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

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.

Safety of Praziquantel and Albendazole Coadministration for the Control and Elimination of Schistosomiasis and Soil-Transmitted Helminths Among Children in Rwanda: An Active Surveillance Study

“…The most observed AEs in our study were headache (21%), dizziness or fainting (15.2%), nausea (12.8%), and stomach pain (12.2%), as similarly reported by other studies from Angola, Ethiopia, Kenya, and Tanzania [ 19 , 24 , 25 , 34 ]. Wide interindividual variations in plasma praziquantel concentrations partly due to pharmacogenetic variations has recently been reported [ 41 , 42 ]. Any association of praziquantel pharmacokinetics and pharmacogenetic variation with susceptibility to treatment-induced AEs remains to be investigated.…”

Safety and Tolerability of Ivermectin and Albendazole Mass Drug Administration in Lymphatic Filariasis Endemic Communities of Tanzania: A Cohort Event Monitoring Study

“…The safety profile of drugs used in public health programs vary between individuals and populations due to host-genetic and environmental factors, including coinfection, comorbidity, and drug-interactions and the use of traditional medicines, which is common in Africa [ 19 , 20 , 21 , 22 , 23 ]. Poor safety surveillance of medicines during MDA campaigns and the under-reporting rate of AEs in SSA makes it challenging to accurately estimate the risks of drugs used in MDA to inform healthcare policy and practice.…”

Pharmacogenetics of Praziquantel Metabolism: Evaluating the Cytochrome P450 Genes of Zimbabwean Patients During a Schistosomiasis Treatment

“…Since this review was published, only one study has been conducted that focused on the pharmacogenetics of PZQ and the treatment of schistosomiasis, despite this disease being the second most important parasitic infection on the continent afflicting over 207 million in sub-Saharan Africa ( Oyeyemi et al, 2020 ). The recent paper by Mnkugwe et al (2021) has presented the first example of pharmacogenetic influences on PZQ concentrations in patients in Tanzania, with CYP2C19*2/*3 genotypes confirmed to increase active PZQ concentrations compared to the CYP2C19*1 and CYP2C19*17 . This finding, and the fact that several studies have reported hotspots of persistent schistosome infections with CR lower than 100% across Africa ( Sang et al, 2014 ; Wiegand et al, 2017 ; Kittur et al, 2019 ; Knopp et al, 2019 ; Mawa et al, 2021 ) only further emphasises the need for research, and particularly pharmacogenetic research, to characterise the determinants of treatment efficacy.…”

“…Increased PZQ concentrations is commonly observed with other CYP polymorphisms, yet high plasma drug exposure may in fact increase the risk of adverse drug reactions (ADRs). PZQ has been known to cause treatment-related side effects including headaches, abdominal pain, and vomiting upon treatment for schistosomiasis ( Midzi et al, 2008 ), and one study concluded that the PZQ-metabolising CYP3A5*3/*6/*7 variants had a significantly higher number of ADRs than those with no defective alleles ( Mnkugwe et al, 2021 ). However, this study found no association with the CYP3A5 alleles and parent PZQ concentrations, it was postulated that increased concentrations of a metabolite was responsible for these adverse events.…”