Pharmacogenetics - Back to reality

Andrew Owen, Ph.D. FRSB. FBPhS.

Professor of Pharmacology

Department of Molecular and Clinical Pharmacology

University of Liverpool, UK

A 15 year summary of HIV pharmacogenetics rhetoric

2001: “individualized therapy based on the genome sequence of each person will be realized in the next decade. ” Science, 293, 489—493

2004: “these tests can be used clinically to improve outcomes for patients undergoing complex and sustained drug regimens” Am J Pharmacogenomics 4, 141-50.

2006:”the multiplicity of the genes involved …… obliges to accumulate more information before claiming that time has arrived to implement it in daily clinical practice.” Pharmacogenomics J. 6, 234-45.

2007: “limited success with the current approach where one or few candidate genes are examined for a limited number of allelic variants. A change in paradigm emerges ….. the wealth of data on less common genetic polymorphisms, and new genotyping technology.” Pharmacogenomics. 8, 623-33.

2008: “it is expected that larger-scale comprehensive genome approaches will profoundly improve the landscape of knowledge of HIV therapy in the future.” Recent Pat Antiinfect Drug Discov. 3, 132-

5.

2011: “The integration of pharmacokinetic, pharmacogenetic and metabolic determinants will more probably address current therapeutic needs in patients.” Expert Opin Drug Metab Toxicol. 7, 609-22.

2014: “The accelerated discovery of new gene mutations and polymorphisms that influence the effects of antiretroviral drugs provides a unique opportunity for a personalized medicine approach in the management of lifelong HIV therapy.” Expert Opin Drug Metab Toxicol. 10, 1119-30.

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Rilpivirine LA (NNRTI) Cabotegravir LA (integrase inhibitor)

Variability in plasma exposure following long-acting nanoformulation delivery

Drug Oral PK variability (AUC CV%) LA PK variability (AUC CV%)

Paliperidone 35.3 40%

Olanzapine 26% 50%

Medroxyprogesterone 52% 34%

Rilpivirine 39% 52%*

Cabotegravir 27% 39%Owen and Rannard. ADDR. 2016

SDNs for long-acting depot delivery of HIV drugs: mechanisms?

Lymph capillary Interstitial space

Muscle cells?

?

Many unanswered questions regarding what regulates drug release!

Owen and Rannard. ADDR. 2016

Towards personalised medicine strategies for long-acting drug delivery: Rilpivirine pharmacogenetics

Unpublished

Personalised frequency of dosing?

Many of the sites local to the depot may express enzymes and transporters (e.g. CYP3A4)

Lymph capillary Interstitial space

Muscle cells

?

Owen and Rannard. ADDR. 2016

Data from fourteen publications discussed in this presentation

David Back played a leading role in eleven of them!

ProfileFirst paper – 1971

Latest paper – 2016Total papers – 527

H-Index – 56Citations – 13662Co-authors – 267

Acknowledgements

www.BritishSocietyNanomedicine.org

The Liverpool Team

TorinoGiovanni Di’Perri

Stefano Bonora

Andrea Calcagno

Antonio D'Avolio

SSATMarta Boffito

Akil Jackson

Emilie Elliot

David Back

Marco Siccardi

Saye Khoo

Neill Liptrott

Laura Dickinson

Steve Rannard

Tom McDonald

Chris David

Pierre Chambon

Fiona Hatton

Sam Auty

Andy Dwyer

Hannah Rogers

Faye Hern

Jane Ford

Helen Cauldbeck

Maude LeHellaye

Rebecca Slater

Tamara Alhilfi

Marco Giardiello

Steph Edwards

Adam Town

Sharon Murphy

Deirdre Egan

Laura Else

Sara Gibbons

Helen Reynolds

Paul Curley

Alessandro Schipani

Darren Moss

Lee Tatham

James Hobson

Rajith Kumar Reddy

Megan Neary

Christina Chan

Justin Chiong

Henry Pertinez

Rana Abutaima

Rohan Gurjar

Sharon Murphy

Ana Jimenez-Valverde

Hannah Kinvig

Nuala Keegan

Louise Tidbury

Martin Levere

UNSWSean Emery

Rebekah Puls