Drug-drug interactions and pharmacogenetics of PZQ metabolism - implications for variable drug exposure and treatment outcomes in the treatment of sch

Schistosomiasis is a prevalent public health problem in sub-Saharan Africa which derives predominantly from parasitic schistosomes and soil transmitted helminths (STH). The current mass drug administration of praziquantel (PZQ) is dosed in combination with other medications and can lead to drug-drug interactions (DDI) that can potentially alter the bioavailability, efficacy, or toxicity of any/all of the drugs.
Data from several countries show variable PZQ efficacy within and between populations; with PZQ efficacy significantly reduced in some individuals. PZQ metabolism is rapid and highly variable in both children and adults resulting in possible differences in treatment outcome and of the drug's transient adverse effects. To date, there are no specific treatment guidelines for these individuals. The major enzymes involved in PZQ metabolism are the Cytochrome P450 (CYP) enzymes: CYP1A2, CYP2C19, CYP3A5, and CYP2D6. These enzymes are polymorphic and different variants are associated with alterations in the rate of PZQ metabolism, which in turn will determine PZQ efficacy. Thus there is a need to tailor the treatment regimens for optimal treatment outcome.
So the main objectives of this project are to evaluate the role of CYP1A2. CYP2C19, CYP3A4, CYP3A5, and CYP2D6 polymorphism in PZQ metabolism and pharmacokinetics (PK) in African children. Important to this factor will be the identification and quantification of PZQ metabolites in circulation following treatment with the standard dose of PZQ to the host genetic variants of CYP enzymes. This is with the eventual aim of quantifying the efficacy of PZQ in schistosome-infected children exhibiting different genetic variants of the CYP genes.
The study will then evaluate the effect of the genetic background on the extent of drug-drug interactions by genotyping samples from ongoing co-infection/comorbidity studies in Zimbabwe and archived samples from prostate cancer patients suffering from schistosomiasis. It will also determine the drugs commonly prescribed in people of different age groups treated for helminth infections in Zimbabwe and determine their co-mention in pharmacy records.
Overall this will provide a drug-drug-gene interaction picture that will help elucidate the nature, rate and mechanism of drug elimination. The results from this project will inform the tailoring of antihelminthic dosing regimen to maximise efficacy while minimising toxicity in people who do not optimally metabolise PZQ given under the current single dose regimen due to CYP genetic restriction or DDI.