Effect of pharmacogenetic variations on praziquantel plasma concentration and safety outcomes among school children in Rwanda

Barry, Abbie; Kabatende, Joseph; Telele, Nigus Fikrie; Mnkugwe, Rajabu Hussein; Mugisha, Michael; Ntirenganya, Lazare; Bienvenu, Emile; Aklillu, Eleni

doi:10.1038/s41598-023-28641-w

Cited by 3 publications

(6 citation statements)

References 42 publications

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“…The CYP2J2 *7 variant allele is reported to be associated with increased enzyme activity 34 , which is in line with our findings. A recent study reported the contribution of CYP2J2 genotype for PZQ metabolism though not statistically significant 31 . The significant association of CYP2J2 genotype with variability in PZQ plasma concentration in our study may indicate the contribution of CYP2J2 enzyme for PZQ metabolism.…”

Section: Discussionmentioning

confidence: 89%

“…The UPLC–MS/MS method of quantification of the analytes was done as described previously 20 , 31 . The calibration curves were constructed within the range of 2.4 to 2500 ng/mL for PZQ and cis -4-OH-PZQ, and from 24 to 25,000 ng/mL for trans -4-OH-PZQ, since the levels of trans- 4-OH-PZQ were very high in the samples.…”

Section: Methodsmentioning

confidence: 99%

“…The purity and quantity of the extracted DNA were measured using NanoDrop 2000 (Thermo Scientific, Saveen Warner, Sweden). Genotyping for the common functional variant alleles in genes coding for CYP enzymes relevant for PZQ disposition was performed using allelic discrimination TaqMan genotyping assays (Applied Biosystems, CA, USA) as previously discussed 20 , 31 .…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, genotyping was performed for CYP3A4 ( *1B ), CYP3A5 ( *3, *6 ), CYP2C19 ( *2, *3, *17 ), CYP2C9 ( *2, *3 ), and CYP2J2 ( *7 ) as described previously 20 , 31 . Genotyping for CYP3A5*7 was not done as previous studies reported its absence in the Ethiopian population 17 , 32 .…”

Section: Methodsmentioning

confidence: 99%

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CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children

Gebreyesus,

Makonnen,

Telele

et al. 2024

Sci Rep

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Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7–15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.

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Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children

Gebreyesus,

Makonnen,

Telele

et al. 2024

Sci Rep

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“…The difference in the PZQ treatment outcome between populations could be due to variability in infection intensity prevalence in different geo-locations, and the follow-up time in the study setting might contribute to the difference in ERR among pre-SAC infected with S. mansoni . Furthermore, recent studies highlight the importance of genetic variation for PZQ disposition [ 19 , 40 ], but the impact of genetic variations on PZQ treatment outcomes needs further investigation. Despite the relatively lower CR of pre-SAC with moderate-to-heavy intensity infection groups than the light-intensity infection, the moderate-to-heavy intensity showed satisfactory ERR.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of praziquantel treatment against Schistosoma mansoni infection among pre-school age children in southern Ethiopia

Tadele,

Astatkie,

Tadesse

et al. 2023

Trop Med Health

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Background Preventive chemotherapy with a single dose of praziquantel given to an all-at-risk population through mass drug administration is the cornerstone intervention to control and eliminate schistosomiasis as a public health problem. This intervention mainly targets school age children, and pre-school age children (pre-SAC) are excluded from receiving preventive chemotherapy, partly due to scarcity of data on praziquantel treatment outcomes. Methods We conducted active efficacy and safety surveillance of praziquantel treatment among 240 Schistosoma mansoni-infected pre-SAC who received a single dose of praziquantel (40 mg/kg) in southern Ethiopia. The study outcomes were egg reduction rates (ERR) and cure rates (CRs) four weeks after treatment using the Kato–Katz technique and treatment-associated adverse events (AEs) that occurred within 8 days post-treatment. Results The overall ERR was 93.3% (WHO reference threshold ≥ 90%), while the CR was 85.2% (95% CI = 80.0–89.5%). Baseline S. mansoni infection intensity was significantly associated with CRs, 100% among light infected than moderate (83.4%) or heavy (29.4%) infected children. An increase of 100 in baseline S. mansoni egg count per gram of stool resulted in a 26% (95% CI: 17%, 34%) reduction in the odds of cure. The incidence of experiencing at least one type of AE was 23.1% (95% CI: 18.0%, 29.0%). Stomachache, diarrhea, and nausea were the most common AEs. AEs were mild-to-moderate grade and transient. Pre-treatment moderate (ARR = 3.2, 95% CI: 1.69, 6.14) or heavy infection intensity (ARR = 6.5, 95% CI: 3.62, 11.52) was a significant predictor of AEs (p < 0.001). Sex, age, or soil-transmitted helminth coinfections were not significant predictors of CR or AEs. Conclusions Single-dose praziquantel is tolerable and effective against S. mansoni infection among pre-SAC, and associated AEs are mostly mild-to-moderate and transient. However, the reduced CR in heavily infected and AEs in one-fourth of S. mansoni-infected pre-SAC underscores the need for safety and efficacy monitoring, especially in moderate-to-high infection settings. Integrating pre-SACs in the national deworming programs is recommended to accelerate the elimination of schistosomiasis as a public health problem.

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Efficacy of Single-Dose Praziquantel for the Treatment of Schistosoma mansoni Infections among School Children in Rwanda

Kabatende,

Ntirenganya,

Mugisha

et al. 2023

Pathogens

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Preventive chemotherapy with single-dose praziquantel is the WHO-recommended intervention strategy to eliminate schistosomiasis as a public health problem in endemic countries. Surveillance of drugs used in mass drug administration (MDA) programs is recommended to evaluate its effectiveness in reducing transmissions. After a decade-long implementation of a school-based MDA program in Rwanda, we conducted efficacy surveillance of single-dose praziquantel MDA against S. mansoni infection. Two weeks before MDA, stool examinations were performed to screen MDA-eligible school children (n = 4998) for S. mansoni infection using the Kato–Katz technique, and 265 (6.5%) children tested positive for the infection. All children received praziquantel and albendazole as preventive chemotherapy through the MDA campaign. Infected children were enrolled and followed for efficacy monitoring, and stool examination was repeated after three weeks post-MDA (n = 188). Before treatment, 173 (92%) had a light infection, and 15 (8%) had a moderate infection intensity. The primary and secondary outcomes were parasitological cure and egg reduction rates at three weeks post-treatment. The overall cure and egg reduction rates for S. mansoni infection were 97.9% (95% CI = 94.6–99.4) and 97.02%, respectively. Among the 173 children with light infection intensity, 170 (98.3%, 95% CI = 95.0–99.6) were cured, and among the 15 children who had moderate infection intensity, 14 (93.3%) were cured. No significant association between cure rate and pre-treatment infection intensity was observed. We conclude that single-dose praziquantel is efficacious against light-to-moderate S. mansoni infection. Preventive chemotherapy with praziquantel effectively reduces schistosome reservoirs and transmission among school-age children.

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Effect of pharmacogenetic variations on praziquantel plasma concentration and safety outcomes among school children in Rwanda

Cited by 3 publications

References 42 publications

CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children

CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children

Efficacy and safety of praziquantel treatment against Schistosoma mansoni infection among pre-school age children in southern Ethiopia

Efficacy of Single-Dose Praziquantel for the Treatment of Schistosoma mansoni Infections among School Children in Rwanda

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