1 / 20

Application of Exposure Response Relationship for Dose Adjustment

Application of Exposure Response Relationship for Dose Adjustment . Jenny J Zheng, Ph.D. Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics CDER/FDA. Background.

ulf
Download Presentation

Application of Exposure Response Relationship for Dose Adjustment

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Application of Exposure Response Relationship for Dose Adjustment Jenny J Zheng, Ph.D. Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics CDER/FDA

  2. Background • Pharmacokinetics of a drug maybe influenced by intrinsic factors such as age, gender, impaired renal or hepatic function and extrinsic factors such as drug-drug interactions. • What is the clinical significance of the changes in concentrations? • Clinical Assessment: clinical experience but not quantitative or could be subjective • Exposure response relationship can bridge safety and exposure data to quantitate the influence of the increase in exposure.

  3. Example

  4. Drug Z • Drug Z is a non-cardiac drug. • Both pre-clinical and phase 1 studies showed that the drug causes QT prolongation. • The QT prolongation is concentration dependent.

  5. The Extrinsic and Intrinsic Factors • Elderly: The mean steady state Cmax was 100% higher as compared with Cmax in young subjects. • Renal Impaired Subjects: The steady state Cmax in severe renal impaired subjects was 50% higher as compared with healthy subjects. • Drug Drug Interaction: Ketoconazole increased the steady state Cmax by 60%.

  6. Questions? • Should dose be adjusted in elderly, renal impaired subjects or when co-administered with ketoconazole? • What is the effect of increase in drug Z concentration on QT prolongation?

  7. Exposure Response Studies • Several Phase 1 studies are pooled. • Cross over, placebo controlled • Doses included in the studies were clinical dose (X), 2X and 3X • The blood samples were collected for drug measurements. • QTs were measured.

  8. Change of QTc vs Concentration by Linear Mixed-Effect Model

  9. Simulation • Assuming a logarithmic distribution, Cmax (n=2000) was simulated based on phase 1 studies. • Age effect (young vs elderly (age>65 years)) • Renal impaired study (severe renal impaired (CLcr<30 mL/min)) • ketoconazole drug drug interaction study • The QTc were predicted using simulated concentrations and the linear mixed fitted model using NONMEM.

  10. Age Effect

  11. Renal Function

  12. Drug Interaction-Ketoconazole

  13. The Effect of Age, Renal Function and Ketoconazole

  14. Age vs Renal Effect on Pharmacokinetics of Drug Z • The age effect might be partially attributed by reduced renal function. • In the study, CLcr was 50% lower in elderly subjects as compared with young subjects). • The age effect would be reduced if renal function effect was corrected by dose reduction.

  15. What would be the effect of ketoconazole in subject with severe renal impairment?

  16. Method • Steady state Cmax in severe renal impaired subjects was simulated (n=2000). • The Cmax ratio of drug Z at presence and absence of ketoconazole was obtained from cross over study. The ratio ranged from 1 to 4 (n=10). • The combined effect for both factors was simulated by randomly multiplying the Cmax from step 1 and the ratio from step 2.

  17. Ketoconazole in Severe Renal Impaired Subjects

  18. % of Subjects with QTc>40 ms

  19. Conclusion • The increase of concentrations by age, severe renal function and co-administration with ketoconazole resulted in increased number of subjects with QTc longer than 40 ms. • The effect is more significant when two factors are combined.

  20. Recommendation • Considering the nature of adverse event (QT prolongation). • A dose reduction was recommended in severe renal impaired subjects. • A dose reduction was recommended when Drug Z is co-administered with ketoconazole.

More Related