Inter-individual variability in pharmacokinetics and response to protease inhibitor-based antiretroviral therapy

Lead Research Organisation: University of Liverpool
Department Name: Biomedical Sciences

Abstract

Treatment for HIV clearly improves survival. However, some patients fail therapy either because of toxicity or because the virus mutates, allowing it to multiply even in the presence of the drug. Both of these factors are strongly influenced by the amount of drug that enters a patient?s bloodstream. For example, too much drug and the patient will experience some types of toxicity and too little drug and the virus is able to try out different mutations, eventually finding those which allow it to survive. Our knowledge of the factors that influence drug concentrations in the blood is rapidly developing. Our recent work has shown that SLCO transporters, which are molecular pumps that transfer anti-HIV drugs into gut and liver cells can influence the absorption and clearance of some drugs from the body. These transporters are encoded by the human genome and there are differences in these genes meaning that in some individuals they have different activity than in others. Therefore, the reason for this research is to assess whether differences in SLCO transporter genes are able to explain some of the differences in drug concentrations and susceptibility to toxicity and failure of anti-HIV drugs. Ultimately, if this project is successful it will aid the development of tests that help HIV doctors to give the right drug, at the right dose to the right patient.

Technical Summary

The DOH acknowledges that ?pharmacogenomics should help make medicine use more effective?. Drug treatment (costing the NHS #220 million/year) becomes more expensive with each successive failure and Protease inhibitors (PIs) are associated with long term toxicities (e.g. fat redistribution), which are stigmatising but, like acquisition of resistance, are also difficult to reverse. Strategies to improve drug use are therefore needed and Pharmacogenetics offers a way of selecting drugs (by avoiding use in those with highest risk of toxicity) and individualising dosage. Using Xenopus laevis oocyte expression systems we have shown that PIs are substrates for SLCO (OATP) influx transporters. Moreover, in a proof of concept preliminary analysis we have shown a significant association between one common variant of SLCO1B1 (OATP1B1*1b; 521C T) and LPV concentrations in patients. We now propose to utilise high throughput genotyping (Sequenom) of single nucleotide polymorphisms to study associations with drug concentrations (through a therapeutic drug monitoring registry) and clinical response (through the UK CHIC cohort). We will also mine and assess copy number polymorphisms. For polymorphisms associated with response to therapy, we will determine the mechanism in intestinal biopsies (expression) and oocytes (function). Replication of pharmacogenetics studies is paramount and we will also confirm pharmacological phenotype by assessing full pharmacokinetic profiles in patients selected based on their genotype. We plan to gather substantive information on genetic influences associated with response and to assess how this information could be used in clinical practice, by using it to predict durability of LPV, DRV and ATV based regimens.

Publications

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Bienczak A (2016) The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children. in British journal of clinical pharmacology

 
Description A randomised, double-blind, placebo-controlled, clinical trial to compare the safety and efficacy of reduced dose efavirenz (EFV) with stardard dose EFV
Amount £317,353 (GBP)
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2013 
End 12/2014
 
Description Antiepileptic drug transport at the blood-brain barrier; more than just P-glycoprotein
Amount £98,758 (GBP)
Organisation Epilepsy Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Antiretroviral therapy (ART) simplification
Amount £4,203,686 (GBP)
Funding ID AID-OAA-A-15-00069 
Organisation United States Agency for International Development 
Sector Public
Country United States
Start 10/2015 
End 10/2020
 
Description Application of nanomedicine to childhood diseases
Amount £37,500 (GBP)
Organisation Alder Hey Children's NHS Foundation Trust 
Sector Hospitals
Country United Kingdom
Start 10/2013 
End 12/2016
 
Description Assessing the intracellular accumulation of TMC114 and other Tibotec Compounds.
Amount £78,030 (GBP)
Organisation Johnson & Johnson 
Department Tibotec
Sector Private
Country United Kingdom
Start 10/2005 
End 09/2008
 
Description Assessment of drug and system parameters for quantitative predictions of drug-drug interactions (DDIs) arising from induction of drug metabolising enzymes and drug transporters
Amount £12,000 (GBP)
Organisation SimCyp Ltd 
Sector Private
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Assessment of the impact of host genetic variation on the response to lopinavir-containing regimens in HIV+ patients.
Amount £1,320 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2005 
End 08/2006
 
Description BBSRC CASE studentship
Amount £24,116 (GBP)
Funding ID AZ217862 
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start  
 
Description BBSRC Ind Partnership case studentship.
Amount £16,551 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description Bridging and accelerating the translation of novel scientific findings for health and wealth gain
Amount £78,012 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2014 
End 05/2015
 
Description Cellular determinants of raltegravir exposure
Amount £81,392 (GBP)
Organisation Merck 
Sector Private
Country Germany
Start  
 
Description Computational models for the prediction of PK in special populations
Amount £90,906 (GBP)
Organisation University of Basel 
Department University Hospital Basel
Sector Hospitals
Country Switzerland
Start 01/2017 
End 01/2020
 
Description Development of an Antiviral Powder that forms a Nanodispersion on Addition to Water
Amount £8,000 (GBP)
Organisation IOTA Nanosolutions Limited 
Sector Private
Country United Kingdom
Start  
 
Description Development of solid drug nanoparticle for treatment of tuberculosis
Amount £88,511 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 10/2013 
End 12/2013
 
Description EPSRC Responsive Mode Grant
Amount £1,120,609 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description EURIPIDES - EUropean Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substances
Amount £265,086 (GBP)
Funding ID 201380 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start  
 
Description European Nanotechnology Characterisation Laboratory
Amount £645,058 (GBP)
Funding ID 654190 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2015 
End 05/2019
 
Description Factors influencing drug absorption from small bowel.
Amount £28,754 (GBP)
Organisation Royal Liverpool and Broadgreen University Hospitals NHS Trust 
Sector Public
Country United Kingdom
Start 10/2006 
End 09/2008
 
Description Host susceptibility to EVF-associated treatment limiting toxicity in the German competence Network. (Kurztitel: "KompNet-GenTox-Study")
Amount £18,800 (GBP)
Organisation Competence Network for HIV/AIDS 
Sector Public
Country Germany
Start  
 
Description Influence of genetic polymorphisms on antiretroviral pharmacokinetics
Amount £1,440 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2013 
End 08/2013
 
Description Integrated radiomaterials chemistry for simultaneous multi-component tracking of nanomedicines in biological matrices
Amount £896,475 (GBP)
Funding ID EP/L02635X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 09/2017
 
Description Inter-individual variability in pharmacokinetics and response to protease inhibitor-based antiretroviral therapy.
Amount £355,752 (GBP)
Funding ID G0800247 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2009 
End 07/2012
 
Description Interactions between chemokine receptor antagonists and other drugs.
Amount £60,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 05/2004 
End 06/2006
 
Description Investigating the influence of pregnancy-induced changes in antiretroviral pharmacokinetics, together with polymorphisms in drug disposition genes, on viral decay dynamics in HIV positive women starting therapy late in pregnancy and postpartum
Amount £175,903 (GBP)
Funding ID 204776/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 01/2020
 
Description Investigation of the role of ABCB5 in corticosteroid transport and response in IBD
Amount £119,942 (GBP)
Organisation National Association for Colitis and Crohn’s Disease (NACC) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Liverpool Imaging Partnership: Molecular physiology and drug response
Amount £932,728 (GBP)
Funding ID MR/K015931/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2013 
End 02/2017
 
Description Long-Acting/Extended Release Antiretroviral Resource Program (LEAP)
Amount £503,485 (GBP)
Funding ID R24AI118397 
Organisation National Institutes of Health Clinical Center 
Sector Hospitals
Country United States
Start 07/2015 
End 06/2020
 
Description Modulation of TB-HIV drug interaction by host genetic influences
Amount £154,266 (GBP)
Funding ID G0901364 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Modulation of bioavailability via tissue specific induction of metabolising enzyme and transporter proteins by ritonavir and other drugs.
Amount £58,500 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 03/2004 
End 03/2007
 
Description New Nanoscale Drug Delivery Systems and their Application to HIV/AIDS treatment
Amount £878,569 (GBP)
Funding ID EP/I038721/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Non-Attrition HAART nanoparticle therapies for HIV/AIDS Drug Delivery
Amount £1,422,399 (GBP)
Funding ID EP/G066272/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Pharmacogenetic and functional analysis of novel GSTP1 polymorphism.
Amount £19,675 (GBP)
Organisation Royal Liverpool and Broadgreen University Hospitals NHS Trust 
Sector Public
Country United Kingdom
Start 05/2005 
End 01/2007
 
Description Pharmacogenetic and pharmacokinetic studies.
Amount £56,000 (GBP)
Organisation The Sainsbury Family Charitable Trusts 
Department Monument Trust
Sector Charity/Non Profit
Country United Kingdom
Start 08/2005 
End 09/2008
 
Description Pharmacogenetic predictors of antiretroviral drugs pharmacokinetics, efficacy and safety during pregnancy and lactation
Amount £30,000 (GBP)
Organisation Obafemi Awolowo University 
Sector Academic/University
Country Nigeria
Start 09/2013 
End 09/2016
 
Description Pharmacologic strategies to use the levonorgestrel implant in HIV-infected women
Amount £216,219 (GBP)
Funding ID 1R01HD085887-01A1 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 12/2015 
End 11/2020
 
Description Pickering-stabilised Nanoemulsions as Novel Antiretroviral Drug Delivery Systems
Amount £99,583 (GBP)
Organisation British Society for Antimicrobial Chemotherapy 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Prediction of drug-drug interaction between Rifampicin and Boosted Darunavir using pharmacokinetic modelling approaches
Amount £123,163 (GBP)
Organisation Johnson & Johnson 
Department Janssen Pharmaceutica
Sector Private
Country Global
Start 10/2013 
End 09/2014
 
Description Raltegravir pharmacokinetics
Amount £143,878 (GBP)
Organisation Merck 
Sector Private
Country Germany
Start 10/2013 
End 12/2014
 
Description Solid drug nanoparticles
Amount £432,281 (GBP)
Organisation Viiv Healthcare 
Sector Private
Country United Kingdom
Start 03/2015 
End 02/2018
 
Description TAILoR
Amount £999,975 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description TDF combination solid drug nanoparticles
Amount £93,064 (GBP)
Organisation Clinton Health Access Initiative 
Sector Charity/Non Profit
Country United States
Start 02/2014 
End 06/2015
 
Description Towards NanoMedicine Interventions for HIV/AIDS
Amount £1,333,141 (GBP)
Funding ID EP/K002201/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Towards complete sustained release nanoformulations of NRTI based regimens
Amount £1,210,035 (GBP)
Funding ID R01AI114405 
Organisation National Institutes of Health Clinical Center 
Sector Hospitals
Country United States
Start 07/2014 
End 07/2018
 
Description Towards complete sustained release nanoformulations of NRTI based regimens
Amount £808,127 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 07/2014 
End 07/2018
 
Description Vacation Scholarship: Influence of genetic polymorphisms on antiretroviral pharmacokinetics
Amount £1,440 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title OATP expressing oocyte expression systems 
Description X. Laevis oocyte expression systems have been developed for OATP1A2, OATP1B1, OATP1B3 and OATP3A1. Models have also been developed for functional genetic variants of these transporters. 
Type Of Material Cell line 
Provided To Others? No  
Impact The OATP transporters continue to emerge as important determinants of the pharmacokinetics of many different drug classes across most disease areas. These tools have been utilised for antiretrovirals within this project and this has so far resulted in two publications. Ongoing work is now applying these models to other infectious disease agents and the models have also been provided to other research groups in Liverpool as part of projects in epilepsy, colitis and cancer. 
 
Title Pharmacogenetics database 
Description We have expanded our access to DNA and plasma from HIV+ patients. The sample bank and database now contain data and samples for cohorts from Chile, Germany, Italy, UK, Spain, South Africa, Ghana and Thailand (>3000 samples). 
Type Of Material Biological samples 
Provided To Others? No  
Impact The database and samples have had a huge impact upon our pharmacogenetics reseaarch and outputs. The PI has co-authored 27 papers since establishing the clinical links that were greatly facilitated by the current grant. 
 
Title Sequenom based assays for genotyping 260 SNPs across the SLCO transporter gene family 
Description Sequenom based assays have been developed to capture 95% of the genetic variability across the SLCO family of transporters. The assays include an analysis of tagging SNPs supplemented with SNPs of known and of putative functional significance. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Successful development of these assays has resulted in studies to assess the impact of these polymorphisms on antiretroviral drugs but has also led to a new collaboration in South Africa to establish the importance of these variants for antituberculosis drugs. The assays have also been shared with other research groups in Liverpool and are being employed for analysis in other disease areas. 
 
Title TDM registry 
Description We have been the sole provider of therapeutic drug monitoring in the UK (and beyond) since 2002. This has reulted in the archiving of samples and data from >12000 TDM requests across multiple antiretroviral drugs. This grant has enabled us to establish a TDM registry with anonomysed database to accellerate pharmacogenetics research. 
Type Of Material Biological samples 
Provided To Others? No  
Impact The registry provides a tool for rapid assessment of putative pharmacogenetic associations enabling us to quickly validate our in vitro studies with a clinical endpoint - a strategy that has resulted in multiple publications to date. 
 
Description Baltimore 
Organisation Johns Hopkins University
Department Division of Clinical Pharmacology
Country United States 
Sector Academic/University 
PI Contribution As part of a supplement from the US National Institutes of Health a collaboration was initiated to assess the impact of drugs used in the treatment of tuberculosis on expression of drug metabolising enzymes and transporters in primary human hepatocytes.
Collaborator Contribution The collaborators have existing funding for clinical trials in TB. The supplement was awarded to generate data to help rationalise the observations in these trials. The collaborators bring clinical and pharmacological expertise and interpretation while the Liverpool team conducted data generation.
Impact Williamson B, Dooley KE, Zhang Y, Back D, Owen A. Induction of Influx and Efflux Transporters and Cytochrome P450 3A4 in Primary Human Hepatocytes by Rifampicin, Rifabutin and Rifapentine. Antimicrob Agents Chemother. 2013 Dec;57(12):6366-9. doi: 10.1128/AAC.01124-13.
Start Year 2012
 
Description Barcelona 
Organisation Autonomous University of Barcelona (UAB)
Country Spain 
Sector Academic/University 
PI Contribution My team and I are part of this active collaboration to identify pharmacogenetic associations with antiretroviral protease inhibitors. As such, we have and are conducting genotyping, analysis and interpretation.
Collaborator Contribution The partners in Barcelona have and are conducting the clinical recruitment of patients into the studies and population pharmacokinetic analyses that incorporate assessment of demographic factors including genetic factors.
Impact Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs. Moltó J, Rajoli R, Back D, Valle M, Miranda C, Owen A, Clotet B, Siccardi M. J Antimicrob Chemother. 2016 Dec 20. pii: dkw485. doi: 10.1093/jac/dkw485. Moltó J, Xinarianos G, Miranda C, Pushpakom S, Cedeño S, Clotet B, Owen A, Valle M. Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients. Clin Pharmacokinet. 2013 Jul;52(7):543-53. doi: 10.1007/s40262-013-0057-6. The collaboration is multidisciplinary and involved pharmacologists (Liverpool), Clinicians (Barcelona) and population pharmacokinetic modellers (Liverpool and Barcelona).
Start Year 2011
 
Description Barcelona 
Organisation Germans Trias i Pujol University Hospital
Department Fight Against Aids Foundation (FLS)
Country Spain 
Sector Charity/Non Profit 
PI Contribution My team and I are part of this active collaboration to identify pharmacogenetic associations with antiretroviral protease inhibitors. As such, we have and are conducting genotyping, analysis and interpretation.
Collaborator Contribution The partners in Barcelona have and are conducting the clinical recruitment of patients into the studies and population pharmacokinetic analyses that incorporate assessment of demographic factors including genetic factors.
Impact Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs. Moltó J, Rajoli R, Back D, Valle M, Miranda C, Owen A, Clotet B, Siccardi M. J Antimicrob Chemother. 2016 Dec 20. pii: dkw485. doi: 10.1093/jac/dkw485. Moltó J, Xinarianos G, Miranda C, Pushpakom S, Cedeño S, Clotet B, Owen A, Valle M. Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients. Clin Pharmacokinet. 2013 Jul;52(7):543-53. doi: 10.1007/s40262-013-0057-6. The collaboration is multidisciplinary and involved pharmacologists (Liverpool), Clinicians (Barcelona) and population pharmacokinetic modellers (Liverpool and Barcelona).
Start Year 2011
 
Description Brazil 
Organisation Federal University of Santa Maria
Country Brazil 
Sector Academic/University 
PI Contribution Hosted a visiting scientist from Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina P.O. Box 476, Florianópolis, SC, 88040-900, Brazil to undertake the evaluation of novel nanomaterials intended for drug delivery strategies. The Liverpool team provided hands on training and direct research relating to in vitro immunological characterisation, in vitro drug disposition assays and physiologically-based pharmacokinetic modelling. The collaboration has resulted in two publications.
Collaborator Contribution Adny Silva spent a period of 8 months at Liverpool learning various assays for pre-clinical assessment of nanomaterials that were generated by her and her colleagues in Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina P.O. Box 476, Florianópolis, SC, 88040-900, Brazil. The Brazilian collaborators therefore generated the materials and helped characterise them in Liverpool. They also co-wrote the two publications.
Impact Silva AH, Locatelli C, Filippin-Monteiro FB, Martin P, Liptrott NJ, Zanetti-Ramos BG, Benetti LC, Nazari EM, Albuquerque CA, Pasa AA, Owen A, Creczynski-Pasa TB. Toxicity and inflammatory response in Swiss albino mice after intraperitoneal and oral administration of polyurethane nanoparticles. Toxicol Lett. 2016 Mar 30;246:17-27. doi: 10.1016/j.toxlet.2016.01.018. Epub 2016 Jan 25.
Start Year 2014
 
Description Cape Town 
Organisation University of Otago
Department Department of Medicine
Country New Zealand 
Sector Academic/University 
PI Contribution On the back of this research funding we have developed assays that allow us to investigate the influence of SLCO transporters for other relevant pharmacological agents. This has allowed us to expand our network of collaborations. One particularly important collaboration has been established with Dr Helen McIlleron in Cape Town, South Africa. Together we have begun to assess the influence of SLCO1B1 polymorphisms on the pharmacokinetics and response to rifampicin, rifabutin and rifapentin in tuberculosis infected patients.
Collaborator Contribution This collaboration has expanded my clinical collaborations thereby allowing access to clinical specimens and accelerating local pharmacogenetic research.
Impact Arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of Rifapentine: a population pharmacokinetics analysis. Francis J, Zvada SP, Denti P, Hatherill M, Charalambous S, Mungofa S, Dawson R, Dorman S, Gupte N, Wiesner L, Jindani A, Harrison TS, Olagunju A, Egan D, Owen A, McIlleron HM. Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01964-18. doi: 10.1128/AAC.01964-18. [Epub ahead of print] PMID: 30670438 Effect of diurnal variation, CYP2B6 genotype and age on the pharmacokinetics of nevirapine in African children. Bienczak A, Cook A, Wiesner L, Mulenga V, Kityo C, Kekitiinwa A, Walker AS, Owen A, Gibb DM, Burger D, McIlleron H, Denti P. J Antimicrob Chemother. 2017 Jan;72(1):190-199. The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children. Bienczak A, Cook A, Wiesner L, Olagunju A, Mulenga V, Kityo C, Kekitiinwa A, Owen A, Walker AS, Gibb DM, McIlleron H, Burger D, Denti P. Br J Clin Pharmacol. 2016 Jul;82(1):185-98. doi: 10.1111/bcp.12934. Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis. Hennig S, Naiker S, Reddy T, Egan D, Kellerman T, Wiesner L, Owen A, McIlleron H, Pym A. Antimicrob Agents Chemother. 2015 Oct 19;60(1):617-20. doi: 10.1128/AAC.01195-15. Special populations and pharmacogenetic issues in tuberculosis drug development and clinical research. McIlleron H, Abdel-Rahman S, Dave JA, Blockman M, Owen A. J Infect Dis. 2015 Jun 15;211 Suppl 3:S115-25. doi: 10.1093/infdis/jiu600. Review. Research capacity. Enabling the genomic revolution in Africa. H3Africa Consortium, Rotimi C, Abayomi A, Abimiku A, Adabayeri VM, Adebamowo C, Adebiyi E, Ademola AD, Adeyemo A, Adu D, Affolabi D, Agongo G, Ajayi S, Akarolo-Anthony S, Akinyemi R, Akpalu A, Alberts M, Alonso Betancourt O, Alzohairy AM, Ameni G, Amodu O, Anabwani G, Andersen K, Arogundade F, Arulogun O, Asogun D, Bakare R, Balde N, Baniecki ML, Beiswanger C, Benkahla A, Bethke L, Boehnke M, Boima V, Brandful J, Brooks AI, Brosius FC, Brown C, Bucheton B, Burke DT, Burnett BG, Carrington-Lawrence S, Carstens N, Chisi J, Christoffels A, Cooper R, Cordell H, Crowther N, Croxton T, de Vries J, Derr L, Donkor P, Doumbia S, Duncanson A, Ekem I, El Sayed A, Engel ME, Enyaru JC, Everett D, Fadlelmola FM, Fakunle E, Fischbeck KH, Fischer A, Folarin O, Gamieldien J, Garry RF, Gaseitsiwe S, Gbadegesin R, Ghansah A, Giovanni M, Goesbeck P, Gomez-Olive FX, Grant DS, Grewal R, Guyer M, Hanchard NA, Happi CT, Hazelhurst S, Hennig BJ, Hertz- C, Fowler, Hide W, Hilderbrandt F, Hugo-Hamman C, Ibrahim ME, James R, Jaufeerally-Fakim Y, Jenkins C, Jentsch U, Jiang PP, Joloba M, Jongeneel V, Joubert F, Kader M, Kahn K, Kaleebu P, Kapiga SH, Kassim SK, Kasvosve I, Kayondo J, Keavney B, Kekitiinwa A, Khan SH, Kimmel P, King MC, Kleta R, Koffi M, Kopp J, Kretzler M, Kumuthini J, Kyobe S, Kyobutungi C, Lackland DT, Lacourciere KA, Landouré G, Lawlor R, Lehner T, Lesosky M, Levitt N, Littler K, Lombard Z, Loring JF, Lyantagaye S, Macleod A, Madden EB, Mahomva CR, Makani J, Mamven M, Marape M, Mardon G, Marshall P, Martin DP, Masiga D, Mason R, Mate-Kole M, Matovu E, Mayige M, Mayosi BM, Mbanya JC, McCurdy SA, McCarthy MI, McIlleron H, Mc'Ligeyo SO, Merle C, Mocumbi AO, Mondo C, Moran JV, Motala A, Moxey-Mims M, Mpoloka WS, Msefula CL, Mthiyane T, Mulder N, Mulugeta Gh, Mumba D, Musuku J, Nagdee M, Nash O, Ndiaye D, Nguyen AQ, Nicol M, Nkomazana O, Norris S, Nsangi B, Nyarko A, Nyirenda M, Obe E, Obiakor R, Oduro A, Ofori-Acquah SF, Ogah O, Ogendo S, Ohene-Frempong K, Ojo A, Olanrewaju T, Oli J, Osafo C, Ouwe Missi Oukem-Boyer O, Ovbiagele B, Owen A, Owolabi MO, Owolabi L, Owusu-Dabo E, Pare G, Parekh R, Patterton HG, Penno MB, Peterson J, Pieper R, Plange-Rhule J, Pollak M, Puzak J, Ramesar RS, Ramsay M, Rasooly R, Reddy S, Sabeti PC, Sagoe K, Salako T, Samassékou O, Sandhu MS, Sankoh O, Sarfo FS, Sarr M, Shaboodien G, Sidibe I, Simo G, Simuunza M, Smeeth L, Sobngwi E, Soodyall H, Sorgho H, Sow Bah O, Srinivasan S, Stein DJ, Susser ES, Swanepoel C, Tangwa G, Tareila A, Tastan Bishop O, Tayo B, Tiffin N, Tinto H, Tobin E, Tollman SM, Traoré M, Treadwell MJ, Troyer J, Tsimako-Johnstone M, Tukei V, Ulasi I, Ulenga N, van Rooyen B, Wachinou AP, Waddy SP, Wade A, Wayengera M, Whitworth J, Wideroff L, Winkler CA, Winnicki S, Wonkam A, Yewondwos M, sen T, Yozwiak N, Zar H. Science. 2014 Jun 20;344(6190):1346-8. doi: 10.1126/science.1251546. No abstract available. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. Chigutsa E, Visser ME, Swart EC, Denti P, Pushpakom S, Egan D, Holford NH, Smith PJ, Maartens G, Owen A, McIlleron H. Antimicrob Agents Chemother. 2011 Sep;55(9):4122-7. doi: 10.1128/AAC.01833-10. The collaboration is multidisciplinary involving pharmacogenetics and in vitro expertise from my laboratory and clinical and population pharmacokinetic modelling expertise from Cape Town. Other publications are also currently in progress and the collaboration has been expanded to include genetic analysis in a number of additional ongoing clinical trials.
Start Year 2010
 
Description Chiang Mai 
Organisation Chiang Mai University
Department Faculty of Associated Medical Sciences
Country Thailand 
Sector Academic/University 
PI Contribution This is an ongoing collaboration with Thailand to validate the pharmacogenetics of antiviral drug pharmacokinetics in Thai patient populations. The Liverpool team have contributed expertise in terms of knowledge of mechanisms that underpin variability in drug exposure.
Collaborator Contribution The Thai collaborators have recruited patients and conducted the pharmacokinetic and pharmacogenetic assessments with guidance from Liverpool.
Impact No relationship between drug transporter genetic variants and tenofovir plasma concentrations or changes in glomerular filtration rate in HIV-infected adults. Sirirungsi W, Urien S, Harrison L, Kamkon J, Tawon Y, Luekamlung N, Thongpaen S, Nilmanat A, Jourdain G, Lallemant M, Le Coeur S, Ngo-Giang-Huong N, Owen A, Cressey TR. J Acquir Immune Defic Syndr. 2015 Apr 1;68(4):e56-9. doi: 10.1097/QAI.0000000000000504. No abstract available. Potential effect of pharmacogenetics on maternal, fetal and infant antiretroviral drug exposure during pregnancy and breastfeeding. Olagunju A, Owen A, Cressey TR. Pharmacogenomics. 2012 Oct;13(13):1501-22. doi: 10.2217/pgs.12.138.
Start Year 2014
 
Description Cologne 
Organisation University of Cologne
Department Department of Internal Medicine
Country Germany 
Sector Academic/University 
PI Contribution My team and I are conducting genotyping and drug concentration measurements on patients from Cologne and the wider German Competence Network for HIV and AIDS. We also conduct the analysis, interpretation and manuscript writing.
Collaborator Contribution Our clinical collaborators in Germany have and continue to conduct patient recruitment and supply biological material in terms of patient whole blood and plasma. Patient demographic data and data relating to therapy response are also provided.
Impact The collaboration is multdiciplinary in terms of pharmacology (Liverpool) and clinical (Germany). The collaboation has yielded five research publications to date: Pharmacokinetic and pharmacodynamic analysis of efavirenz dose reduction using an in vitro-in vivo extrapolation model. Siccardi M, Almond L, Schipani A, Csajka C, Marzolini C, Wyen C, Brockmeyer NH, Boffito M, Owen A, Back D. Clin Pharmacol Ther. 2012 Oct;92(4):494-502. doi: 10.1038/clpt.2012.61. Epub 2012 Jul 18. Association of ABCC10 polymorphisms with nevirapine plasma concentrations in the German Competence Network for HIV/AIDS. Liptrott NJ, Pushpakom S, Wyen C, Fätkenheuer G, Hoffmann C, Mauss S, Knechten H, Brockmeyer NH, Hopper-Borge E, Siccardi M, Back DJ, Khoo SH, Pirmohamed M, Owen A; German Competence Network for HIV/AIDS. Pharmacogenet Genomics. 2012 Jan;22(1):10-9. doi: 10.1097/FPC.0b013e32834dd82e. Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. Wyen C, Hendra H, Siccardi M, Platten M, Jaeger H, Harrer T, Esser S, Bogner JR, Brockmeyer NH, Bieniek B, Rockstroh J, Hoffmann C, Stoehr A, Michalik C, Dlugay V, Jetter A, Knechten H, Klinker H, Skaletz-Rorowski A, Fätkenheuer G, Egan D, Back DJ, Owen A; German Competence Network for HIV/AIDS Coordinators. J Antimicrob Chemother. 2011 Sep;66(9):2092-8. doi: 10.1093/jac/dkr272. Epub 2011 Jun 29. Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals. Schipani A, Wyen C, Mahungu T, Hendra H, Egan D, Siccardi M, Davies G, Khoo S, Fätkenheuer G, Youle M, Rockstroh J, Brockmeyer NH, Johnson MA, Owen A, Back DJ; German Competence Network for HIV/AIDS. J Antimicrob Chemother. 2011 Jun;66(6):1332-9. doi: 10.1093/jac/dkr087. Epub 2011 Mar 25. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. Wyen C, Hendra H, Vogel M, Hoffmann C, Knechten H, Brockmeyer NH, Bogner JR, Rockstroh J, Esser S, Jaeger H, Harrer T, Mauss S, van Lunzen J, Skoetz N, Jetter A, Groneuer C, Fätkenheuer G, Khoo SH, Egan D, Back DJ, Owen A; German Competence Network for HIV/AIDS. J Antimicrob Chemother. 2008 Apr;61(4):914-8. doi: 10.1093/jac/dkn029. Epub 2008 Feb 14.
Start Year 2008
 
Description Ghana 
Organisation Komfo Anokye Teaching Hospital (KATH)
Department Department of Medicine
Country Ghana 
Sector Hospitals 
PI Contribution The Liverpool team provided training and access to laboratories and facilities to conduct an assessment of genetic determinants of pharmacokinetics and response to HIV drugs in Ghana. In subsequent studies, the Liverpool team have led and delivered pharmacokinetic and pharmacogenetic evaluations, as well as statistical analyses and manuscript writing.
Collaborator Contribution Dr Sarfo visited my laboratory to conduct collaborative research to assess the impact of host genetic polymorphisms on pharmacokinetics and response to HIV drugs. The collaborators also provided clinical samples for analysis.
Impact Sarfo FS, Zhang Y, Egan D, Tetteh LA, Phillips R, Bedu-Addo G, Sarfo MA, Khoo S, Owen A, Chadwick DR. Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients. J Antimicrob Chemother. 2014 Feb;69(2):491-9. doi: 10.1093/jac/dkt372.
Start Year 2011
 
Description Lausanne 
Organisation Lausanne University Hospital (CHUV)
Department Division of Clinical Pharmacology and Toxicology
Country Switzerland 
Sector Hospitals 
PI Contribution My team and I are conducted genotyping to support data generated in Lausanne for a collaboration. We also contributed to analysis, interpretation and manuscript writing.
Collaborator Contribution Our collaborators in Lausanne are working on related topics and we continue to collaborate to progress the field when appropriate.
Impact Outputs: Siccardi M, Marzolini C, Seden K, Almond L, Kirov A, Khoo S, Owen A, Back D. Prediction of drug-drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach. Clin Pharmacokinet. 2013 Jul;52(7):583-92. doi: 10.1007/s40262-013-0056-7. Erratum in: Clin Pharmacokinet. 2013 Jul;52(7):613-4. Arab-Alameddine M, Fayet-Mello A, Lubomirov R, Neely M, di Iulio J, Boffito M, Owen A, Cavassini M, Guenthard H, Rentsch K, Buclin T, Aouri M, Telenti A, Decosterd L, Rotger M, and Csajka C. Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir In HIV positive and Healthy Individuals. (2012) Antimicrob Agents Chemother. 56, 2959-66. The skill sets in Liverpool and Lausanne are similar so the collaboration predominantly serves to cross-validate research findings.
Start Year 2010
 
Description New South Wales 
Organisation University of New South Wales
Country Australia 
Sector Academic/University 
PI Contribution A randomised, double-blind, placebo-controlled, clinical trial to compare the safety and efficacy of reduced dose efavirenz (ENCORE I). ENCORE1 was a non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Funded by the Australian Medical Research Council, Professor Owen's team conducted the pharmacokinetic and pharmacogenetics assessments within the trial (including the CNS substudy) that have recently been published. Encore I was the study that demonstrated equivalent efficacy between 400mg and 600mg efavirenz with a reduced incidence of adverse events within the 400mg arm, irrespective of host CYP2B6 genotype. The pharmacokinetic assessment was key to the recent announcement by the World Health Organisation that guidelines will be changed to incorporate the 400mg dose of efavirenz as an alternative first-line option for HIV.
Collaborator Contribution The trial was coordinated and administered through the Kirby Institute in New South Wales.
Impact Validation of Computational Approaches for Antiretroviral Dose Optimization. Siccardi M, Dickinson L, Owen A. Antimicrob Agents Chemother. 2016 May 23;60(6):3838-9. doi: 10.1128/AAC.00094-16. Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study. Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, Khoo S, Back D, Orrell C, Clarke A, Losso M, Phanuphak P, Carey D, Cooper DA, Emery S, Puls R. Clin Pharmacokinet. 2016 Jul;55(7):861-73. doi: 10.1007/s40262-015-0360-5. Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study. Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, Khoo S, Back D, Orrell C, Clarke A, Losso M, Phanuphak P, Carey D, Cooper DA, Emery S, Puls R; ENCORE1 Study Group. Clin Pharmacol Ther. 2015 Oct;98(4):406-16. doi: 10.1002/cpt.156. Epub 2015 Jul 14. Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. Winston A, Amin J, Clarke A, Else L, Amara A, Owen A, Barber T, Jessen H, Avihingsanon A, Chetchotisakd P, Khoo S, Cooper DA, Emery S, Puls R; ENCORE Cerebrospinal Fluid (CSF) Substudy Team; ENCORE Cerebrospinal Fluid CSF Substudy Team. Clin Infect Dis. 2015 Apr 1;60(7):1026-32. doi: 10.1093/cid/ciu976.
Start Year 2013
 
Description Nigeria 
Organisation Obafemi Awolowo University
Country Nigeria 
Sector Academic/University 
PI Contribution Direct supervision of a PhD student (Adeniyi Olagunju) as well as pharmacokinetic and pharmacogenetic analysis of a cohort of HIV positive pregnant and postpartum women, and their breastfed infants. n, 2)All women were receiving efavirenz or nevirapine based therapy and the collaboration identified 1) differences in pharmacokinetics between pregnant and post partum wome exposure of infants to these drugs via breast milk, and 3) the pharmacogentic determinants of these endpoints. The student has now graduated from their PhD and returned to Nigeria. With our support he was awarded a Wellcome Trust Fellowship in 2017, enabling us to further develop the collaboration. A number of other grant proposals are also in development including an imminent application for an MRC/DFID African Leader Fellowship.
Collaborator Contribution All patients are recruited at the partners site and the original studentship was funded from Obafemi Awolowo University.
Impact Evaluation of universal versus genotype-guided efavirenz dose reduction in pregnant women using population pharmacokinetic modelling. Olagunju A, Schipani A, Bolaji O, Khoo S, Owen A. J Antimicrob Chemother. 2018 Jan 1;73(1):165-172. doi: 10.1093/jac/dkx334. PMID: 29029267 Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing African mother-infant pairs. Waitt C, Olagunju A, Nakalema S, Kyohaire I, Owen A, Lamorde M, Khoo S. J Antimicrob Chemother. 2018 Apr 1;73(4):1013-1019. doi: 10.1093/jac/dkx507. PMID: 29309634 Effect of Pregnancy on the Pharmacokinetic Interaction between Efavirenz and Lumefantrine in HIV-Malaria Coinfection. Adegbola A, Abutaima R, Olagunju A, Ijarotimi O, Siccardi M, Owen A, Soyinka J, Bolaji O. Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e01252-18. doi: 10.1128/AAC.01252-18. Print 2018 Oct. PMID: 30082286 Pharmacogenetics of artemether-lumefantrine influence on nevirapine disposition: Clinically significant drug-drug interaction? Abdullahi ST, Olagunju A, Soyinka JO, Bolarinwa RA, Olarewaju OJ, Bakare-Odunola MT, Owen A, Khoo S. Br J Clin Pharmacol. 2019 Mar;85(3):540-550. doi: 10.1111/bcp.13821. Epub 2019 Jan 2. PMID: 30471138 Arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of Rifapentine: a population pharmacokinetics analysis. Francis J, Zvada SP, Denti P, Hatherill M, Charalambous S, Mungofa S, Dawson R, Dorman S, Gupte N, Wiesner L, Jindani A, Harrison TS, Olagunju A, Egan D, Owen A, McIlleron HM. Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01964-18. doi: 10.1128/AAC.01964-18. [Epub ahead of print] PMID: 30670438 The Effect of Gene Variants on Levonorgestrel Pharmacokinetics when Combined with Antiretroviral Therapy containing Efavirenz or Nevirapine. Neary M, Lamorde M, Olagunju A, Darin KM, Merry C, Byakika-Kibwika P, Back DJ, Siccardi M, Owen A, Scarsi KK. Clin Pharmacol Ther. 2017 Feb 10. doi: 10.1002/cpt.667. [Epub ahead of print] Pharmacogenetics of nevirapine excretion into breast milk and infants' exposure through breast milk versus postexposure prophylaxis. Olagunju A, Khoo S, Owen A. Pharmacogenomics. 2016 Jun;17(8):891-906. doi: 10.2217/pgs-2015-0016. Pregnancy affects nevirapine pharmacokinetics: evidence from a CYP2B6 genotype-guided observational study. Olagunju A, Bolaji O, Neary M, Back D, Khoo S, Owen A. Pharmacogenet Genomics. 2016 Aug;26(8):381-9. doi: 10.1097/FPC.0000000000000227. The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children. Bienczak A, Cook A, Wiesner L, Olagunju A, Mulenga V, Kityo C, Kekitiinwa A, Owen A, Walker AS, Gibb DM, McIlleron H, Burger D, Denti P. Br J Clin Pharmacol. 2016 Jul;82(1):185-98. doi: 10.1111/bcp.12934. Class-specific relative genetic contribution for key antiretroviral drugs. Siccardi M, Olagunju A, Simiele M, D'Avolio A, Calcagno A, Di Perri G, Bonora S, Owen A. J Antimicrob Chemother. 2015 Nov;70(11):3074-9. doi: 10.1093/jac/dkv207. Epub 2015 Jul 28. Validation and clinical application of a method to quantify nevirapine in dried blood spots and dried breast-milk spots. Olagunju A, Amara A, Waitt C, Else L, Penchala SD, Bolaji O, Soyinka J, Siccardi M, Back D, Owen A, Khoo S. J Antimicrob Chemother. 2015 Oct;70(10):2816-22. doi: 10.1093/jac/dkv174. Epub 2015 Jun 24. Breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in genetically defined subgroups of mother-infant pairs: an observational study. Olagunju A, Bolaji O, Amara A, Waitt C, Else L, Adejuyigbe E, Siccardi M, Back D, Khoo S, Owen A. Clin Infect Dis. 2015 Aug 1;61(3):453-63. doi: 10.1093/cid/civ317. Epub 2015 Apr 16. Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics. Olagunju A, Bolaji O, Amara A, Else L, Okafor O, Adejuyigbe E, Oyigboja J, Back D, Khoo S, Owen A. Clin Pharmacol Ther. 2015 Mar;97(3):298-306. doi: 10.1002/cpt.43. Epub 2015 Jan 20. Development, validation and clinical application of a novel method for the quantification of efavirenz in dried breast milk spots using LC-MS/MS. Olagunju A, Bolaji OO, Amara A, Waitt C, Else L, Soyinka J, Adeagbo B, Adejuyigbe E, Siccardi M, Back D, Owen A, Khoo S. J Antimicrob Chemother. 2015 Feb;70(2):555-61. doi: 10.1093/jac/dku420. Epub 2014 Oct 17. CYP3A4*22 (c.522-191 C>T; rs35599367) is associated with lopinavir pharmacokinetics in HIV-positive adults. Olagunju A, Schipani A, Siccardi M, Egan D, Khoo S, Back D, Owen A. Pharmacogenet Genomics. 2014 Sep;24(9):459-63. doi: 10.1097/FPC.0000000000000073. CYP2B6 516G>T (rs3745274) and smoking status are associated with efavirenz plasma concentration in a Serbian cohort of HIV patients. Olagunju A, Siccardi M, Amara A, Jevtovic D, Kusic J, Owen A, Dragovic G. Ther Drug Monit. 2014 Dec;36(6):734-8. doi: 10.1097/FTD.0000000000000098. Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz. Siccardi M, Olagunju A, Seden K, Ebrahimjee F, Rannard S, Back D, Owen A. In Silico Pharmacol. 2013 Mar 1;1:4. doi: 10.1186/2193-9616-1-4. eCollection 2013. Potential effect of pharmacogenetics on maternal, fetal and infant antiretroviral drug exposure during pregnancy and breastfeeding. Olagunju A, Owen A, Cressey TR. Pharmacogenomics. 2012 Oct;13(13):1501-22. doi: 10.2217/pgs.12.138. Review.
Start Year 2013
 
Description Ottawa 
Organisation University of Ottawa
Department Ottawa Health Research Institute
Country Canada 
Sector Academic/University 
PI Contribution Collaboration was established as a 3-way partnership with Santiago that has resulted in 1 paper and another currently under review. Our group conducts genetic analysis on samples provided by Santiago and bioanalysis (plasma drug concentrations) are monitored in Ottawa. Beyond this, Dr Owen has now established additional collaboration with Ottawa in terms of intestinal biopsies being sent for analysis in Liverpool to assess impact of intestinal expression of drug dispostiion genes on plasma HIV drug concentrations. A manuscript on this second phase of collaboration (not involving Santiago) is now also in preparation.
Collaborator Contribution The collaboration allowed us to identify a novel association between CAR polymorphism with efavirenz plasma concentrations and also to assess the contribution of other genetic factors in a resource limited setting (Chile). Beyond this Ottawa are now supplying intestinal biopsies from individuals that recieved lopinavir and ritonavir - samples of this nature are rare and will significantly add to our knowledge of the mechanisms controlling absorption of this important antiretroviral drug.
Impact Outputs: Cortes CP, Siccardi M, Chaikan A, Owen A, Zhang G, Porte CJ. Correlates of Efavirenz Exposure in Chilean Patients Affected With Human Immunodeficiency Virus Reveals a Novel Association With a Polymorphism in the Constitutive Androstane Receptor. Ther Drug Monit. 2012 Nov 20. [Epub ahead of print] Carr DF, la Porte CJ, Pirmohamed M, Owen A, Cortes CP. Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. J Antimicrob Chemother. 2010 Sep;65(9):1889-93. Epub 2010 Jul 17 Multidisiplinarity comes from expertise in genetics/gene expression (Liverpool) and clinical/bioanalytical (Ottawa).
Start Year 2009
 
Description Santiago 
Organisation Arriaran Foundation
Country Chile 
Sector Charity/Non Profit 
PI Contribution This collaboration was established as a result of the funding and resulted in a paper published in JAC and another paper that was recently submitted. Clinical samples are now being routinely supplied by the School of Medicine, University of Chile and Fundacio´n Arriara´n, Santiago, Chile. Our group continues to conduct pharmacogenetic studies with samples from Santiago in order to assess the impact on plasma drug concentrations.
Collaborator Contribution Identification of a novel association of CAR polymorphism with efavirenz plasma concentrations that is subsequently being assessed in other clinical cohorts in Liverpool. Also, the confirmation of associations with CYP2B6 in resource limited countries broaden the relevance of ongoing research.Identification of a novel association of CAR polymorphism with efavirenz plasma concentrations that is subsequently being assessed in other clinical cohorts in Liverpool. Also, the confirmation of associations with CYP2B6 in resource limited countries broaden the relevance of ongoing research.
Impact Output: Cortes CP, Siccardi M, Chaikan A, Owen A, Zhang G, Porte CJ. Correlates of Efavirenz Exposure in Chilean Patients Affected With Human Immunodeficiency Virus Reveals a Novel Association With a Polymorphism in the Constitutive Androstane Receptor. Ther Drug Monit. 2012 Nov 20. [Epub ahead of print] Carr DF, la Porte CJ, Pirmohamed M, Owen A, Cortes CP. Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. J Antimicrob Chemother. 2010 Sep;65(9):1889-93. Epub 2010 Jul 17 Multidisiplinarity comes from genetic (Liverpool) and clinical (Santiago) sites.
Start Year 2009
 
Description Santiago 
Organisation University of Chile
Department School of Medicine Chile
Country Chile 
Sector Academic/University 
PI Contribution This collaboration was established as a result of the funding and resulted in a paper published in JAC and another paper that was recently submitted. Clinical samples are now being routinely supplied by the School of Medicine, University of Chile and Fundacio´n Arriara´n, Santiago, Chile. Our group continues to conduct pharmacogenetic studies with samples from Santiago in order to assess the impact on plasma drug concentrations.
Collaborator Contribution Identification of a novel association of CAR polymorphism with efavirenz plasma concentrations that is subsequently being assessed in other clinical cohorts in Liverpool. Also, the confirmation of associations with CYP2B6 in resource limited countries broaden the relevance of ongoing research.Identification of a novel association of CAR polymorphism with efavirenz plasma concentrations that is subsequently being assessed in other clinical cohorts in Liverpool. Also, the confirmation of associations with CYP2B6 in resource limited countries broaden the relevance of ongoing research.
Impact Output: Cortes CP, Siccardi M, Chaikan A, Owen A, Zhang G, Porte CJ. Correlates of Efavirenz Exposure in Chilean Patients Affected With Human Immunodeficiency Virus Reveals a Novel Association With a Polymorphism in the Constitutive Androstane Receptor. Ther Drug Monit. 2012 Nov 20. [Epub ahead of print] Carr DF, la Porte CJ, Pirmohamed M, Owen A, Cortes CP. Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. J Antimicrob Chemother. 2010 Sep;65(9):1889-93. Epub 2010 Jul 17 Multidisiplinarity comes from genetic (Liverpool) and clinical (Santiago) sites.
Start Year 2009
 
Description Torino 
Organisation University of Turin
Department Department of Infectious Diseases
Country Italy 
Sector Academic/University 
PI Contribution My team and I are conducting genotyping on patients from Torino. We also contribute to the analysis, interpretation and manuscript writing.
Collaborator Contribution Our clinical collaborators in Italy have and continue to conduct patient recruitment, drug concentration analysis and supply biological material in terms of patient whole blood. Patient demographic data and data relating to therapy response are also provided.
Impact Class-specific relative genetic contribution for key antiretroviral drugs. Siccardi M, Olagunju A, Simiele M, D'Avolio A, Calcagno A, Di Perri G, Bonora S, Owen A. J Antimicrob Chemother. 2015 Nov;70(11):3074-9. doi: 10.1093/jac/dkv207. Epub 2015 Jul 28. Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting. Siccardi M, D'Avolio A, Rodriguez-Novoa S, Cuenca L, Simiele M, Baietto L, Calcagno A, Moss D, Bonora S, Soriano V, Back DJ, Owen A, Di Perri G. Ther Drug Monit. 2012 Apr;34(2):232-5. doi: 10.1097/FTD.0b013e31824aa50a. Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M, Hopper-Borge E, Bonora S, Di Perri G, Back DJ, Khoo S, Pirmohamed M, Owen A. J Infect Dis. 2011 Jul 1;204(1):145-53. doi: 10.1093/infdis/jir215. Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism. Siccardi M, D'Avolio A, Nozza S, Simiele M, Baietto L, Stefani FR, Moss D, Kwan WS, Castagna A, Lazzarin A, Calcagno A, Bonora S, Back D, Di Perri G, Owen A. Pharmacogenet Genomics. 2010 Dec;20(12):759-65. doi: 10.1097/FPC.0b013e3283402efb. Population pharmacokinetic modeling of the association between 63396C->T pregnane X receptor polymorphism and unboosted atazanavir clearance. Schipani A, Siccardi M, D'Avolio A, Baietto L, Simiele M, Bonora S, Rodríguez Novoa S, Cuenca L, Soriano V, Chierakul N, Saguenwong N, Chuchuttaworn C, Hoskins JM, Dvorak AM, McLeod HL, Davies G, Khoo S, Back DJ, Di Perri G, Owen A. Antimicrob Agents Chemother. 2010 Dec;54(12):5242-50. doi: 10.1128/AAC.00781-10. Epub 2010 Oct 4. Association of a single-nucleotide polymorphism in the pregnane X receptor (PXR 63396C-->T) with reduced concentrations of unboosted atazanavir. Siccardi M, D'Avolio A, Baietto L, Gibbons S, Sciandra M, Colucci D, Bonora S, Khoo S, Back DJ, Di Perri G, Owen A. Clin Infect Dis. 2008 Nov 1;47(9):1222-5. doi: 10.1086/592304. Detection of low-frequency K103N mutants after unstructured discontinuation of efavirenz in the presence of the CYP2B6 516 TT polymorphism. Garcia-Diaz A, Lok CB, Madge S, Booth C, Tyrer M, Bonora S, Mahungu T, Owen A, Johnson M, Geretti AM. J Antimicrob Chemother. 2008 Dec;62(6):1188-90. doi: 10.1093/jac/dkn374. Epub 2008 Sep 10. Erratum in: J Antimicrob Chemother. 2011 Mar;66(3):688. The collaboration is multdiciplinary in terms of pharmacology (Liverpool and Torino) and clinical (Torino). The collaboration has yielded four research publications to date with more papers planned for the near future.
Start Year 2006
 
Description University Hospital Basel 
Organisation University of Basel
Department University Hospital Basel
Country Switzerland 
Sector Hospitals 
PI Contribution Our team are leading the physiologically-based pharmacokinetic assessments to further understand and predict pharmacokinetic drug-drug interactions in special populations including pregnancy, paediatrics and aging populations.
Collaborator Contribution The partners are contributing complementary knowledge and expertise in terms of clinical perspectives.
Impact Analysis of Clinical Drug-Drug Interaction Data To Predict Magnitudes of Uncharacterized Interactions between Antiretroviral Drugs and Comedications. Stader F, Kinvig H, Battegay M, Khoo S, Owen A, Siccardi M, Marzolini C. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: e00717-18. doi: 10.1128/AAC.00717-18. Print 2018 Jul. PMID: 29686151
Start Year 2017
 
Title COMPOSITIONS OF EFAVIRENZ 
Description The present inventions relates to a solid composition and an aqueous dispersion comprising nanoparticles of the anti-retroviral drug efavirenz. The solid composition and aqueous dispersion additionally comprise a mixture of a hydrophilic polymer and a surfactant. The surfactant is selected from vitamin-E-polyethylene glycol-succinate (Vit- E-PEG-succinate), a polyoxyethylene sorbitan fatty acid ester, N-alkyldimethylbenzylammonium chloride, sodium deoxycholate, dioctyl sodium sulfosuccinate, polyethyleneglycol-12-hydroxystearate, polyvinyl alcohol (PVA), and a block copolymer of polyoxyethylene and polyoxypropylene, or a combination thereof. The hydrophilic polymer is suitably selected from polyvinyl alcohol (PVA), a polyvinyl alcohol-polyethylene glycol graft copolymer, a block copolymer of polyoxyethylene and polyoxypropylene, polyethylene glycol, hydroxypropyl methyl cellulose (HPMC), and polyvinylpyrrolidone, or a combination thereof. The present invention also relates to processes for preparing both the solid composition and the aqueous dispersion, as well as to their use in therapy for the treatment and/or prevention of retroviral infections such as human immunodeficiency virus (HIV). 
IP Reference WO2013034925 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact The patent is supporting a human clinical trial and has initiated interest from global charities and the NIH (US)
 
Title COMPOSITIONS OF LOPINAVIR 
Description The present invention relates to a solid composition and an aqueous dispersion comprising nanoparticles of the anti-retroviral drug lopinavir. The solid composition and aqueous dispersion additionally comprise a mixture of a hydrophilic polymer and a surfactant. The surfactant is selected from vitamin-E-polyethylene glycol-succinate (Vit- E-PEG-succinate), a polyoxyethylene sorbitan fatty acid ester, N- alkyldimethylbenzylammonium chloride, sodium deoxycholate, dioctyl sodium sulfosuccinate, polyethyleneglycol-12-hydroxystearate, polyvinyl alcohol (PVA), and a block copolymer of polyoxyethylene and polyoxypropylene, or a combination thereof. The hydrophilic polymer is suitably selected from polyvinyl alcohol (PVA), a polyvinyl alcohol-polyethylene glycol graft copolymer, a block copolymer of polyoxyethylene and polyoxypropylene, polyethylene glycol, hydroxypropyl methyl cellulose (HPMC), and polyvinylpyrrolidone, or a combination thereof. The present invention also relates to processes for preparing both the solid composition and the aqueous dispersion, as well as to their use in therapy for the treatment and/or prevention of retroviral infections such as human immunodeficiency virus (HIV). 
IP Reference WO2013034926 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact This patent is underpinning a human clinical trial and has attracted considerable global interest from charities and NIH (US)
 
Title COMPOSITIONS OF LOPINAVIR AND RITONAVIR 
Description The present inventions relates to a solid compn. and an aq. dispersion comprising nanoparticles of the antiretroviral drugs lopinavir and ritonavir. The solid compn. and aq. dispersion addnl. comprise a mixt. of a hydrophilic polymer and a surfactant. The surfactant is selected from vitamin-E-polyethylene glycol succinate (Vit-E-PEG-succinate), a polyoxyethylene sorbitan fatty acid ester, N-alkyldimethylbenzylammonium chloride, sodium deoxycholate, dioctyl sodium sulfosuccinate, polyeth 
IP Reference WO2013034927 
Protection Patent application published
Year Protection Granted 2014
Licensed No
Impact Much interest in this patent application as part of a larger portfolio and negotiations to progress to human trials are ongoing
 
Title NANOPARTICLES 
Description The present invention relates to a porous composite material comprising a hydrophilic carrier carrying a magnetic material. The porous composite material can include a hydrophobic polymer, hydrophobic material, organic compound, and/or pharmaceutically active ingredient. The porous composite material is prepared by a modified emulsion templating and freeze-drying procedure. Magnetic nanoparticles are released from the porous composite material on application of water. 
IP Reference WO2012143733 
Protection Patent granted
Year Protection Granted 2012
Licensed No
Impact The patent application was marketed and latterly allowed to lapse
 
Company Name Tandem Nano Ltd 
Description Tandem Nano Ltd is a nanoformulation company aiming to improve the action, delievry, use and behaviour of poorly soluble compounds 
Year Established 2014 
Impact Currently negotiating meaningful interactions with numerous global companies
Website http://www.tandemnano.com/
 
Description 2bio 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Approximately 50 representatives from local businesses attended this talk about how our research may interface with what their commercial ambitions. The talked sparked interest and discussion and interfaced with a networking event run on the same evening.

The potential for collaboration is now being discussed with a number of attendees.
Year(s) Of Engagement Activity 2012
 
Description IFARA interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact A podcast interview that was published online at http://www.ifarablog.org/2010/02/pharmacogenetics-upcoming-applications.html

Patients requested additional information about pharmacogenetic research in HIV
Year(s) Of Engagement Activity 2010
 
Description Little Big Medicine 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact The University of Liverpool event was co-ordinated with ISTH meeting. Approximately 60 teachers and pupils attended this talk on our scientific research (layman language). The talk preceded a formalised question, answer and discussion session with which the audience (particularly the pupils) fully engaged.

A huge level of interest was received from the students at the event and this was evidenced by lots of extremely well informed and logical questions from the pupils during the Q&A. As a result of the session, two students request work experience in my laboratory over the summer period.
Year(s) Of Engagement Activity 2012
 
Description Wales Gene Park 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A public engagement lay presentation on the role of pharmacogenetics in tailoring infectious diseases therapy.
Year(s) Of Engagement Activity 2016