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TRANSCRIPT
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Unpublished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