Ongoing Research Projects

 

Pharmacogenetics in HIV/AIDS and TB treatment in Zimbabwe- Biomarkers for drug safety

Milcah Dhoro

Individuals vary in the way they respond to a drug. The differences in response to ART and anti-TB therapy can be attributed to several factors which include physiological factors (age, gender, body mass index, disease being treated, concomitant drugs) and environmental factors. Growing evidence suggests genetics to be one of the most important factors in determining efficacy and safety of drugs, with drug metabolizing enzymes (DMEs) and transporters playing a crucial role in drug exposure levels in patients, which in turn influence drug efficacy and safety. Genetic polymorphisms in the genes coding for the DMEs and transporters, have been shown to influence drug exposure levels hence potential biomarkers for efficacy and safety. The spectrum of adverse effects associated with ART and anti-TB therapy may vary between individuals, ethnic groups and gender. Most of ART and anti-TB drugs have high efficacy and safety in developed countries, primarily in Caucasian populations, but now being widely used in developing countries, where vast majority of HIV-infected people live. Some biomarkers have been established for known adverse reactions in these populations. However, in order to implement the concept of individualized therapy in our population, there is need to study these biomarkers and identify those with high predictive power for these adverse side effects. Findings from this study may be used to inform policy to guide the effective prescription of safer drugs with optimal therapeutic dosages.The aim of this project is to identify physiologic and/or genetic biomarkers with high specificity for adverse drug reactions associated with the use of ARVs and anti-TB drugs and to understand the molecular mechanisms underlying their associations. This is achieved by conducting a case-control study on prevalence, progression and severity of common adverse reactions (lipodystrophy, CNS, peripheral neuropathy, and hypersensitivity reactions) associated with anti-retroviral therapy (ART) and anti-TB treatment in outpatients in Zimbabwe. In addition, screening for some of the existing and new biomarkers for adverse events in HIV/AIDS and TB patients observed in other populations is also performed to understand the molecular mechanisms underlying their associations.



Population pharmacogenetics and pharmacokinetics of Rosuvastatin in African populations and Zimbabwean HIV/AIDS patients with dyslipidemia.

Nyarai Desiree Soko

The presence of cardiovascular disease among African populations is on an steady increase owing to numerous factors, chief among them changes in lifestyles and diet and the use of Highly Active Antiretroviral Therapy (HAART) among HIV positive patients. Consequently the use of statins is also on the increase. However, there is a great variation to the safe and efficacious use of the drugs along ethnic lines with pharmacogenetic data showing marked differences to the tolerance of Rosuvastatin between Asians and Caucasians. Consequently dose adjustments for the Asian populations have since been effected. Such data for African populations is still not yet available. My PhD project study therefore is designed to understand the pharmacokinetics of Rosuvastatin in African populations and the genetic variations responsible for these observed differences.



HIV drug resistance testing

Benjamin Chimukangara

My research has been focused on determining HIV-1 subtype C drug resistance mutations in treatment-experienced patients, analyzing patterns of the resistance mutations and relating the HIV drug resistance mutations to current treatment regimens.

My current research interests are focused on development of low-cost genotyping protocols for HIV drug resistance detection in treatment-experienced patients and understanding the impact of HIV drug resistance on the quality and clinical outcome of 1st and 2nd line therapies. This includes detection of minority variants with the use of Next Generation Sequencing (NGS) techniques, and the implications of minority variants on treatment outcome. I also have interest in the use of bioinformatics tools for large-scale data analysis, a skill that is vital for merging the informatics and biology disciplines in HIV epidemiological studies. The goal is to develop effective and affordable treatment monitoring methods that will help to predict treatment response, as well as to preserve and make maximum use of the limited drugs and resources currently available.

 

 

Praziquantel projects

Praziquantel is used in the treatment of schistosomiasis. It is on the WHO’s essential drug list and is the drug of choice in most countries because it is both affordable and effective against all five forms of parasites which cause the disease. However, when the drug is administered, only a very small percentage reaches the blood an intact molecule. This is because most of it is disintegrated by enzymes, mainly CYP1A2 and CYP3A4, in the liver during the “first pass effect”. This necessitates large doses of up to 1500mg of the drug in a single dose in order for it to be effective. The large dose is hard to handle, especially in children. At AiBST we are, in the following projects, aiming to learn more about pharmacokinetics and pharmacodynamics of praziquantel, ultimately seeking to improve schistosomiasis treatment.



Simulation of pharmacokinetic interactions of praziquantel with CYP inhibitors and inducers and field pharmacokinetics and pharmacodynamics of praziquantel in children in national mass drug administration programs in Zimbabwe

Masimirembwa, C., Njaanake, H.K., Hugues Dolgos, Reinhard-Rupp, J., Nleya L., Mafaiti, Z.

In this project we are conducting in silico drug-drug interaction simulations involving praziquantel as a victim drug and CYP450 inducers and inhibitors as perpetrator drugs based on in vitro metabolism data with a view to derive physiologically-based pharmacokinetic models that can reproduce observed in vivo interactions and predict likely interactions in children receiving praziquantel and anti-HIV and anti-TB drugs. We are also conducting population pharmacokinetics and pharmacokinetics of praziquantel in children in national mass administration programs with a view to evaluate co-variant determinants of drug exposure and efficacy.



Praziquantel Pharmacokinetics and CYP1A2, CYP3A4 Phenotyping in Rural and Urban Zimbabwean Populations.

Zibusiso Mafaiti

My project seeks to relate praziquantel pharmacokinetics to the CYP1A2 and CYP3A4 phenotype in rural Zimbabwean children, using a caffeine probe to determine the CYP1A2 phenotype and 4β-hydroxycholesterol as endogenous marker to evaluate the CYP3A4 phenotype. I have collected blood samples at 3 time points over a period of 4 hours (30 min, 1 h and 4 h post administration of praziquantel) from 300 children aged 6-15 years. I am currently analysing the plasma samples for obtaining the drug concentration and phenotype data.

 

 

Bioavailability and variability of Praziquantel pharmacokinetics due to drug-drug interactions

Lovejoy Nleya

This project seeks to address the issues of praziquantel by identifying the relevant enzymes in the liver which are responsible for breaking down the active chemical form of the drug. Once conclusively identified, a computer based approach called “pharmacokinetic modelling and simulation” will be used to come up with an optimal way of administering the drug without using such large doses. The idea is to give the drug, together with other substances which inhibit those enzymes which are responsible for depleting it, so that the same blood concentrations are achieved with a smaller dose.