Abstract
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 Schistosoma mansoni 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 trans-4-OH-PZQ concentrations were quantified using UPLCMS/MS. Genotyping for CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), and CYP2C9 (*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 (trans-4-OH-PZQ/PZQ). PZQ concentration was significantly higher among CYP2C19 (*2, *3) carriers than CYP2C19 *1/*1 and CYP2C19 *17 carriers (ultra-rapid metabolizers) (p = 0.04). The metabolic ratio was significantly higher among CYP2C19*17 carriers than CYP2C19 (*2, *3) carriers (p = 0.01). No significant effect of CYP3A4, CYP3A5, CYP2C19, and CYP2C9 genotypes on treatment efficacy or adverse events were observed. Baseline infection intensity and CYP3A5 genotype were significant predictors of treatment associated-adverse events. In conclusion, CYP2C19 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.
Highlights
Since 1984, praziquantel (PZQ) has been used in large-scale mass drug administration (MDA) programs for the treatment, control, and prevention of schistosomiasis worldwide (WHO, 2015)
We report the first pharmacogenetics study of PZQ and its relevance on plasma drug concentrations, treatment efficacy defined by cure rates, and adverse events among Schistosoma mansoni infected children treated with single-dose PZQ in Tanzania
We investigated the effect of pharmacogenetics variations on PZQ pharmacokinetics and its treatment outcomes among schistosomiasis infected school-aged children
Summary
Since 1984, praziquantel (PZQ) has been used in large-scale mass drug administration (MDA) programs for the treatment, control, and prevention of schistosomiasis worldwide (WHO, 2015). PZQ is the only drug of choice recommended by the World Health Organization (WHO) (WHO, 2015). PZQ is reported to be safe and efficacious against all Schistosoma species, including Schistosoma haematobium (urogenital schistosomiasis) and Schistosoma mansoni (intestinal schistosomiasis). More than 800 million people are at risk of schistosomiasis infection, and about 250 million are infected and need treatment (Hotez et al, 2014; Mazigo, 2019). The disease is still endemic throughout the country despite ongoing interventions (Mazigo et al, 2012; Mnkugwe et al, 2020b). In 2017, approximately 99 million people of whom 81.1 million were school-aged children, received treatment worldwide (WHO, 2018). The WHO target is to control (heavy infections
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