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Development of HIV and HCV Drug Interaction
Websites. Story and Perspective
David Back
University of Liverpool
UK
David BackUniversity of Liverpool
January 2018
14th Residential Course on Clinical
Pharmacology of Antiretrovirals Torino
Drug Interactions between HIV drugs and
other co-meds recognised as a major
clinical problem in the late 90’s
1998 – ‘In-house’ website launched
1999 – Re-launch of website with
Gardiner-Caldwell Communications
2002 – Launch of
Interactive/Searchable website
www.hiv-druginteractions.org
2010 – Launch of HIV iCharts
Total Interactions in Database (end 2017)
Web stats 2017: HIV
MixPanel Analytics in Real Time
Country Queries
Total
Sessions
Query per
Session
UK 546,224 79,231 6.89
USA 386,976 49,757 7.78
Spain 169,474 25,251 6.71
Italy 98,192 12,331 7.96
France 87,925 9,820 8.95
Interactions
Status
Queries
Red 111,166
Amber 590,008
Green 1,716,618
Yellow 16,608
Key ARVs by Interaction Classification (Green,
Amber/Yellow, Red) in Liverpool Database
Darunavir/r Darunavir/cobi Efavirenz
EVG/cobi Raltegravir Dolutegravir
Note: Data from 665 co-meds (excluding ARV-ARV interactions) in www.hiv-druginteraction.org
Differences between RTV & COBI
Differences between the Integrase Inhibitors
Web stats 2017: Hepatitis
Country Queries Sessions
Queries per
Session
USA 512,581 72,353 7.08
Italy 277,975 35,406 7.85
United
Kingdom 266,478 27,638 9.64
Spain 234,514 33,429 7.02
Brazil 183,122 842 217.48
Interaction
Status Queries
Red 187,603
Amber 511,154
Green 2,096,204
Yellow 47,418
Key HCV drugs by Interaction Classification
(Green, Amber, Red) in Liverpool Database
SOF/LDV 3D ELB/GZR
86%
Note: Data from 650 co-meds (excluding DAA-DAA interactions) in www.hep-druginteraction.org
86% 53%
SOF/VEL
88%
SOF/VEL/VOX
82%
GLE/PIB
79%
Process
1. Collate all DDI and PK studies in the public domain
2. Get a clear understanding of:
i) Absorption, distribution, metabolism, excretion of drug/regimen (in vitro and in vivo data).
ii) Potential as a Victim of DDIs; Therapeutic window; Clinical efficacy and AE data.
iii) Potential as a Perpetrator of DDIs.
3. Obtain draft USPI and/or SPC prior to launch.
4. Make commentaries for potential interaction with each co-med. Done by specialist pharmacists (CM, FM & AB).
5. Address queries/difficult assignments within team.
6. QA.
7. Launch post-approval.
Difficult Issues
• Differences in USPI and the SmPC.
eg. Contraindicated vs Not recommended vs
Consider Alternative.
• Interactions with a regimen where one component is
affected eg Glecaprevir/Pibrentasvir and PPIs.
• Interactions where there are multiple doses of the
victim drug – eg quetiapine.
• Multiple drugs in a regimen which can interact.
• Interaction in a patient with hepatic or renal
impairment.
G/P: Comparison of DDI sections of the USPI
and SPCCo-Medication USPI Recommendation SmPC Recommendation
Pravastatin Dose reduce by 50% Caution; dose not exceed 20mg
Rosuvastatin Dose not exceed 10mg Caution; dose not exceed 5mg
Atorvastatin Not recommended Contraindicated
Lovastatin Not recommended Not recommended
Simvastatin Not recommended Contraindicated
Fluvastatin n/m Caution; low dose recommended
Pitavastatin n/m Caution; low dose recommended
Cyclosporine Not recommended for use in pts
needing >100 mg/day
Not recommended for use in pts
needing >100 mg/day
Tacrolimus No clinically significant interaction Caution; TDM
Sofosbuvir No clinically significant interaction No dose adjustment
Losartan No clinically significant interaction No dose adjustment
Valsartan No clinically significant interaction No dose adjustment
Omeprazole No clinically significant interaction OMP 40mg not recommended
Vit K antagonists Close monitoring of INRs Close monitoring of INRs
n/m: not mentioned
Maviret SPC July 31st 2017; Mavyret USPI July 2017.
Effect of Omeprazole on Glecaprevir
and Pibrentasvir exposure
• GLE AUC was decreased by 29% with omeprazole 20 mg QD, and ~50%
with omeprazole 40 mg regimens regardless to timing
• PIB AUC was unaffected by any omeprazole regimens
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OmeprazoleRegimen
PKParameter
Central Value Ratio (90% Confidence Interval)
GLE PIB
20 mg QDCmax 0.78 (0.60 – 1.00) 1.00 (0.83 – 1.22)
AUCinf 0.71 (0.58 – 0.86) 0.97 (0.80 – 1.18)
40 mg QDCmax 0.36 (0.21 – 0.59) 0.85 (0.70 – 1.03)
AUCinf 0.49 (0.35 – 0.68) 1.15 (0.94 – 1.40)
40 mg QPMCmax 0.54 (0.44 – 0.65) 0.93 (0.79 – 1.09)
AUCinf 0.51 (0.45 – 0.59) 1.01 (0.85 – 1.20)
GLE Exposure Changes Have Minimal Impact
on Efficacy
• Exposure-response modeling indicated that AUC of PIB, but not GLE, was significantly associated
with SVR12 in Non-GT3 and TN–GT3 subjects
• Neither GLE or PIB AUC was predictive of SVR12 in PRS-experienced GT3 or GT1/4 NS5A-
experienced subjects
• For GLE/PIB 300 mg/120 mg, exposures of GLE and PIB in individual subjects are highly correlated
• Limited ability of exposure-response models to inform effect of decreasing GLE exposure only on
SVR12
• What is the clinical relevance of decreases in exposure for GLE, but not PIB?
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DDI – where there is difference in labels
and potentially also dose-dependent
HIV Drug Interactions. Available at:
www.hiv-druginteractions.org (accessed Aug 2017).
2018 Projects and Partnerships
• Add new drugs (eg BFTAF)
• Improve existing ARVs ie ATV/c; DRV/c;
DRV/c/F/TAF
• Add brand names to search list
• Add new co-meds
• API links to major studies
• IDI, Kampala – prescribing errors
• Web talks and educational symposia on DDIs
• Translation of website database – launch of
Japanese version of HEP site Q1/2 2018;
discussions re Russian.
Acknowledgments
Saye Khoo
Sara Gibbons
Fiona Marra
Alison Boyle
Justin Chiong
Katie McAllister
Jasmine Martin
Laura Dickinson
Marco Siccardi
Andrew Owen
Catia Marzolini David Burger
Nielka va Earp
Frank Jansman
Kaylee Ferrier
Website Editorial BoardsJonathan Schapiro
Mas Chaponda
Charles Flexner
Doug Dieterich
Graham Foster
Jennifer Kiser.
EASL Representative (to be appointed)