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

46

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?

47

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)