pharmacology and Biopharmaceutics Division of Pharmaceutical Evaluation 2

2. 2 Clinical Pharmacology Therapeutic area: –Lipid lowering Mechanism of Action: –Competitive inhibition of HMG-CoA reductase Pharmacokinetics –Absolute BA: about 20% –Food: ↓Cmax 20%, ↔ AUC –Metabolism: not extensively metabolized –Cyp P450 2C9 –Elimination t½: 19 hr

3. 3 Clinical Pharmacology (Cont’d) Race: –Japanese and Chinese ancestry: 2x ↑ Renal Insufficiency: –Severe: 3x ↑ Drug-Drug Interactions –Cyclosporine:C max, AUC – ↑11x, 7x –Gemfibrozil:C max, AUC – ↑2x, 2x

4. 4 Regulatory Activities June 2001, NDA submission –Proposed doses of 10, 20, 40, and 80 mg. May 2002, approvable –80 mg: not approvable --little added benefit, safety concerns –10 mg, 20 mg, 40 mg: approvable Additional safety data on 20 and 40 mg; Address renal issue Assess optimal dosing and others August 2003, approval –5 - 40 mg

5. 5 How could exposure-response (or PK-PD) guide ‘optimal dosing’ for rosuvastatin?

6. 6 LDL-C: % Change From Baseline Rosuvastatin vs Placebo Trials 8 and 23 Pooled (Wk 6) P <.001 vs placebo; data presented as LS mean ± SE. 12.5510204080Placebo n =14151817 3431 Baseline characteristics Mean age: 56 yr Mean LDL-C: 190 mg/dL http://cdernet.cder.fda.gov/ACS/index.html

7. 7 Exposure-Response Relationship

8. 8 PK/PD Model

9. 9 Incidence of CK elevations and myopathy seen in phase II/III Baycol Rosuva All marketed STATINS a (mg)CK>10xULNMYOPATHY (all cases) 0.41.6%1.0-1.6% 0.82.1%0.9-1.0% Pbo0%0% 50.4%0.2% 100.2%0.1% 200.2%0.1% 400.4%0.2% 801.9%1.0% 5-800.03-0.9%0-0.5% http://cdernet.cder.fda.gov/ACS/index.html

10. 10 % of patients with proteinuria (  ++) At any visit Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools

11. 11 Plasma rosuvastatin concentrations by dose in 6 patients with rhabdomyolysis or renal toxicity http://cdernet.cder.fda.gov/ACS/index.html

12. 12 Dosing considerations AUC C max Gemfibrozil 2x 2x Japanese Ancestry 2x 2x Severe Renal Insufficiency 3x 3x (CrCL < 30 mL/min) http://cdernet.cder.fda.gov/ACS/index.html Cyclosporine 7x 11x

13. 13 Precautions - General in Labeling Pharmacokinetic studies show.. 2-fold elevation in median exposure in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore compared with Caucasians residing in North America and Europe….. these increases should be considered … dosing decisions for..Japanese and Chinese ancestry ( see WARNINGs Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Special Populations, Race).

14. 14 Dosage and Administration in Labeling <Crestor® approved labeling; http://www.fda.gov/cder/approval/index.htmhttp://www.fda.gov/cder/approval/index.htm Hypercholesterolemia and mixed dislipidemia: (baseline LDL-C < 190mg/dL) Dose range: 5 to 40 mg once daily- individualized - usual recommended starting dose is 10 mg - 5 mg may be… less aggressive LDL-C reductions or predisposing factors for myopathy…

15. 15 Dosage and Administration in Labeling (cont’d) Limit maximal doses –Cyclosporin5 mg –Gemfibrozil10mg –Severe RF5 – 10mg <Crestor® approved labeling; http://www.fda.gov/cder/approval/index.htmhttp://www.fda.gov/cder/approval/index.htm

16. 16 Conclusion Expose-Response clearly shows Although the sponsor has proposed doses of 10, 20, 40, and 80mg, doses lower than 10mg have potential clinical utility. There is apparent relationship between adverse events and plasma concentrations of the drug. Findings from Exposure-Response relationships were used in recommendation for dosing adjustments.