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

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          Abstract

          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.

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          Most cited references28

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          Human schistosomiasis.

          Human schistosomiasis--or bilharzia--is a parasitic disease caused by trematode flukes of the genus Schistosoma. By conservative estimates, at least 230 million people worldwide are infected with Schistosoma spp. Adult schistosome worms colonise human blood vessels for years, successfully evading the immune system while excreting hundreds to thousands of eggs daily, which must either leave the body in excreta or become trapped in nearby tissues. Trapped eggs induce a distinct immune-mediated granulomatous response that causes local and systemic pathological effects ranging from anaemia, growth stunting, impaired cognition, and decreased physical fitness, to organ-specific effects such as severe hepatosplenism, periportal fibrosis with portal hypertension, and urogenital inflammation and scarring. At present, preventive public health measures in endemic regions consist of treatment once every 1 or 2 years with the isoquinolinone drug, praziquantel, to suppress morbidity. In some locations, elimination of transmission is now the goal; however, more sensitive diagnostics are needed in both the field and clinics, and integrated environmental and health-care management will be needed to ensure elimination. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State

            The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is known about the time courses and distribution of water volumes in vivo in an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds.
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              Taste, A New Incentive to Switch to (R)-Praziquantel in Schistosomiasis Treatment

              Introduction Praziquantel [1] (PZQ) is the drug compound of choice in the control and treatment of schistosomiasis [2], in fact, it is the only commercially readily available drug. So far, no backup compound for PZQ of comparable efficacy and breadth of application is available. Clinically relevant resistance has not been observed, however differences in responses of PZQ-resistant and -susceptible Schistosoma mansoni to PZQ in vitro have been described [3]. PZQ is included in the WHO Model List of Essential Drugs [4] and is at the core of numerous schistosomiasis control programmes. The WHO's strategy for schistosomiasis control [5] aims at reducing morbidity through treatment with PZQ, with a focus on periodic treatment of school-age children and adults considered to be at risk. School-age children are seen as a high-risk group for schistosome infections because they are more susceptible to infection in cases where their increased nutritional needs are not adequately met, might be compromised by helminth infections in their cognitive development, and are continuously exposed to contaminated soil and water but probably less aware of the need for good personal hygiene [6]. While the safety and efficacy against all schistosoma species are outstanding, PZQ has two major administration drawbacks, the first being the high dose needed, 40 mg PZQ/kg bodyweight: Dosages in children are determined by measurement of children's heights using tablet poles, and range from one to five 600 mg-tablets for one treatment. Especially young children have been reported not to be able to swallow these 600 mg tablets [7]. The second drawback is PZQ's well documented bitter and disgusting taste, which can lead to gagging or vomiting if tablets are chewed contrary to recommendation [8]. In veterinary medicine, the oral delivery of PZQ to taste-sensitive companion animals like cats is known to be a challenge. Traditional methods of taste-masking, like the addition of aromas or sugar, are ineffective for PZQ. The bitterness of PZQ even led to PZQ's use as a bitter model drug compound in the effectiveness testing of sophisticated and expensive taste-masking techniques like micro-encapsulation [9] or drug active coating [10]. Apart from anecdotal evidence [2], we are not aware of reports of low compliance among children treated within schistosoma programmes due to the bitter taste. However, we have to assume that the unpleasant taste of PZQ does not lead to a treatment situation which school-age children would enjoy. PZQ is administered as a racemate, i. e. 1∶1, mixture of two compounds of identical constitution but non-superimposable mirror-image configuration, so called enantiomers. The straightforward and low-cost chemical synthesis has to be assumed as the reason for the use of the racemate, although it has been known for years that the schistosomicidal activity mainly relies in one PZQ-enantiomer, designated (−)-PZQ (alternatively termed levo-PZQ, l-PZQ, sometimes L-PZQ), whereas the other enantiomer, designated (+)-PZQ (alternatively termed dextro-PZQ, d-PZQ), does not contribute to the activity [11]–[13] (Figure 1). From this perspective, only half of the drug compound administered is in fact the drug active, whereas the other half must be considered molecular ballast, which has to be metabolized and excreted while not contributing to the schistosomicidal activity. To the best of our knowledge, no clinical studies in humans exist if and how non-schistosomicidal (+)-PZQ alone contributes to the side effects known of racemic PZQ, but this may be assumed: Upon incubation of PZQ and both enantiomers with isolated rat hepatocytes, additional metabolites were detected resulting from the non-contributing (+)-PZQ [14]. Various methods of producing the pure schistosomicidal component (−)-PZQ exist, which are considerably more expensive than the production of racemic PZQ itself. So far, the potential alone to administer half the current dose by replacing racemic PZQ by (−)-PZQ did not lead to a production process for (−)-PZQ comparable in costs for racemic PZQ. 10.1371/journal.pntd.0000357.g001 Figure 1 Molecular structures of the two mirror-image components of PZQ; asymmetric carbon atom highlighted in yellow. In the context of the WHO's Global Plan to combat NTDs [15], the Special Programme for Research and Training in Tropical Diseases (TDR) set up an incentive for further R&D work by emphasizing the low-cost preparation of pure schistosomicidal (−)-PZQ (see also the schistosomiasis research collaborative community within The Synaptic Leap [16]) as a key priority for future R&D on PZQ [17]. Three pharmacological goals for the development were stated: (1) same dose of (−)-PZQ as currently in regular, racemic PZQ, with smaller tablet size and less frequent/severe adverse events, (2) higher dose of (−)-PZQ with similar tablet size and possibly similar adverse event profile as current treatment which could reduce the probability of or delay the development of resistance, or (3) a combination of these two objectives. As we already mentioned, a smaller tablet size would be more suitable for the treatment of children. Taking into account that the WHO's strategy specifically aims at school-age children, we were intrigued by the question whether the taste disadvantage of PZQ could be turned into an additional incentive to introduce (−)-PZQ against schistosomiasis as the drug active of choice. Background to our consideration was the well-documented fact that in most cases taste experiences depend on the stereochemical configuration of the agent [18], i. e. the taste buds react enantioselectively–like all natural receptors which are composed of chiral constituents like L-amino acids. We hypothesized that (−)-PZQ and (+)-PZQ would contribute to the bitter taste to a different extent, and that the non-schistosomicidal (+)-PZQ would be the main or sole contributor to the disgusting taste. Surprisingly, no public knowledge exists on the tastes of the two enantiomers. We prepared schistosomicidal (−)-PZQ, assigned the stereochemical configuration by X-ray crystallography, and determined the extent of bitterness for regular racemic PZQ versus the schistosomicidal component (−)-PZQ in a taste study in humans. We chose this comparison over the comparison of (−)-PZQ to non-schistosomicidal (+)-PZQ because the latter alone does not have any role in a treatment situation. Also the pharmacological studies by others had compared racemic PZQ to (−)-PZQ, and not (+)-PZQ to (−)-PZQ [19]. Methods Preparation and stereochemical assignment of (−)-PZQ Although effective synthetic methods for the enantioselective preparation of PZQ have been reported [20], we opted for the direct enantioseparation of the racemate yielding gram quantities of both optical forms. The preparative scale chromatography was performed on microcrystalline cellulose triacetate using methanol as the mobile phase, conditions under which the enantiomer having the negative optical rotation emerged first from the column [21]. After crystallisation from methanol/water, (−)-PZQ was obtained in enantiomeric excess >99%, as determined by HPLC (column used Chiralcel OD-H). No residual other enantiomer (+)-PZQ was detected in this sample. X-ray structural analysis, using Cu-Kα radiation, of a monoclinic crystal in hemi-hydrate form obtained from said fraction by crystallization from methanol/water unequivocally proved the R-configuration of the molecule by measuring Friedel pairs and the Flack parameter (x = −0.1(3)) (Figure 2). Further details of the crystal structure analysis are available on request from the CCDC (www.ccdc.cam.ac.uk) quoting the names of the authors and journal citation. 10.1371/journal.pntd.0000357.g002 Figure 2 X-ray crystallographic structure of (R)-PZQ; asymmetric carbon atom highlighted in yellow. Determination of the bitterness value The bitterness values of racemic PZQ and its schistosomicidal component (R)-PZQ were determined according to the European Pharmacopoeia [22] by comparison with quinine hydrochloride, the bitterness value of which is set at 2×105. The bitterness value is defined by the European Pharmacopoeia as the reciprocal of the concentration of a solution in a dilution series of a compound, a liquid or an extract that still has a bitter taste. Concentrations of solutions used in the tests ranged from 1.69×10−8 to 1.0×10−4 g/mL. A test panel consisting of sixteen members was assembled. Although children comprise the treatment target group no children were included in the test panel. All panel members were adults completely untrained in performing sensory tests. To correct for individual differences in tasting bitterness amongst the panel members a correction factor was determined for each panel member by preparing dilutions of quinine hydrochloride. The mouth was rinsed with water before tasting. The dilution with the lowest concentration having a bitter taste was determined by taking 10 mL of the weakest solution into the mouth and passing it from side to side over the back of the tongue for 30 seconds. If the solution was not found to be bitter, the panellist had to spit out and wait for one minute before the mouth was rinsed again with water. After 10 minutes, the next dilution in order of increasing concentration was tasted. The correction factor k for each panel member was calculated according to the European Pharmacopoeia by k = n/5, where n is the number of millilitres of the stock solution in the dilution of the lowest concentration that is judged to be bitter. One panel member detected bitterness already in pure water, and was therefore excluded from the test panel. Dilutions of the test compounds racemic PZQ and (R)-PZQ were prepared and tasted by the remaining fifteen members of the test panel in the same manner as described for quinine hydrochloride. The bitterness value as experienced by each member was calculated according to the European Pharmacopoeia taking the individual-related correction factor into account by Y×k/X×0.1, where Y is the dilution factor of the dilution, and X is the number of millilitres of the respective dilution which, when diluted to 10 mL with water, still has a bitter taste. The bitterness value of the test compounds resulted from calculating the average of the individual values. Requested statement: Informed written consent was obtained from all panelists to participate in this taste study. As a taste study, and not a medical study in the sense of the WMA Declaration of Helsinki, it did not require approval of an independent review board (highly diluted preparations were tasted and spat out–they were not ingested). Nevertheless, it was conducted according to the principles of the WMA Declaration of Helsinki where applicable. Results The results of the determination of bitterness values are shown in Table 1. Remarkable is the variation of the individuals' results as indicated by the relative standard deviation and the dispersion of the results in the box-and-whisker diagram (Figure 3). In contrast to the average, the medians of the results, as depicted in the box-and-whisker diagram, are different from each other. The observed variation was probably provoked by the test panel consisting of untrained members only [23]. Thirteen out of fifteen panel members found (R)-PZQ to taste less bitter than racemic PZQ. Although no statistical test is required or proposed by the European Pharmacopoeia, a statistical test (using SAS software, release 9.1.3, SAS Institute Inc., Cary, NC, USA) was conducted to investigate the observed difference between the compounds. Considering the small sample size and the nature of the data which does not justify the assumption of a normal distribution, a nonparametric, distribution-free method was chosen. On the 5% level of significance, Wilcoxon's Signed Rank Test (two-sided) resulted in a significant difference between the taste of racemic PZQ and (R)-PZQ (p = 0.0107). This result was confirmed by the Sign Test (two-sided, p = 0.0018). 10.1371/journal.pntd.0000357.g003 Figure 3 Box-and-whisker diagram of the individual bitterness values for racemic PZQ and (R)-PZQ. 10.1371/journal.pntd.0000357.t001 Table 1 Bitterness values for racemic PZQ and schistosomicidal (R)-PZQ Member of the test panel Racemic PZQ (R)-PZQ Individual bitterness values/105 A 1.03 0.14 B 0.46 0.11 C 7.85 0.68 D 7.85 0.09 E 1.92 1.23 F 1.71 0.27 G 355 592 H 177 178 I 250 0.37 J 0.62 0.25 K 14.5 0.29 L 39.4 0.10 M 5.52 0.41 N 7.23 0.14 O 0.55 0.28 Bitterness value (average) 58.1 51.6 Standard deviation 110 156 Relative standard deviation 191% 303% In addition to the quantitative determination of the bitterness values, qualitative taste sensations were noted by the members of the test panel for each compound. For racemic PZQ, all panel members commonly observed the sensation of an unpleasant chemical or metallic taste or a taste circumscribed best by old rubber. On the other hand, for (R)-PZQ the panellists commonly described the sensation of a moderate chemical taste, comparable to that of a polyethylene or a rubber pipe. Although the tastes were not recognized alike across the test panel, for the majority of the test panel we can state that (R)-PZQ had a less unpleasant taste compared to racemic PZQ. Discussion The schistosomicidal component of regular PZQ, (R)-PZQ has a less unpleasant taste compared to racemic PZQ, which was found to be comparably bitter or unpleasant. It can be assumed that the disgusting taste of racemic PZQ stems from the non-schistosomicidal component, (S)-PZQ. Removing the latter from currently used racemic PZQ therefore not only offers the chance to halve the dose, with the potential to decrease the number or size of the tablets, but also addresses the second disadvantage of regular, racemic PZQ-its unpleasant taste. With this finding and its publication we would like to offer an additional incentive to focus work of the PZQ R&D community on further decreasing the cost of production of (R)-PZQ with the goal to switch to pure (R)-PZQ as a replacement for racemic PZQ for the treatment of school-age children against schistosomiasis.
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                Author and article information

                Contributors
                peter.bonate@astellas.com
                Journal
                J Pharmacokinet Pharmacodyn
                J Pharmacokinet Pharmacodyn
                Journal of Pharmacokinetics and Pharmacodynamics
                Springer US (New York )
                1567-567X
                1573-8744
                14 September 2018
                14 September 2018
                2018
                : 45
                : 5
                : 747-762
                Affiliations
                [1 ]ISNI 0000 0004 0507 1326, GRID grid.423286.9, Astellas, ; 1 Astellas Way, Northbrook, IL 60062 USA
                [2 ]GRID grid.422303.4, Present Address: Alkermes, ; Waltham, MA 02451 USA
                [3 ]GRID grid.428920.5, Present Address: Galapagos BV, ; Zernikedreef 16, Leiden, The Netherlands
                [4 ]Merck Serono SA, Merck Institute for Pharmacometrics (A Subsidiary of Merck KGaA, Darmstadt, Germany), Lausanne, Switzerland
                [5 ]GRID grid.437832.9, Simcyp (a Certara company), Blades Enterprise Centre, ; John Street, Sheffield, S2 4SU UK
                [6 ]ISNI 0000 0001 0672 7022, GRID grid.39009.33, Merck KGaA, Translational Quantitative Pharmacology, ; Frankfurter Str. 250, 64293 Darmstadt, Germany
                [7 ]Merck Global Health Institute, Ares Trading S.A. (A Subsidiary of Merck KGaA, Darmstadt, Germany), 1262 Eysins, Switzerland
                [8 ]ISNI 0000 0004 0587 0574, GRID grid.416786.a, Swiss Tropical and Public Health Institute, ; Socinstr. 57, CH-4002 Basel, Switzerland
                [9 ]ISNI 0000 0004 1937 0642, GRID grid.6612.3, University of Basel, ; Basel, Switzerland
                Article
                9601
                10.1007/s10928-018-9601-1
                6182730
                30218416
                d538ee97-9861-4dee-9914-96f5c5dfdafb
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 9 October 2017
                : 13 July 2018
                Funding
                Funded by: H2020 European Research Council ()
                Funded by: Global Health Innovative Technology Fund
                Award ID: RFP 2013-002
                Categories
                Original Paper
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                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Pharmacology & Pharmaceutical medicine
                population pharmacokinetics,nonmem,linear mixed effects models,root cause analysis,oral dispersion tablet,complex pharmacokinetics

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