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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 DecisionsCase Study: Rosuvastatin

Hae-Young Ahn, Ph.D.

Office of Clinical Pharmacology and Biopharmaceutics

Division of Pharmaceutical Evaluation 2


Clinical pharmacology l.jpg
Clinical Pharmacology Development and Regulatory Decisions

  • 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


Clinical pharmacology cont d l.jpg
Clinical Pharmacology Development and Regulatory Decisions(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


Regulatory activities l.jpg
Regulatory Activities Development and Regulatory Decisions

  • 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



Ldl c change from baseline rosuvastatin vs placebo trials 8 and 23 pooled wk 6 l.jpg
LDL-C: dosing’ for rosuvastatin?% Change From BaselineRosuvastatin vs PlaceboTrials 8 and 23 Pooled (Wk 6)

1 2.5 5 10 20 40 80 Placebo

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


Exposure response relationship l.jpg
Exposure-Response Relationship dosing’ for rosuvastatin?


Pk pd model l.jpg
PK/PD Model dosing’ for rosuvastatin?


Incidence of ck elevations and myopathy seen in phase ii iii l.jpg
Incidence of CK elevations and myopathy seen in phase II/III dosing’ for rosuvastatin?

(mg) CK>10xULN MYOPATHY

(all cases)

0.4 1.6% 1.0-1.6%

0.8 2.1% 0.9-1.0%

Pbo 0% 0%

5 0.4% 0.2%

10 0.2% 0.1%

20 0.2% 0.1%

40 0.4% 0.2%

80 1.9% 1.0%

5-80 0.03-0.9% 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


Of patients with proteinuria at any visit l.jpg
% of patients with proteinuria ( dosing’ for rosuvastatin? ++)At any visit

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


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


Dosing considerations l.jpg
Dosing considerations with rhabdomyolysis or renal toxicity

  • AUC Cmax

Cyclosporine 7x 11x

Gemfibrozil 2x 2x

Japanese Ancestry 2x 2x

Severe Renal Insufficiency 3x 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 with rhabdomyolysis or renal toxicity

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 with rhabdomyolysis or renal toxicityin 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


Dosage and administration in labeling cont d l.jpg
Dosage and Administration in Labeling (cont’d) with rhabdomyolysis or renal toxicity

  • Limit maximal doses

    • Cyclosporin 5 mg

    • Gemfibrozil 10mg

    • Severe RF 5 – 10mg

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


Conclusion l.jpg
Conclusion with rhabdomyolysis or renal toxicity

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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