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The Role of Exposure-Response Evaluation in Drug Development and Regulatory Decisions Case Study: Rosuvastatin PowerPoint PPT Presentation


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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. Clinical Pharmacology. Therapeutic area: Lipid lowering

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The Role of Exposure-Response Evaluation in Drug Development and Regulatory Decisions Case Study: Rosuvastatin

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The Role of Exposure-Response Evaluation in Drug Development and Regulatory DecisionsCase Study: Rosuvastatin

Hae-Young Ahn, Ph.D.

Office of Clinical Pharmacology and Biopharmaceutics

Division of Pharmaceutical Evaluation 2


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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


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Clinical Pharmacology (Cont’d)

  • Race:

    • Japanese and Chinese ancestry: 2x ↑

  • Renal Insufficiency:

    • Severe: 3x ↑

  • Drug-Drug Interactions

    • Cyclosporine:Cmax, AUC – ↑11x, 7x

    • Gemfibrozil:Cmax, AUC – ↑2x, 2x


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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


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


Ldl c change from baseline rosuvastatin vs placebo trials 8 and 23 pooled wk 6 l.jpg

LDL-C: % Change From BaselineRosuvastatin vs PlaceboTrials 8 and 23 Pooled (Wk 6)

12.5510204080Placebo

n =

14

15

18

17

17

34

31

31

Baseline characteristicsMean age: 56 yrMean LDL-C: 190 mg/dL

P < .001 vs placebo; data presented as LS mean ± SE.

<Crestor® Clinical Development Efficacy, Dr. James Blasetto, MD, MPH, AstraZeneca July 9, 2003>

http://cdernet.cder.fda.gov/ACS/index.html


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Exposure-Response Relationship


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PK/PD Model


Incidence of ck elevations and myopathy seen in phase ii iii l.jpg

Incidence of CK elevations and myopathy seen in phase II/III

(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%

Baycol

Rosuva

All marketed STATINSa

<Crestor® William Lubas, MD, PhD, CDER, FDA, Advisory Committee meeting, July 9, 2003>

http://cdernet.cder.fda.gov/ACS/index.html


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% of patients with proteinuria ( ++)At any visit

Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools


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Plasma rosuvastatin concentrations by dose in 6 patients with rhabdomyolysis or renal toxicity

<Crestor® William Lubas, MD, PhD, CDER, FDA, Advisory Committee meeting, July 9, 2003>

http://cdernet.cder.fda.gov/ACS/index.html


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Dosing considerations

  • AUC Cmax

Cyclosporine 7x 11x

Gemfibrozil2x 2x

Japanese Ancestry2x 2x

Severe Renal Insufficiency3x 3x

(CrCL < 30 mL/min)

<extracted from: William Lubas, MD, PhD, CDER, FDA, Advisory Committee meeting, July 9, 2003>

http://cdernet.cder.fda.gov/ACS/index.html


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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).


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Dosage and Administration in Labeling

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…

<Crestor® approved labeling; http://www.fda.gov/cder/approval/index.htm


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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.htm


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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.


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