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

Abstract

Schistosomiasis is a parasitic disease infecting over 236 million people annually, with the majority affected residing on the African continent. Control of this disease is reliant on the drug praziquantel (PZQ), with treatment success dependent on an individual reaching PZQ concentrations lethal to schistosomes. Despite the complete reliance on PZQ to treat schistosomiasis in Africa, the characterization of the pharmacogenetics associated with PZQ metabolism in African populations has been sparse. We aimed to characterize genetic variation in the drug-metabolising cytochrome P450 enzymes (CYPs) and determine the association between each variant and the efficacy of PZQ treatment in Zimbabwean patients exposed to Schistosoma haematobium infection. Genomic DNA from blood samples of 114 case-control Zimbabweans infected with schistosomes were sequenced using the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genes as targets. Bioinformatic tools were used to identify and predict functional effects of detected single nucleotide polymorphisms (SNPs). A random forest (RF) model was then used to assess SNPs most predictive of PZQ efficacy, with a misclassification rate of 29%. SNPs were detected across all six genes, with 70 SNPs identified and multiple functional changes to the CYP enzymes predicted. Only four SNPs were significantly associated with PZQ efficacy using χ2 tests, with rs951840747 (OR: 3.61, p = 0.01) in the CYP1A2 gene having the highest odds of an individual possessing this SNP clearing infection, and rs6976017 (OR: 2.19, p = 0.045) of CYP3A5 determined to be the most predictive of PZQ efficacy via the RF. Only the rs28371702 (CC) genotype (OR: 2.36, p = 0.024) of CYP2D6 was significantly associated with an unsuccessful PZQ treatment. This study adds to the genomic characterization of the diverse populations in Africa and identifies variants relevant to other pharmacogenetic studies crucial for the development and usage of drugs in these populations.

Safety and infectivity of female cercariae in Schistosoma-naïve, healthy participants: a controlled human Schistosoma mansoni infection study

“…Another explanation for the reduced susceptibility may be the location of the worms: single-sex female worms may be unable to migrate to the mesenteric vessels and stay in the liver, where the effective drug concentration is lower due to high first-pass effect of PZQ. Other individual pharmacogenetic factors, particularly in drug-metabolising cytochrome P450 enzymes, have also been found to influence effective drug concentrations, 28 however given the high frequency of PZQ failure in our study, this seems unlikely as a single cause of drug failure. Despite the excellent safety profile, the lack of cure after PZQ treatment unfortunately precludes the use of the female-only CHI-S model at a larger scale.…”

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

“…Genes coding for these metabolizing enzymes are genetically polymorphic. Thus, investigating the effect of genetics on PZQ exposure is important, especially in the genetically diverse SSA population 20 , 21 , and variations in treatment outcomes have been reported 13 . Moreover, the African continent contributes more than 90% of the global disease burden 4 , and Preventive chemotherapy through MDA campaigns periodically without prior diagnosis to all at-risk children living in endemic areas.…”

“…Genetic variations influence variability in drug exposure and treatment response of various infectious diseases 15 – 17 . However, data on the importance of genetic variation for variability in PZQ plasma exposure between populations and individuals is scarce 18 – 21 . Assessing the importance of genetic and non-genetic factors that influence variation in PZQ exposure in genetically diverse populations of Africa, where the disease is most prevalent, is imperative 22 to optimize treatment 23 .…”

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans

“…Tis has, in past years, stimulated stakeholder interest and funds have been mobilised to support research in these areas. Researchers across Africa have actively participated in pharmacogenetic research in this area with emanated dosing guidelines for efavirenz and praziquantel [150][151][152], which have found their way into the clinic. Te same could also be realised for hypertension, where genetics could inform therapy seeing that it has now been "dubbed" a major public health concern in Africa after HIV/AIDs [3,6].…”