The Role of Clinical Pharmacology in HCV Drug Development ......Viekira Pak & Clopidogrel Courtesy:...
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.