AUTHOR=Mnkugwe Rajabu Hussein , Minzi Omary , Kinung’hi Safari , Kamuhabwa Appolinary , Aklillu Eleni 

TITLE=Effect of Pharmacogenetics Variations on Praziquantel Plasma Concentrations and Schistosomiasis Treatment Outcomes Among Infected School-Aged Children in Tanzania

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.712084

DOI=10.3389/fphar.2021.712084

ISSN=1663-9812

ABSTRACT=<p>Studies on pharmacogenetics of praziquantel (PZQ) and its relevance on plasma drug concentrations and schistosomiasis treatment outcomes are lacking. We investigated the effect of pharmacogenetics variations of PZQ on plasma drug levels and schistosomiasis treatment outcomes among infected Tanzanian school-aged children. A total of 340 <italic>Schistosoma mansoni</italic> infected children were enrolled and treated with single-dose PZQ. Stool samples analysis was done by thick smear Kato-Katz technique, and treatment efficacy was assessed at 3-weeks post-treatment. Safety was assessed within 4 h after PZQ intake. Plasma samples were collected at 4 h post-dose, and PZQ and <italic>trans</italic>-4-OH-PZQ concentrations were quantified using UPLCMS/MS. Genotyping for <italic>CYP3A4*1B</italic>, <italic>CYP3A5</italic> (*3, *6, *7), <italic>CYP2C19</italic> (*2, *3, *17), and <italic>CYP2C9</italic> (*2, *3) were done by Real-Time PCR. The median age (range) of the study participants was 12 years (7–17). There was a significant association of CYP2C19 genotypes with PZQ concentrations and its metabolic ratio (<italic>trans</italic>-4-OH-PZQ/PZQ). PZQ concentration was significantly higher among <italic>CYP2C19</italic> (*2, *3) carriers than <italic>CYP2C19 *1/*1</italic> and <italic>CYP2C19 *17</italic> carriers (ultra-rapid metabolizers) (<italic>p</italic> = 0.04). The metabolic ratio was significantly higher among <italic>CYP2C19*17</italic> carriers than <italic>CYP2C19</italic> (*2, *3) carriers (<italic>p</italic> = 0.01). No significant effect of <italic>CYP3A4</italic>, <italic>CYP3A5</italic>, <italic>CYP2C19</italic>, and <italic>CYP2C9</italic> genotypes on treatment efficacy or adverse events were observed. Baseline infection intensity and <italic>CYP3A5</italic> genotype were significant predictors of treatment associated-adverse events. In conclusion, <italic>CYP2C19</italic> genotype significantly affects plasma PZQ concentration and its metabolic ratio. For the first time, we report the importance of pharmacogenetic variation for the treatment of schistosomiasis, a neglected tropical disease.</p>