MICA: NTD Highlight Notice - Defining PK/PD relationships of anti-leishmanial drugs - a novel approach for anti-leishmanial drug development
Lead Research Organisation:
London School of Hygiene & Tropical Medicine
Department Name: Infectious and Tropical Diseases
Abstract
Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. The disease has many forms, ranging from localized and self-healing cutaneous leishmaniasis (CL) to the systemic visceral leishmaniasis (VL), which is fatal if not treated. There are more than 12 million people at risk of disease worldwide and an estimated 50 000 deaths per year due to VL. There are no vaccines and there are few drugs available. All the drugs have limitations, for example, resistance, long treatment courses, toxicity, methods of administration and high cost. In humans the Leishmania parasites survive and multiply inside macrophage cells, which in case of VL are found in the liver, spleen and bone marrow.
For a drug to be effective it should ideally reach a concentration at the site of infection (it's pharmacokinetic property, PK) which can kill the parasite (it's pharmacodynamic property, PD) without being toxic to other parts of the body. The aim of a good dosing regimen is to deliver and keep effective drug levels at the site of infection to successfully kill all the parasites over several days. The aim of the chemists designing a new drug is to give it the properties that maximise its distribution to these sites of infection. The determination of the relationship between drug PKs and PDs is therefore important in both drug development and drug treatment.
Currently we know very little about the PKs and PDs of any of the drugs used for leishmaniasis and nothing about drug action and drug concentration at the site of infection. The dosing regimens used in treatments today have not been optimised based upon this PK PD understanding, which could lead to improved efficacy, lower toxicity, and less chance of resistance; the same applies to the design of drug combinations.
We aim to fill this knowledge gap by characterising the PK/PD relationships of established anti-leishmanial drugs and provision of predictive models that can be used in both drug development, by academic groups and the pharmaceutical industry, and in determining dose regimens and the best drug combinations.
We will ensure that the successfully established methods and models are made available to the academic community and pharmaceutical and biotechnology companies with programmes in this field. We intend to make a contribution to the more cost-effective and efficient development of novel and much-needed therapeutic agents for this neglected tropical disease.
For a drug to be effective it should ideally reach a concentration at the site of infection (it's pharmacokinetic property, PK) which can kill the parasite (it's pharmacodynamic property, PD) without being toxic to other parts of the body. The aim of a good dosing regimen is to deliver and keep effective drug levels at the site of infection to successfully kill all the parasites over several days. The aim of the chemists designing a new drug is to give it the properties that maximise its distribution to these sites of infection. The determination of the relationship between drug PKs and PDs is therefore important in both drug development and drug treatment.
Currently we know very little about the PKs and PDs of any of the drugs used for leishmaniasis and nothing about drug action and drug concentration at the site of infection. The dosing regimens used in treatments today have not been optimised based upon this PK PD understanding, which could lead to improved efficacy, lower toxicity, and less chance of resistance; the same applies to the design of drug combinations.
We aim to fill this knowledge gap by characterising the PK/PD relationships of established anti-leishmanial drugs and provision of predictive models that can be used in both drug development, by academic groups and the pharmaceutical industry, and in determining dose regimens and the best drug combinations.
We will ensure that the successfully established methods and models are made available to the academic community and pharmaceutical and biotechnology companies with programmes in this field. We intend to make a contribution to the more cost-effective and efficient development of novel and much-needed therapeutic agents for this neglected tropical disease.
Technical Summary
Leishmaniasis is caused by obligate intracellular parasites of the genus Leishmania. Visceral leishmaniasis (VL) is a systemic manifestation of disease with more than 50 000 deaths per year and fatal if not treated. There are no vaccines and few drugs available with severe limitations.
The full pharmacological profile of an anti-infective agent entails characterisation of its i) pharmacodynamics (PDs) and ii) pharmacokinetics (PKs). In antibiotic therapy PK/PD analysis has emerged as a new discipline which aims to understand the relationship between drug concentration and effect. This knowledge base can i) guide selection and optimisation of potential drug candidates, ii) provide the scientific rationale for selecting dosing regimens that increase efficacy and reduce probability of emerging drug resistance and iii) decrease the risk and cost of drug development. However current knowledge of the PK/PD basis of anti-leishmanial drug activity is severly limited.
We aim to fill this gap by defining PK/PD relationships of anti-leishmanial drugs as a novel approach for anti-leishmanial drug development. Our specific objectives are to characterise PK/PD relationships of established anti-leishmanial drugs in models of infection, construct PK/PD parameters that are predictive of clinical efficacy, perform dose simulation studies and provide a basis for refined lead optimisation and adjusted methodologies in the drug development process. We will then move to demonstrate that methodologies established can be translated into future anti-leishmanial lead optimisation, design of drug combinations and use for clinical trials. We will use a reverse translational approach with inclusion of clinical data for approved anti-leishmanial drugs, novel technologies for assessment of PKs and an iterative process in our investigations. The outcome of our studies will contribute to the understanding and refinement of the anti-leishmanial drug development process.
The full pharmacological profile of an anti-infective agent entails characterisation of its i) pharmacodynamics (PDs) and ii) pharmacokinetics (PKs). In antibiotic therapy PK/PD analysis has emerged as a new discipline which aims to understand the relationship between drug concentration and effect. This knowledge base can i) guide selection and optimisation of potential drug candidates, ii) provide the scientific rationale for selecting dosing regimens that increase efficacy and reduce probability of emerging drug resistance and iii) decrease the risk and cost of drug development. However current knowledge of the PK/PD basis of anti-leishmanial drug activity is severly limited.
We aim to fill this gap by defining PK/PD relationships of anti-leishmanial drugs as a novel approach for anti-leishmanial drug development. Our specific objectives are to characterise PK/PD relationships of established anti-leishmanial drugs in models of infection, construct PK/PD parameters that are predictive of clinical efficacy, perform dose simulation studies and provide a basis for refined lead optimisation and adjusted methodologies in the drug development process. We will then move to demonstrate that methodologies established can be translated into future anti-leishmanial lead optimisation, design of drug combinations and use for clinical trials. We will use a reverse translational approach with inclusion of clinical data for approved anti-leishmanial drugs, novel technologies for assessment of PKs and an iterative process in our investigations. The outcome of our studies will contribute to the understanding and refinement of the anti-leishmanial drug development process.
Planned Impact
The aim of the project is to develop a rodent model to define pharmacokinetic - pharmacodynamic (PK/PD) relationships of anti-leishmanial drugs. The output will be a predictive model which can be used to support pre-clinical development of novel anti-leishmanial compounds, in particular lead optimisation, as well to support clinical development, in particular guiding dose regimens.
Expected beneficiaries include i) the academic reputation of the LSHTM and UK contribution to research on neglected tropical diseases by leading cutting edge and innovative research, ii) academia, pharma industry, SMEs, PPPs and not for profit organisations concerned with the development of anti-leishmanial drugs and research on drugs for neglected diseases (University of Dundee, and worldwide, UCSF USA, DNDi, GSK Tres Cantos, GNF San Diego, GNF Novartis), will have access to a refined model to support anti-leishmanial drug development, iii) decision makers, for example PPPs and funders at national and international level who review programmes that decide which compounds / combinations to move forward by access to the evidence base provided by a predictive model, and iv) in the longer term patients in disease endemic areas, who will benefit from a higher success rate in drug development, decreased costs and drugs with improved profiles and dosing regimens for prevention of resistance and toxicity.
Timescales to realise these benefits are in short term (life time of the project and one year beyond) for points i) to ii), medium term (3-5 years and beyond) for point iii) and medium to long term (5-10 years) for point iv). The project will also generate long lasting impact by fostering collaboration between academia, SME and pharma and develop interdisciplinary research and communication skills of staff working in this setting.
Expected beneficiaries include i) the academic reputation of the LSHTM and UK contribution to research on neglected tropical diseases by leading cutting edge and innovative research, ii) academia, pharma industry, SMEs, PPPs and not for profit organisations concerned with the development of anti-leishmanial drugs and research on drugs for neglected diseases (University of Dundee, and worldwide, UCSF USA, DNDi, GSK Tres Cantos, GNF San Diego, GNF Novartis), will have access to a refined model to support anti-leishmanial drug development, iii) decision makers, for example PPPs and funders at national and international level who review programmes that decide which compounds / combinations to move forward by access to the evidence base provided by a predictive model, and iv) in the longer term patients in disease endemic areas, who will benefit from a higher success rate in drug development, decreased costs and drugs with improved profiles and dosing regimens for prevention of resistance and toxicity.
Timescales to realise these benefits are in short term (life time of the project and one year beyond) for points i) to ii), medium term (3-5 years and beyond) for point iii) and medium to long term (5-10 years) for point iv). The project will also generate long lasting impact by fostering collaboration between academia, SME and pharma and develop interdisciplinary research and communication skills of staff working in this setting.
People |
ORCID iD |
Simon Croft (Principal Investigator) | |
Karin Seifert (Co-Investigator) |
Publications
Ashwin H
(2019)
Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis
in Wellcome Open Research
Ashwin H
(2018)
Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis
in Wellcome Open Research
Croft S
(2017)
[Design of treatments for cutaneous and visceral leishmaniasis].
in Nihon yakurigaku zasshi. Folia pharmacologica Japonica
Croft SL
(2018)
Leishmania and other intracellular pathogens: selectivity, drug distribution and PK-PD.
in Parasitology
Forrester S
(2019)
Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis.
in Wellcome open research
Koniordou M
(2017)
Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells
in Antimicrobial Agents and Chemotherapy
Prabowo S
(2019)
Historical BCG vaccination combined with drug treatment enhances inhibition of mycobacterial growth ex vivo in human peripheral blood cells
in Scientific Reports
Salguero FJ
(2018)
Histopathological and immunohistochemical characterisation of hepatic granulomas in Leishmania donovani-infected BALB/c mice: a time-course study.
in Parasites & vectors
Seifert K.
(2014)
Pharmacodynamics of single dose liposomal amphotericin B in a mouse model of visceral leishmaniasis
in ICAAC Abstracts 54th Conference
Description | MRC |
Amount | £500,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Department | MRC Confidence in Concept Scheme |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2015 |
End | 08/2016 |
Description | Marie Curie Fellowships |
Amount | € 100,000 (EUR) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 07/2015 |
End | 06/2018 |
Description | NC3Rs CRACK-IT |
Amount | £188,000 (GBP) |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 01/2015 |
End | 12/2017 |
Description | Tres Cantos Open Lab Foundation |
Amount | £158,000 (GBP) |
Funding ID | TC046 |
Organisation | Tres Cantos Open Lab Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2013 |
End | 12/2014 |
Description | A multiscale model to minimise animal usage in leishmaniasis drug development |
Organisation | University of York |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Animal models of infection and determination of PK PD relationships. |
Collaborator Contribution | Immunology of leishmaniasis, molecular biology of leishmaniasis and in silico computational biology and models. |
Impact | No outputs as the grant has only just been awarded in October 2014 |
Start Year | 2014 |
Description | In silico model to support drug development for leishmaniasis |
Organisation | Pharmidex |
Country | United Kingdom |
Sector | Private |
PI Contribution | University of York has developed an in silico model of liver infection with Leishmania parasites. This was developed initially for immunological studies. LSHTM and York University are now seeking to utilise the model for drug development . |
Collaborator Contribution | York are leading this project as they have developed the in silico model. LSHTM provides the drug development expertise. |
Impact | Two grant applications submitted (at November 2013) |
Start Year | 2013 |
Description | In silico model to support drug development for leishmaniasis |
Organisation | University of York |
Department | Centre for Immunology and Infection |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | University of York has developed an in silico model of liver infection with Leishmania parasites. This was developed initially for immunological studies. LSHTM and York University are now seeking to utilise the model for drug development . |
Collaborator Contribution | York are leading this project as they have developed the in silico model. LSHTM provides the drug development expertise. |
Impact | Two grant applications submitted (at November 2013) |
Start Year | 2013 |