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					                                          JOB DESCRIPTION

Job title:              Research Assistant / Post Doctoral Research Assistant

Grade:                  Grade 6/ 7 (dependant on experience and qualifications)

Contract:               Fixed Term, three years from date of appointment

Group:                  Molecular and Biochemical Pharmacology

Responsible to:         Dr Ian Hastings (Dr Anja Terlouw)


Background Information

This project aims to identify optimal ways of deploying drugs against malaria.

Treatment of malaria has to ensure that patients receive sufficient amounts of the drug(s) to cure
the infection, but not so much drug that toxicity occurs. This is not easy to achieve.

Humans vary enormously in how they absorb and metabolise antimalarial drugs, and malaria
parasites vary enormously in their sensitivity to these drugs. Consequently, there is consideration
variation in what constitutes a minimum effective drug dosage in any given patient. We cannot
simply give everyone high drug dosages because most antimalarial drugs are toxic at higher
concentrations. Correct dosing is further complicated because antimalarial drugs generally have to
be distributed as tablets used to treat an entire ‘band’ of patient, where banding is usually in terms
of age, height or weight. Adults vary in weight from around 50 to 120Kg and the differences in
weights are proportionally much larger in paediatric treatment bands. The problem is therefore to
ensure treatment is successful in heavier members of the banding (who get lower drug dosages in
terms of bodyweight) while not poisoning lighter members of the banding (who get higher drug
doses in terms of bodyweight). Practical considerations of supply chains and ease of prescription in
resource-poor health systems mean we have to minimise the number of treatment bands while
avoiding under- and over-dosing within the bands.

We have building pharmacological models of antimalarial drug treatment, that should provide a
more objective method of designing these bandings, see:
Winter, K. and I. M. Hastings (2011). Development, evaluation and application of an in silico model
for antimalarial drug treatment and failure. Antimicrobial Agents & Chemotherapy 55: 3380-3392.
This methodology needs to be further developed in several key ways.

        We need to incorporate drug absorption, conversion and distribution phases; these
         determine peak serum concentrations that are markers of potential toxicity.

        Drugs only affect malaria parasites at certain stages of their 48hr development cycle and we
         need to incorporate this element of drug action.

        We need to mesh these models with age/height/weight growth curves obtained from
         several malaria-endemic countries.
We have resources to fund a RA/postdoctoral post. The ideal candidate would need a near-unique
set of skills: knowledge of malaria epidemiology and current antimalarial drug treatment protocols,
pharmacological modelling skills, an understanding of drug toxicity, programming skills in R, and
strong interpersonal skills. We doubt we will find anyone with exactly this set of skills so general
intelligence and an ability to learn and develop any missing skills will be an important element of
their personal profile


Responsibilities:

Develop an algebraic description of drug absorption, conversion, distribution, and elimination within
pharmacokinetic compartment models.

Develop a methodology that incorporates the parasite stage-sensitivity to drugs, and the putative
presence of insensitive ‘dormant’ parasite stages.

Formulate these models in the R statistical and simulation package, and link them to growth curves
describing age/height/weight obtained from malaria-endemic regions. The R programs must take
putative drug bandings as inputs and provide outputs of use to policy makers, putatively: proportion
of patients cured, proportion of patients receiving potentially mildly/moderately/grossly toxic drug
levels, the effectiveness of the drug regimens in the face of poor patient compliance.

Undertake an extensive literature review to find the means and distributions of the pharmacological
parameters in the models, and how these may change with patient age.

Review the literature on antimalarial drug toxicity to determine the likely key determinants of
toxicity (typically peak serum concentration and/or area under the drug concentration curves).

Extensively test the calibrated models to determine their robustness and to check their outputs are
consistent with results obtained from field and clinical and clinical studies.

Prepare the results for distribution/publication and interact with scientists involved in the drug
development and deployment processes.
PERSON SPECIFICATION
                         Research Associate in PK/PD modelling
                        (Molecular and Biochemical Parasitology)

                                    Essential                           Desirable

Education & training   BSc in Biology or Pharmacology,      PhD in Biology or Pharmacology
                       or equivalent degree in medical
                       or veterinary sciences.
Experience             Working to targets and deadlines.    Experience in PK/PD modelling
                                                            of drugs.

                                                            Preparation of manuscripts for
                                                            publication.

Skills & abilities     Excellent organisational skills.     Ability to use calculus to solve
                                                            time-dependent differential
                                                            equation often using Laplace
                                                            transforms.

Knowledge              Computer literate with               Knowledge        of       current
                       knowledge of Microsoft Office        antimalarial drug regimens and
                       applications.                        their PK/PD characteristics.

                                                            Knowledge of programming in
                                                            the open-source R language.

                                                            Understanding of malaria
                                                            epidemiology and control
                                                            interventions.

Special aptitude       Ability to use initiative and
                       organise own workload.

                       Ability to work as an integral and
                       co-operative member of a multi-
                       disciplinary research team.


Interests              Working with people/networking.

                       An interest in tropical diseases
                       and healthcare in developing
                       countries.


Circumstances          Fixed term – three years from
                       date of appointment

				
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posted:11/30/2011
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