The Role of Clinical Pharmacology in HCV Drug Development ......Viekira Pak & Clopidogrel Courtesy:...
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The Role of Clinical Pharmacology in HCV Drug Development: Regulatory Experience Islam R. Younis, Ph.D. Team Leader Office of Clinical Pharmacology Center for Drug Evaluation and Research U.S. Food and Drug Administration
Transcript of The Role of Clinical Pharmacology in HCV Drug Development ......Viekira Pak & Clopidogrel Courtesy:...
The Role of Clinical Pharmacology in HCV Drug Development: Regulatory Experience
Islam R. Younis, Ph.D. Team Leader
Office of Clinical PharmacologyCenter for Drug Evaluation and Research
U.S. Food and Drug Administration
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Disclaimer
• This presentation reflects the views of the presenter and not the position or policies of the Food and Drug Administration.
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Landscape of HCV Therapy
Modified from Florian et al, CPT, 2015
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Role of Clinical Pharmacology
• Dose Selection• Shortening Trial Duration• Pharmacogenomics• Specific Populations• DDI• Biopharmaceutics • Post-Marketing
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Shortening Trial Duration (SVR12 vs SVR24)
• Retrospective analysis from 5 drug development programs:– 15 phase II and phase III trials– 3 Pediatric trials
• Database included 13,599 adult subjects
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Shortening Trial Duration (SVR12 vs SVR24)
Gastroenterology. 2013 Jun;144(7):1450-1455.
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0 5 10 15 20 25
In Vitro
Human PK
Biopharmaceutics
Specific Populations
Drug-Drug Interactions(in vivo)
Median Number of Studies
Stud
y Ty
pe
Number of In Vitro and Phase I Studies Submitted to Approved HCV NME NDAs
7 (3,32)
3 (2,9)
6 (1,15)
3 (1,8)
21 (7,63)
Data do not include TQT studies or PD studies in healthy volunteers
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Example 1: PharmacogenomicsSimeprevir HCV Q80K: Impact on SVR12 Rates
Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)
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Example 1: PharmacogenomicsSimeprevir HCV Q80K
Excerpt from simeprevir label approved on 11/22/2013
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Example 2: Race- Based DosingSimeprevir (East Asian)
systemic circulation
bile
hepatocyte
OATP1B1/3
CYP3A
simeprevirmetabolite
diffusion
Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)
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Example 2: Race- Based DosingSimeprevir (East Asian)
Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)
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Example 2: Race- Based DosingSimeprevir (East Asian)
Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)
All Subjects
Asian Subjects
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Example 2: Race- Based DosingSimeprevir (East Asian)
Excerpt from simeprevir label approved on 11/22/2013
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Example 2: Race- Based DosingSimeprevir (East Asian)
Excerpt from simeprevir approval letter dated 11/22/2013
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Example 2: Race- Based DosingSimeprevir (East Asian)
J Gastroenterol Hepatol. 2016 May;31(5):912-20.
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Example 2: Race- Based DosingSimeprevir (East Asian)
PL SMV 100 mg SMV 150 mgN 152 153 152
Efficacy SVR12 76% 89% 91%
Safety Any AEs 97% 95% 97%Rash 13% 16% 18%Pruritus 9% 13% 9%Photosensitivity 0% 1% 1%
J Gastroenterol Hepatol. 2016 May;31(5):912-20.
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Example 2: Race- Based DosingSimeprevir (East Asian)
Excerpt from simeprevir label approved on 02/26/2016
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Example 3: DDI Sofosbuvir/Velpatasvir-Omeprazole
Data obtained from Epclusa Clinical Pharmacology Review
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Example 3: DDI Sofosbuvir/Velpatasvir-Omeprazole
Excerpt from Epclusa label approved on 06/28/2016
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Example 4: Relative Bioavailability Based ApprovalViekira XRTM
Viekira PakTM Viekira XRTM
AM PM
PAR/OMB/RTV
DAS DAS
PAR/OMB/DAS/RTV
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Example 4: Relative Bioavailability Based ApprovalViekira XRTM
Viekira XR CDTL Review
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Example 4: Relative Bioavailability Based ApprovalViekira XRTM (Food Effecct)
Viekira XR CDTL Review
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Example 6:Post-MarketingViekira Pak & Clopidogrel
Dasabuvir is a substrate of CYP2C8 enzyme and is contraindicated with strong inhibitors of CYP2C8 due to an increased risk of QT prolongation associated with increased dasabuvir exposure
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Example 6:Post-MarketingViekira Pak & Clopidogrel
Courtesy: Vikram Arya, FCP, Ph.D.
Repaglinide Dasabuvir
Primary Route of Metabolism CYP2C8 CYP2C8
Other Routes of Metabolism CYP3A4 CYP3A4
OATP Transporters OATP1B1 None
Exposure Change in Presence of Gemfibrozil
↑~7-8 fold ↑~11-fold
Exposure Change in Presence of Clopidogrel
↑~4-fold Not known
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Example 6:Post-MarketingViekira Pak & Clopidogrel
Clinical Pharmacology & Therapeutics, Vol 99, Issue Supplement S1
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Conclusions
• Clinical pharmacology plays a critical role in advancing the development of HCV DAAs.
• Clinical pharmacology plays a critical role in dose selection of HCV DAAs.
• Clinical pharmacology contributions span over the life cycle of HCV DAAs.
• Combination therapy contribute to the complexity of designing and reviewing HCV DAAs clinical pharmacology programs.
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Acknowledgment
Clinical Pharmacology Antiviral Team Members:• Vikram Arya, Ph.D.• Stanley Au, Pharm.D.• Amal Ayyoub, Ph.D.• Su-Young Choi, Pharm.D., Ph.D.• Mario Sampson, Pharm.D. • Shirley Seo, Ph.D.• Jenny Zheng, Ph.D.
