Key Issues in Drug Interactions in the Direct-Acting Antiviral - IAPAC

57 Pages·2014·9.28 MB·English

by  Media Services

Key
 Issues
 in
 Drug
 Interac0ons
 in
 the

DAA
 Era.

David
 Back
 -­‐
 Liverpool,
 UK
Disclosures

•  Honoraria
 received
 from
 Gilead,
 Janssen,

Merck,
 Abbvie,
 BMS,
 Boehringer-­‐Ingelheim,

Viiv.

•  Research
 or
 EducaConal
 Grant
 support
 from

Gilead,
 Janssen,
 Merck,
 Abbvie,
 Roche,
 Vertex,

BMS,
 Boehringer-­‐Ingelheim,
 Viiv.

•  PresentaCon
 refers
 to
 the
 following

unlabelled/unapproved
 drugs:
 faldaprevir,

daclatasvir,
 asunaprevir,
 ledipasvir,
 ABT-­‐450/r,

ABT-­‐267,
 ABT-­‐333;
 MK-­‐5172,
 MK-­‐8742.
HCV DAAs: a success story of multiple
disciplines.
Ø  Molecular Virology

Deciphered the viral replication cycle and identified
druggable targets.
Ø  Structural Biology
Provided high-resolution structures of viral targets such
as NS3, NS5A and NS5B – allowing modelling of drug-
target interactions
Ø  Molecular & Clinical Pharmacology
Shown the disposition profiles of the compounds and
helped develop strategies to optimise therapies – in
particular in relation to drug-drug interactions.
Anti-HCV drugs approved and in
advanced development
Manns M & van Hahn Nature Rev Drug Discovery, 2013; 12: 595-610
Direct Acting Antivirals against HCV
Drug- Drug Interactions
Toxicity
Co-
DAA
med*
Concentration Concentration
of DAA of Co-med
Reduced Efficacy
* The Co-med may be an antiretroviral
Perpetrator
Co-
DAA
med
Victim
1st Generation DAAs
Telaprevir and Boceprevir
Statement
 from
 Page
 20
 of
 www.hcvguidelines.org
Telaprevir and Boceprevir Interactions:
What have we learned?
Non-CYP
Drug CYP 3A4 Transporters metabolism
§  Transported by P-gp
§  Metabolised by
Telaprevir §  Inhibits P-gp; –
§  Inhibits
OATP1B1/2
§  Transported by P-gp; AKR
§  Metabolised by
Boceprevir BCRP §  Metabolised
§  Inhibits
§  Inhibits P-gp; OCT1/2 by
CYP 3A isozymes are
§  The most abundant CYP enzymes in the liver
§  Involved in the metabolism of many drugs
P-gp: P-glycoprotein; AKR: aldo-keto reductase
Kessara C et al 18th CROI, Abs 118; Garg V et al 18th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser
JJ et al Hepatology 2012; 55: 1620-1628; Kunze A et al Biochem Pharmacol 2012; 84: 1096-1102.
Slide 10
Importance of metabolism and transport in
relation to systemic drug levels
drug

Ø  Dissolution
Hepatocytes

Ø  Food effects
100%

UGTs

Ø Enzyme induction/inhibition
Ø Transporter induction/
CYP3A4
  inhibition
Enterocytes

2

OATP1A2

OATP1B1

OATP2B1

OATP1B3

OCT1

CYP 2A6 CYP 2B6 CYP3A4

1

CYP 2C8
CYP 1A2
P-­‐gp

CYP 2C9
BCRP

CYP 2C19 MRP2

CYP 2D6
CYP 3A
CYP 2E1
Adapted from: Bailey DG, et al. CMAJ 2013;185:1066