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

School-based mass drug administration (MDA) of Praziquantel (PZQ) is the global intervention strategy for elimination of schistosomiasis. Genetic variations in drug metabolizing enzymes and transporter proteins influences drug exposure and treatment outcomes, but data on PZQ pharmacokinetics and safety outcomes are scarce. We investigated the effect of pharmacogenetics variations on PZQ plasma concentrations and safety outcomes among 462 Rwandan schoolchildren who received single dose PZQ and albendazole in MDA. Genotyping for common functional variant alleles CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3) and CYP2J2*7 were done. Plasma concentration of PZQ, cis-4-OH-PZQ and trans-4-OH-PZQ were measured using LC/MS/MS. Active safety monitoring was done on days 1, 2, and 7 post-MDA. CYP2C9 and CYP2C19 genotypes were significantly associated with PZQ plasma concentrations and its cis- and trans-4-OH-PZQ/PZQ metabolic ratios (MR). CYP2C9*2 and CYP2C9*3 carriers had significantly higher PZQ concentration (p = 0.02), lower trans-4-OH-PZQ/PZQ (p < 0.001), and cis-4-OH-PZQ/PZQ (p = 0.02) MR. CYP2C19 (*2, *3) carriers had significantly higher plasma PZQ concentration than CYP2C19 *1/*1 and CYP2C19 *17 carriers (*1/*17 or *17/*17) (p < 0.001). CYP3A4 was significantly associated with cis-4-OH-PZQ MR (p = 0.04). Lower cis-4-OH-PZQ/PZQ MR (p < 0.0001) was a predictor of MDA-associated adverse events, but no significant association with genotypes were found. In conclusion, CYP2C9 and CYP2C19 genotypes significantly influence the plasma PZQ concentration and its MR. Lower cis-4-OH-PZQ/PZQ MR is significant predictor of adverse events following MDA.

R-praziquantel integrated population pharmacokinetics in preschool- and school-aged African children infected with Schistosoma mansoni and S. haematobium and Lao adults infected with Opisthorchis viverrini.

Racemic praziquantel (PZQ) is the standard treatment for schistosomiasis and liver fluke infections (opisthorchiasis and clonorchiasis). The development of an optimal pediatric formulation and dose selection would benefit from a population pharmacokinetic (popPK) model. A popPK model was developed for R-PZQ, the active enantiomer of PZQ, in 664 subjects, 493 African children (2-15 years) infected with Schistosoma mansoni and S. haematobium, and 171 Lao adults (15-78 years) infected with Opisthorchis viverrini. Racemate tablets were administered as single doses of 20, 40 and 60 mg/kg in children and 30, 40 and 50 mg/kg in 129 adults, and as 3 × 25 mg/kg apart in 42 adults. Samples collected by the dried-blood-spot technique were assayed by LC-MS/MS. A two-compartment disposition model, with allometric scaling and dual first-order and transit absorption, was developed using Phoenix™ software. Inversely parallel functions of age described the apparent oral bioavailability (BA) and clearance maturation in children and ageing in adults. BA decreased slightly in children with dose increase, and by 35% in adults with multiple dosing. Crushing tablets for preschool-aged children increased the first-order absorption rate by 64%. The mean transit absorption time was 70% higher in children. A popPK model for R-PZQ integrated African children over 2 years of age with schistosomiasis and Lao adults with opisthorchiasis, and should be useful to support dose optimization in children. In vitro hepatic and intestinal metabolism data would help refining and validating the model in younger children as well as in target ethnic pediatric and adult groups.

Optimal single sampling time-point for monitoring of praziquantel exposure in children.

Praziquantel pharmacokinetics studies in schistosomiasis infected children are scarce partly due to the challenges/complexity of intensive blood sampling in the target population. This study was aimed to investigate the optimal single sampling time-point for monitoring praziquantel exposure. This was intensive pharmacokinetic study conducted among 32 Schistosoma mansoni infected children treated with an oral standard single-dose 40 mg/kg praziquantel. Plasma samples were collected at 0, 1, 2, 4, 6 and 8 h post-praziquantel administration. Quantification of praziquantel and its enantiomers (R- and S-praziquantel) concentrations was done by Liquid chromatography-tandem mass spectrometer (LC-MS/MS). The correlation between area under the plasma concentration-time curve from 0 to 8 h (AUC8) and plasma concentrations at each specific sampling time-point was determined by Pearson's correlation coefficient (r2). The median age (range) of the study population was 12.5 years (10-17). The study participants were 17 males and 15 females. Both total praziquantel and its enantiomers (R- and S-praziquantel) displayed a wide inter-individual pharmacokinetic variability. Regression analysis indicated that, plasma concentrations collected at 4 h post-dose had a significantly highest correlation with the AUC8 for both total praziquantel (r2 = 0.81, p < 0.001) and S-praziquantel (r2 = 0.84, p < 0.001) than any other sampling time-point; while for R-praziquantel, plasma concentrations collected at 6 h sampling time-point had a significantly highest correlation with the AUC8 (r2 = 0.79, p < 0.001) than any other sampling time-point. Four hours sampling time-point post-praziquantel administration is ideal optimal single sampling time-point for therapeutic monitoring of total praziquantel exposure while 6 h sampling time-point is suitable for monitoring of a pharmacologically active R-praziquantel enantiomer.

Clinically relevant enantiomer specific R- and S-praziquantel pharmacokinetic drug-drug interactions with efavirenz and ritonavir.

We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R- and S-PZQ in healthy male participants. This was toward evaluating the risk of drug-drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non-randomized, open-label, single-dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC-MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2 , Cmin , and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4-fold (1213.15 vs. 281.35 h·ng/ml for R-PZQ and 5669 vs. 871.84 h·ng/ml for S-PZQ). Ritonavir had no significant effect on R-PZQ but increased the AUC 2-fold for S-PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively.

Synthesis and therapeutic delivery approaches for praziquantel: a patent review (2010-present).

INTRODUCTION: : Among all the anti-schistosomal drugs, praziquantel has been the most widely used. However, some major challenges have been faced using the drug in the treatment of schistosome infections. AREAS COVERED: : Several approaches used in the synthesis of praziquantel aimed at reducing the time and cost of production, the toxicity and experimental harsh conditions are discussed. Also, patented methods involved in the pharmaceutical reformulation of praziquantel in the treatment of diverse endoparasitic infestations are reported. Additionally, future perspectives in terms of nanomedicine approach in the formulation of praziquantel are highlighted. EXPERT OPINION: : Lipid-based nanosystems (LBNSs) formulations can be used to overcome the shortcomings associated with the use of praziquantel in the schistosomiasis treatment due to their amphipathic nature. This could be a promising vehicle for the delivery of praziquantel, which could in turn improve the bioavailability, as well as reduce the frequent dose of the drug and improve patient compliance. This may sustain the release of the drug and improve the rapid conversion of the drug into inactive metabolite due to rapid metabolism. Additionally, LBNSs approach could increase and improve the lipophilicity of the drug, which could make it easier to interact with the hydrophobic cores of the worm tegument.

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

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.

In vitro and in vivo human metabolism and pharmacokinetics of S- and R-praziquantel.

Racemic praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis. R-Praziquantel (R-PZQ) has been shown as the therapeutic form, whereas S-PZQ is less efficacious and responsible for the bitter taste of the tablet. This study aimed at investigating the metabolism of R- and S-PZQ as this could have implications on efficacy and safety of racemate and R-PZQ specific formulations under development. In vitro CYP reaction phenotyping assay using 10 recombinant CYP (rCYP) isoenzymes showed hepatic CYP1A2, 2C19, 2D6, 3A4, and 3A5 were the major enzymes involved in metabolism of PZQ. Enzyme kinetic studies were performed by substrate depletion and metabolite formation methods, by incubating PZQ and its R- or S-enantiomers in human liver microsomes (HLM) and the rCYP enzymes. The effect of selective CYP inhibitors on PZQ metabolism was assessed in HLM. CYP1A2, 2C19, and 3A4 exhibited different catalytic activity toward PZQ, R- and S-enantiomers. Metabolism of R-PZQ was mainly catalyzed by CYP1A2 and CYP2C19, whereas metabolism of S-PZQ was mainly by CYP2C19 and CYP3A4. Based on metabolic CLint obtained through formation of hydroxylated metabolites, CYP3A4 was estimated to contribute 89.88% to metabolism of S-PZQ using SIMCYP® IVIVE prediction. Reanalysis of samples from a human PZQ-ketoconazole (KTZ) drug-drug interaction pharmacokinetic study confirmed these findings in that KTZ, a potent inhibitor of CYP3A, selectively increased area under the curve of S-PZQ by 68% and that of R-PZQ by just 9%. Knowledge of enantioselective metabolism will enable better understanding of variable efficacy of PZQ in patients and the R-PZQ formulation under development.

First steps in the formulation of praziquantel nanosuspensions for pharmaceutical applications.

Praziquantel (PZQ), a broad spectrum anthelmintic drug, cannot be found in acceptable dosage forms for elderly patients, paediatric patients, and for veterinary use. In fact, very little has been done up to now in the formulation of liquid dosage forms, being they always formulated for parenteral administration. To beat this important challenge, it was accomplished a comprehensive analysis of the influence of two elementary physicochemical aspects, i.e. surface thermodynamic and electrokinetic properties, on the colloidal stability of PZQ nanosuspensions. The hydrophobic character of the drug, intensely determining the flocculation curves, was confirmed by the thermodynamic characterization. The electrophoretic characterization, in combination with the sedimentation and relative absorbance versus time curves, highlighted that the electrical double layer thickness and the surface charge can play an essential role in the stability of the pharmaceutical colloid. Finally, it was demonstrated that controlling the pH values and the incorporation of electrolytes can help in formulating PZQ aqueous nanosuspensions with appropriate stability and redispersibility behaviours for pharmaceutical use.

Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450-Mediated Drug-Drug Interaction.

The active enantiomer R-Praziquantel (PZQ) shows a clinically lower relative exposure when administered enantiomerically pure compared with a racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on cytochrome P450 (P450) enzymes could explain this observation and aimed to further deepen the understanding of PZQ metabolism. First, in an in vitro metabolite profiling study, the formation of multiple metabolites per P450, together with an observed interconversion of cis-4'-OH-PZQ to trans-4'-OH-PZQ in human hepatocytes, pointed out the inadequacy of measuring metabolite formation in kinetic studies. Thus, a substrate depletion approach to study PZQ enantiomeric interactions was applied. Second, an abundant CYP3A4 metabolite found in previous studies was structurally characterized. Third, substrate depletion methodologies were applied to determine P450 enzyme kinetics of PZQ and to further estimate enantiomer-enantiomer inhibitory parameters. A competitive inhibition between PZQ enantiomers for CYP2C9, 2C19, 3A4, and 3A5 was revealed. Analyses considering the clearance of only one or both enantiomers provided comparable enantiomer-enantiomer inhibition estimates. To conclude, this paper provides new insights into PZQ metabolic profile to enable a better understanding of enantioselective pharmacokinetics using substrate depletion-based methods. SIGNIFICANCE STATEMENT: In this study, enantiomer-enantiomer interactions of praziquantel on cytochrome P450 metabolizing enzymes are investigated via substrate depletion measurement using modeling methods. Together with new insights into the praziquantel metabolism, this work provides a novel data set to understand its pharmacokinetics.

Enhanced dissolution and oral bioavailability of praziquantel by emulsification with human serum albumin followed by spray drying.

The goal of this study was to enhance the oral bioavailability of praziquantel through its conjugation with human serum albumin (HSA). Praziquantel-HSA particles were produced by spray drying an emulsion of an aqueous solution of HSA and a solution of praziquantel in oil. The particles were agglomerates of multiple smooth corrugated particles containing amorphous praziquantel nearly equivalent to the theoretical doses. The solubility of praziquantel in an aqueous medium was enhanced in both the produced particles and the physical mixture. In addition, the dissolution rate in an aqueous medium was enhanced in the case of particles, but not in a physical mixture. Thus, the inclusion of HSA by emulsification followed by spray drying appeared to contribute to the enhanced dissolution rate. In a pharmacokinetic study, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) for the produced particles (HSA/praziquantel = 1/1 w/w) were approximately two times higher than the corresponding values for raw praziquantel. This increased oral bioavailability of the particles was considered to be due to the enhanced dissolution rate. This process for producing praziquantel-HSA particles could be useful in terms of improving the oral bioavailability of the other hydrophobic drugs.

Activity and pharmacokinetics of a praziquantel crystalline polymorph in the Schistosoma mansoni mouse model.

Schistosomiasis is a global disease of significant public health relevance. Only one racemic drug, praziquantel, characterized by low bioavailability, low water solubility and extensive first pass metabolism, is currently available. We studied a new praziquantel formulation (polymorph B), which is based on a racemic praziquantel crystalline polymorph (TELCEU01). Its in vitro activity was tested on newly transformed schistosomula (NTS) and adult Schistosoma mansoni. In vivo studies were conducted in mice harboring chronic S. mansoni infections. Pharmacokinetic (PK) profiles of R- and S-praziquantel and R- and S- polymorph B following oral administration with both formulations were generated by sampling mice at 30, 60, 240 min and 24 h post-treatment, followed by LC-MS/MS analysis. PK parameters were calculated using a non-compartmental analysis with a linear trapezoidal model. In vitro, commercial praziquantel and the polymorph B performed similarly on both NTS (IC50 = 2.58 and 2.40 µg/mL at 72 h) and adults (IC50 = 0.05 and 0.07 µg/mL at 72 h). Praziquantel showed higher in vivo efficacy with an ED50 of 58.75 mg/kg compared to an ED50 of 122.61 mg/kg for the polymorph B. The PK profiles of the two drugs exhibited differences: R-praziquantel showed an overall 40% higher area under the plasma drug concentration-time curve (AUC0→24) (R-praziquantel = 3.42; R-polymorph B = 2.05 h*µg/mL) and an overall 30% lower apparent clearance (Cl/F) (R-praziquantel = 70.68 and R-polymorph B = 97.63 (mg)/(µg/mL)/h). Despite the lack of improved activity and PK properties of polymorph B against S. mansoni, here presented; research on pharmaceutical polymorphism remains a valid and cost-effective option for the development of new praziquantel formulations with enhanced properties such as increased solubility and/or dissolution.

Glycyrrhizin-Assisted Transport of Praziquantel Anthelmintic Drug through the Lipid Membrane: An Experiment and MD Simulation.

Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with its low solubility, penetration rate, and bioavailability. In the present study, the permeation of PZQ through a 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) membrane was investigated to probe glycyrrhizin-assisted transport. Glycyrrhizin (or glycyrrhizic acid, GA), a natural saponin, shows the ability to enhance the therapeutic activity of various drugs when it is used as a drug delivery system. However, the molecular mechanism of this effect is still under debate. In the present study, the transport rate was measured experimentally by a parallel artificial membrane permeation assay (PAMPA) and molecular dynamics (MD) simulation with DOPC lipid bilayers. The formation of the noncovalent supramolecular complex of PZQ with disodium salt of GA (Na2GA) in an aqueous solution was proved by the NMR relaxation technique. PAMPA experiments show a strong increase in the amount of the penetrating praziquantel molecules in comparison with a saturated aqueous solution of pure drug used as a control. MD simulation of PZQ penetration through the bilayer demonstrates an increase in permeability into the membrane in the presence of a glycyrrhizin molecule. A decrease in the free energy barrier in the middle of the lipid bilayer was obtained, associated with the hydrogen bond between PZQ and GA. Also, GA reduces the local bilayer surface resistance to penetration of PZQ by rearranging the surface lipid headgroups. This study clarifies the mechanism of increasing the drug's bioavailability in the presence of glycyrrhizin.

A novel praziquantel solid lipid nanoparticle formulation shows enhanced bioavailability and antischistosomal efficacy against murine S. mansoni infection.

BACKGROUND: Schistosomiasis is responsible for a considerable global disease burden. This work aimed to improve the therapeutic outcome of the only available antischistosomal drug worldwide, praziquantel (PZQ), by incorporating it into a novel carrier, "solid lipid nanoparticles (SLNs)", to enhance its solubility, bioavailability and efficacy. A simple, cost-effective method was used to prepare SLN-PZQ. RESULTS: Compared to market PZQ (M-PZQ), SLN-PZQ was more bioavailable, as denoted by higher serum concentrations in both normal and infected mice where elevated Ka, AUC0-24, Cmax, and t1/2e with a decrease in kel were demonstrated. The AUC0-24 for SLN-PZQ in normal and Schistosoma mansoni-infected groups was almost nine- and eight-fold higher, respectively, than that for M-PZQ in corresponding groups. In normal and S. mansoni-infected mice, SLN-PZQ was detectable in serum at 24 h, while M-PZQ completely vanished 8 h post-treatment. Additionally, enhanced absorption with extended residence time was recorded for SLN-PZQ. Compared to M-PZQ, SLN-PZQ revealed superior antischistosomal activity coupled with enhanced bioavailability in all treated groups where higher percentages of worm reduction were recorded with all dosages tested. This effect was especially evident at the lower dose levels. The ED95 of SLN-PZQ was 5.29-fold lower than that of M-PZQ, with a significantly higher reduction in both the hepatic and intestinal tissue egg loads of all treated groups and almost complete disappearance of immature deposited eggs (clearly evident at the low dose levels). CONCLUSIONS: SLN-PZQ demonstrated enhanced PZQ bioavailability and antischistosomal efficacy with a safe profile despite the prolonged residence in the systemic circulation.

Investigation of pharmacokinetic interaction between ivermectin and praziquantel after oral administration in healthy dogs.

The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co-administered to dogs after oral treatment. Twelve healthy cross-bred dogs (weighing 18-21 kg, aged 1-3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15-day washout period, respectively. Second group received tablet form of ivermectin plus praziquantel. The plasma concentrations of ivermectin and praziquantel were determined by high-performance liquid chromatography using a fluorescence and ultraviolet detector, respectively. The pharmacokinetic parameters of ivermectin following oral alone-administration were as follows: elimination half-life (t1/2λz ) 110 ± 11.06 hr, area under the plasma concentration-time curve (AUC0-∞ ) 7,805 ± 1,768 hr. ng/ml, maximum concentration (Cmax ) 137 ± 48.09 ng/ml, and time to reach Cmax (Tmax ) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone-administration were as follows: t1/2λz 7.39 ± 3.86 hr, AUC0-∞ 4,301 ± 1,253 hr. ng/ml, Cmax 897 ± 245 ng/ml, and Tmax 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except Tmax of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.

The effect of ketoconazole on praziquantel pharmacokinetics and the role of CYP3A4 in the formation of X-OH-praziquantel and not 4-OH-praziquantel.

AIM: The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects. METHODS: Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment. RESULTS: The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and Cmax (α = 0.05). The geometric mean ratios of the AUC and Cmax were found to be 176.8% and 227% respectively. The 90% CI of the AUC and Cmax were found to be 129.8%-239.8% and 151.4%-341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration. CONCLUSIONS: The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.

Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo- and Racemic Praziquantel: Two Phase I Studies.

Orally dispersible tablet (ODT) formulations of levo praziquantel (L-PZQ) and racemic PZQ (rac-PZQ) are being developed to treat schistosomiasis in preschool-aged children. Two crossover studies (N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Bioavailability for L-PZQ of ODT rac-PZQ and Cysticide at 40 mg/kg was comparable (L-PZQ area under the concentration-time curve from zero to infinity (AUC0-∞ ) test/reference ratio (90% confidence interval (CI)): 96% (84-111%)), whereas relative bioavailability of ODT L-PZQ 20 mg/kg was ~40% that of Cysticide 40 mg/kg (test/reference: 40% (35-46%)). AUC0-∞ and peak plasma concentration (Cmax ) were highly variable in both studies. For both ODTs, L-PZQ AUC0-∞ showed greater than dose-proportional increase over the ranges tested and a significant food effect. Safety was comparable among formulations. The lower bioavailability of ODT L-PZQ, as well as the high variability and nondose-proportionality of pharmacokinetic (PK) parameters, highlighted the need for a dedicated pediatric dose-finding study for the selection of the most appropriate formulation and dose (L-PZQ ODT or rac-PZQ ODT).

Bioavailability and palatability of praziquantel incorporated into solid-lipid nanoparticles fed to yellowtail kingfish Seriola lalandi.

In an effort to overcome the palatability issues currently constraining the effective delivery of praziquantel (PZQ) via feed to treat monogenean parasites in yellowtail kingfish, this study compared the bioavailability and palatability of PZQ in hydrogenated castor oil (HCO) solid lipid nanoparticles (SLN) against pure PZQ in this species. Improving bioavailability would facilitate lower dietary inclusion levels to achieve the same therapeutic dose and therefore reduce the bitterness of feeds containing PZQ. Bioavailability was determined by co-administering feed with either pure PZQ, HCO-SLN or HCO-SLN coated with chitosan via intubation and quantifying the pharmacokinetics response. In contrast to studies with mammals, the results demonstrated that PZQ in HCO-SLN had equal bioavailability to pure PZQ in yellowtail kingfish, including when HCO-SLN were coated with chitosan. We hypothesise that the lack of improvement in bioavailability may be due to the lack of M cells and Peyer's patches in fish and the subsequent inability of fish to take nanoparticles directly into the lymphatic system. Furthermore, palatability of the feeds medicated with PZQ was not improved when the PZQ was incorporated into HCO-SLN, possibly due to the low loading rate of PZQ within the HCO-SLN and the subsequent thick coating of nanoparticles that was required on the surface of the feed pellets. Combined, these data demonstrate that the SLN used in the current study are not capable of delivering the benefits required to enable effective in-feed treatment of PZQ against monogenean parasites in yellowtail kingfish.

Physicochemical Properties and Anti-Opisthorchosis Effect of Mechanochemically Synthesized Solid Compositions of Praziquantel with Glycyrrhizic Acid Disodium Salt.

The mechanochemical preparation of solid compositions of praziquantel with plant saponin (glycyrrhizic acid disodium salt) is described. The study of a number of physicochemical parameters showed that dissolving solid compositions in water is accompanied by the inclusion of praziquantel molecules into micelles, which are formed in the solution of the glycyrrhizic acid disodium salt. Using the opisthorchiasis model caused by Opisthorchis felineus, we found a 4- to 11-fold increase in the anthelmintic activity of praziquantel in the composition as compared to the official praziquantel. According to the pharmacokinetic data, the use of the composition increased the bioavailability of praziquantel 3 times.

Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale.

L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2-5 years old accounting for enzyme maturation and weight. The predicted exposures were compared to an external Phase 1 study conducted by the Swiss Tropical and Public Health Institute using a currently marketed formulation (Cesol 600 mg immediate-release tablets) and found to be substantially lower than observed. A root cause analysis was completed to identify the reason for failure of the models. Various scenarios were proposed and tested. Two possible reasons for the failure were identified. One reason was that the model did not account for the reduced hepatic clearance seen in patients compared to the healthy volunteer population used to build the model. The second possible reason was that PZQ absorption appears sensitive to meal composition and the model did not account for differences in meals between a standardized Phase 1 unit and clinical sites in Africa. Further studies are needed to confirm our hypotheses.

Praziquantel-lipid nanocapsules: an oral nanotherapeutic with potential Schistosoma mansoni tegumental targeting.

PURPOSE: Lipid nanocapsules (LNCs) have shown potential to increase the bioavailability and efficacy of orally administered drugs. However, their intestinal translocation to distal target sites and their implication in pharmacokinetic (PK)-pharmacodynamic (PD) relationships are yet to be elucidated. In this study, the effect of LNCs on the PD activity and pharmacokinetics of praziquantel (PZQ), the mainstay of schistosomiasis chemotherapy, was investigated. MATERIALS AND METHODS: The composition of LNCs was modified to increase PZQ payload and to enhance membrane permeability. PZQ-LNCs were characterized in vitro for colloidal properties, entrapment efficiency (EE%), and drug release. PD activity of the test formulations was assessed in Schistosoma mansoni-infected mice 7 days post-oral administration of a single 250 mg/kg oral dose. Pharmacokinetics of the test formulations and their stability in simulated gastrointestinal (GI) fluids were investigated to substantiate in vivo data. RESULTS: PZQ-LNCs exhibited good pharmaceutical attributes in terms of size (46-62 nm), polydispersity index (0.01-0.08), EE% (>95%), and sustained release profiles. Results indicated significant efficacy enhancement by reduction in worm burden, amelioration of liver pathology, and extensive damage to the fluke suckers and tegument. This was partly explained by PK data determined in rats. In addition, oral targeting of the worms was supported by the stability of PZQ-LNCs in simulated GI fluids and scanning electron microscopy (SEM) visualization of nanostructures on the tegument of worms recovered from mesenteric/hepatic veins. Cytotoxicity data indicated tolerability of PZQ-LNCs. CONCLUSION: Data obtained provide evidence for the ability of oral LNCs to target distal post-absorption sites, leading to enhanced drug efficacy. From a practical standpoint, PZQ-LNCs could be suggested as a potential tolerable single lower dose oral nanomedicine for more effective PZQ mass chemotherapy.