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Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models.

ABSTRACT: Schistosomiasis control is heavily reliant on the drug praziquantel (PZQ), which is used as preventive chemotherapy as part of national helminth control strategies. Given the heavy reliance on PZQ for mass drug administration, there has been considerable research on the potential of parasites developing resistance to the drug, resulting in decreased drug efficacy. However, there have been comparatively fewer studies of other factors that can potentially alter PZQ efficacy. Here, we investigate whether host PZQ metabolism contributes towards variable cure rates. We evaluate factors that can influence the metabolism of PZQ and the resultant effect on the efficacy of PZQ treatment to determine factors that potentially influence an individual's response to the drug. The literature search was directed at published studies from three online databases: Web of Science, PubMed, and EMBASE. The search terms for the review comprised of ([praziquantel OR PZQ] AND [schistosom* OR bilharzia] AND [pharmaco*]) and included studies evaluating PZQ metabolism. Publications were categorised into pharmacokinetics, drug-drug interactions, pharmacogenetics, and metabolite analysis. Forty publications describing human and experimental studies fitted the inclusion criteria and were subjected to data extraction and analysis. The analyses showed that variable exposure to PZQ was associated with alterations in the liver's capacity to metabolise PZQ and observed drug-drug interactions. Other factors influencing the efficacy of PZQ were brand, formulation, and co-administered food. Although some work has been performed on metabolite identification, there was minimal information on PZQ's metabolic pathway, and no pharmacogenetics studies were identified. The study indicated that in both human and experimental studies alterations in the liver's capacity to metabolise PZQ as well as drug-drug interactions affected systemic levels of PZQ that could result in variable cure rates. The study confirmed previous findings of higher antischistosomal activity of (R)-PZQ enantiomer when administered alone compared to the racemate at the same dose as well as improved efficacy when the drug is administered with food. The study also highlighted the need for more comprehensive studies of the PZQ metabolic pathway and PZQ pharmacogenetic studies in humans.

SUBMITTER: Zdesenko G

PROVIDER: S-EPMC7518612 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models.

Zdesenko Grace G Mutapi Francisca F

PLoS neglected tropical diseases 20200925 9

Schistosomiasis control is heavily reliant on the drug praziquantel (PZQ), which is used as preventive chemotherapy as part of national helminth control strategies. Given the heavy reliance on PZQ for mass drug administration, there has been considerable research on the potential of parasites developing resistance to the drug, resulting in decreased drug efficacy. However, there have been comparatively fewer studies of other factors that can potentially alter PZQ efficacy. Here, we investigate w ...[more]

PMID: 32976496

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Project description:BackgroundThere is a general consensus that widespread use of praziquantel in populations where schistosomiasis is endemic prevents development of hepatic schistosomiasis and its complications. However, a few studies have reported discordant findings linking praziquantel to the occurrence of upper gastrointestinal bleeding (UGIB) in some patients with hepatic schistosomiasis and varices.ObjectiveWe explored if there was any causal association between recent praziquantel use (rPZQ) and upper gastrointestinal bleeding in hepatic schistosomiasis in rural Africa.Patients and methodsA quasi-experimental, retrospective case-controlled study was performed. It involved adult patients with past or acute UGIB, varices, periportal fibrosis, and/or cirrhosis. Cases had acute variceal bleeding while controls did not. The outcome was the frequency of lifetime episodes of UGIB and exposure was rPZQ (received praziquantel in the last 11 months from the date of enrollment). The data analysis included 2 × 2 tables, logistic regression, and propensity-score matching. Odds ratios (ORs), average treatment effects (ATEs), and their 95% confidence intervals (CIs) were used for inference.ResultsOver 6 weeks, we enrolled 19 cases with 92 lifetime episodes of UGIB, and 66 controls with 192 lifetime episodes of UGIB. Cases were more likely to experience UGIB than controls following rPZQ (92% vs. 62%; OR 7.6; 95% CI 3.4-17). Factors predictive of more lifetime episodes of UGIB at multivariable analysis included rPZQ (adjusted OR 13; 95% CI 2.9-53), relative leukocytosis (adjusted OR 26; 95% CI 7.6-89), large varices (adjusted OR 5.0; 95% CI 1.7-15), a family member with hepatosplenic schistosomiasis (adjusted OR 19; 95% CI 7.4-51), advanced periportal fibrosis (adjusted OR 8.0; 95% CI 2.6-22), ascites (adjusted OR 14; 95% CI 4.3-47), and jaundice (adjusted OR 32; 95% CI 7.8-128). While the ATE following rPZQ among the treated was 0.40 (95% CI 0.33-0.48).ConclusionsOur findings suggest the presence of a plausible causal association between recent praziquantel use and increased frequency of UGIB in our study population.

Project description: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.

Project description:UnlabelledEach year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.ImportanceSchistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.

Project description:Historic data and baseline surveys showed schistosomiasis as highly/moderately endemic in 7 of 14 districts in Sierra Leone, justifying annual/biennial mass drug administration (MDA) with praziquantel. MDA commenced in 2009 and reported treatment coverage had been above the World Health Organization recommended 75% of target population. Assessment in 2012 showed significant reduction in infection. In 2016, another national school-based survey was conducted to evaluate the progress. Two schools from each category (high, moderate or low) of endemic communities in each MDA district and five schools in non-MDA districts were selected. Fifty children (25 boys and 25 girls) aged 9-14 years were randomly selected per school. Parasitological examination of 1,980 stool and 1,382 urine samples were conducted. Overall Schistosoma mansoni prevalence in the seven MDA districts decreased to 20.4% (95% CI: 18.7-22.3%) in 2016 from 42.2% (95% CI: 39.8-44.5%) at baseline (p < 0.0001). Mean overall S. mansoni intensity of infection reduced to 52.8 epg (95% CI: 43.2-62.4 epg) in 2016 from 100.5 epg (95% CI: 88.7-112.3 epg) at baseline (p < 0.001). The prevalence of Schistosoma haematobium in the five MDA districts that had baseline prevalence data decreased to 2.2% (95% CI: 1.5-3.1%) in 2016 from 18.3% (95% CI: 16.3-20.5%) at baseline (p < 0.0001). Mean overall intensity of infection increased to 1.12 e/10 ml (95% CI: 0.55-0.1.70 e/10 ml) in 2016 compared to 0.47 e/10 ml (95% CI: 0.16-0.78 e/10 ml) in 2012 (p < 0.05) (no baseline data). No district was highly endemic in 2016 compared to three at baseline and there was no significant difference in prevalence or intensity of infection by sex for both species. This survey illustrated the significant progress made in controlling schistosomiasis in Sierra Leone. The fact that prevalence and intensity of infection showed an increase from the 2010 level suggested a detrimental effect of missing MDA due to the Ebola toward schistosomiasis control. The national program needs to continue the treatment and adopt a comprehensive approach including water, hygiene, and sanitation measures to achieve control and elimination of schistosomiasis.

Dataset Information

Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models.

Publications

Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models.

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