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Keywords:

  • schistosomiasis;
  • praziquantel;
  • dosage

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References

Objective

Schistosomiasis is known to occur in preschool-aged children, but achieving accurate dosing of praziquantel in its current form is challenging. While waiting for a paediatric formulation, there is a need to develop a means for using the available products to treat this age group. Current 600-mg tablets are differently scored to give units of 150 mg (a quarter of a tablet) or 300 mg (half a tablet).

Methods

We examined several dosing schemes to dose accurately (40-60 mg/kg) children aged 3–72 months (weight range 4–25 kg, based on available weight-for-age growth references from sub-Saharan Africa and Brazil, n = 106,230).

Results

Adequate dosing can be achieved with formulations that can be split into four 150 mg quarters for children weighing 5 kg or more, and with tablets than can be split into two 300 mg halves for children weighing 10 kg or more. Giving ½ tablet for 5–7 kg; ¾ tablet for 8–10 kg; 1 tablet for 11–15 kg; 1 ½ tablet for 16–21 kg; and two tablets for 22–25 kg will have 100% of subjects correctly dosed within the target 40–60 mg/kg range.

Conclusions

Formulations that can be divided into four parts (to give 150 mg increments) are preferred for children weighing less than 11 kg; the same dosing can be applied with 600 mf praziquantel formulations that can be divided into four quarters or two halves from 11 kg body weight.

Objectif

La schistosomiase est connue pour survenir chez les enfants d’âge préscolaire, mais pour arriver à un dosage précis du praziquantel sous sa formulation actuelle est difficile. En attendant une formulation pédiatrique, il est nécessaire de développer un moyen pour utiliser les produits disponibles pour traiter ce groupe d’âge. Les comprimés actuels de 600 mg sont marqués différemment afin de donner des unités de 150 mg (un quart de comprimé) ou 300 mg (un demi-comprimé).

Méthodes

Nous avons examiné plusieurs régimes de dosage afin de pouvoir doser avec précision (40 à 60 mg/kg) les enfants âgés de 3 à 72 mois (intervalle de poids de 4 à 25 kg, en fonction des références de croissance poids-pour-âge disponibles pour l'Afrique subsaharienne et le Brésil, n = 106 230).

Résultats

Un dosage adéquat peut être atteint avec des formulations qui peuvent être divisées en quatre quarts de 150 mg pour les enfants pesant 5 kg ou plus et avec des comprimés qui peuvent être divisés en deux moitiés de 300 mg pour les enfants pesant 10 kg ou plus. Donner ½ comprimé pour les 5 à 7 kg; ¾ comprimé pour les 8 à 10 kg; 1 comprimé pour les 11à 15 kg, 1 + ½ comprimé pour les 16 à 21 kg et 2 comprimés pour les 22 à 25 kg permettra d'arriver à 100% des sujets correctement dosés dans fourchette cible 40–60 mg/kg.

Conclusions

Les formulations pouvant être divisées en quatre parties (pour donner des incréments de 150 mg) sont préférables pour les enfants pesant moins de 11 kg, le même dosage peut être appliqué avec les formulations de 600 mg de praziquantel qui peuvent être divisées en quatre ou en deux pour les patients à partir de 11 kg de poids corporel.

Objetivo

Se conoce que la esquistosomiasis occure en niños en edad preescolar, pero conseguir una dosificación precisa del praziquantel en su formulación actual es todo un reto. Mientras se espera la llegada de una formulación pediátrica, existe la necesidad de desarrollar una manera de utilizar los productos actualmente disponibles para tratar a este grupo de edad. Actualmente los comprimidos de 600 mg tienen grabadas diferentes líneas para partirlos en unidades de 150 mg (un cuarto de comprimido) o 300 mg (medio comprimido).

Métodos

Hemos examinado varios esquemas de dosificación con el fin de dar la dosis adecuada (40–60 mg/kg) a niños con edades comprendidas entre los 3–72 meses (rango de peso 4–25 kg, basándose en las tablas de crecimiento actualmente disponibles de peso-por-edad para África subsahariana y Brasil, n = 106,230).

Resultados

Las dosis adecuadas se consiguen utilizando formulaciones que puedan partirse en cuatro cuartos de 150 mg para niños con un peso de 5 kg o más, y con comprimidos que puedan partirse en dos mitades de 300 mg para niños con un peso igual o mayor a 10 kg. El dar ½ comprimido para 5–7 kg; ¾ comprimido para 8–10 kg; 1 comprimido para 11–15 kg; 1 ½ comprimido para 16–21 kg y 2 comprimidos para 22–25 kg resulta en una dosificación correcta para el 100% de los sujetos, dentro del rango de 40–60 mg/kg.

Conclusiones

Las formulaciones que pueden dividirse en cuatro partes (para administrar dosis incrementales de 150 mg) son las más adecuadas para niños que pesen menos de 11 kg; la misma dosificación puede alcanzarse con formulaciones de 600 mg praziquantel que pueden dividirse en cuatro cuartos o en dos mitades, para niños con una masa corporal a partir de los 11 kg.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References

Praziquantel is the drug of choice for treating infections with all Schistosoma species. Depending on the prevalence of the infection in a given region, the World Health Organization (WHO) recommends that praziquantel be (1) distributed for preventive chemotherapy (without individual diagnosis) to (1a) either entire communities (through mass treatment) or (1b) school-aged children; or (2) used to treat individuals with demonstrated presence of the parasite as eggs in excreta (urine or stools) and through antigen testing, or (3) used to treat infected children under 4 years of age on an individual basis by medical personnel (World Health Organization 2006).

While school-aged children are the main target population for interventions, it is becoming increasingly clear that younger children (‘pre-schoolers’) are also affected (Stothard & Gabrielli 2007; Stothard et al. 2013). A WHO meeting report (World Health Organization 2010) recommends that ‘(i) preschool-aged children should be regarded as a high-risk group in areas endemic for schistosomiasis; treatment should be made available to them through the regular health services, (ii) administration of praziquantel to preschool-children should be included in ongoing public health interventions such us the Expanded Programme on Immunization (EPI), Mother and Child Days, and Child Health Days, and (iii) in the absence of an appropriate paediatric formulation, broken or crushed tablets are recommended for administration of praziquantel. Development of water-dispersible tablets for this age group is recommended’.

WHO recommends that praziquantel be given as a single dose of 40 mg/kg (whenever scales are available to weigh the patients), or practically using a dosing pole. The pole was originally developed to cover height starting from 110 cm (Montresor et al. 2001). Recently, the application of the pole has been extended to 60 cm (Sousa-Figueiredo et al. 2012), but shorter children are not covered.

It is important to know whether preschool-aged children can be dosed correctly using current praziquantel 600-mg tablets (scored to be divided into four 150 mg quarters or two 300 mg halves) on the basis of weight. This paper reports on the calculations for weight-based dosing of praziquantel for treatment and preventive chemotherapy of schistosomiasis in children weighing 4–25 kg, corresponding largely to the age range 3–72 months based on weight-for-age references available for Brazil and sub-Saharan Africa.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References

The target population were children aged 3–72 months. We used weight-for-age growth references for the age group 3–72 months from sub-Saharan Africa and Brazil (n = 106 230). Their centile curves indicate the attained weights-for-ages for the population in these countries. These references were modelled through application of an extended form of the generalised additive model for location scale and shape (GAMLSS) (van Buuren et al. 2009). Data for these references were compiled from existing health surveys (demographic health surveillance (DHS), multiple indicator cluster survey (MICS), stepwise approach to surveillance (STEPS)) and population-based data from studies made available by research groups from sub-Saharan Africa (total 99 215 measurements; 50 009 males and 49 206 females) and Brazil (total 7015; 3584 males and 3431 females) (Hayes 2011).

Calculations were based on two formulations of praziquantel: (i) the one currently being made available to the WHO through donation, a 600-mg tablet scored to give four 150-mg doses, and (ii) a 600-mg tablet scored to give two 300-mg doses. Therefore, the smallest incremental dosing unit was 150 mg in the first case and 300 mg in the second case.

Rationale for selection of the target dose and therapeutic window

The target dose was 50 mg/kg (therapeutic window 40–60 mg/kg); if more than one dosage existed within the therapeutic window, three options were tested: (i) the dose closest to the target dose, (ii) the highest dose (within 60 mg/kg), and (iii) fewest dosing categories.

The two available Cochrane systematic reviews for S. mansoni (Danso-Appiah et al. 2013) and S. haematobium (Danso-Appiah et al. 2008) show a dose effect for praziquantel S. mansoni (up to, but not beyond, 40 mg/kg) but not for S. haematobium. Extracting data from the S. mansoni systematic review for randomised controlled trials of praziquantel, the odd ratios with 95% confidence intervals (OR, 95% CIs) for cure rates at 1-month follow-up with 40 mg/kg were for studies versus placebo 3.13 (1.03–9.53), versus 20 mg/kg 2.23 (1.64–3.02), versus 30 mg/kg 1.52 (1.15–2.01) and for 60 mg/kg 0.97 (0.73–1.29). It was therefore considered preferable to provide at least 40 mg/kg and not to exceed 60 mg/kg. There was no enough information from these reviews to compare egg reduction rates. Dosage was by weight (1-kg categories).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References

From the references for sub-Saharan Africa and Brazil, the weight range within the 3–72 months group will be between the 10th centile for African girls (lower limit) and 90th centile for Brazilian boys (upper limit), which was approximated to 4–25 kg (Table 1). Three dosing options were compared with the 150 mg incremental unit: (i) dose closest to the 50 mg/kg target dose (eight dosing categories, mean dose 49.4 mg/kg), (ii) highest dose within 60 mg/kg upper limit (eight dosing categories, mean dose 52 mg/kg), and (iii) fewest dosing categories (six dosing categories, mean dose 48.8 mg/kg). With all of the above, all children weighing 5 kg or more will receive the target dose 40–60 mg/kg; only children weighing 4 kg (the lowest weight) will be slightly underdosed (receiving 37.5 mg/kg). The latter is the most practical option: the lowest dose is one quarter of a 600-mg tablet, and the highest dose is two tablets (Figure 1a). One dosing option was tested with the 300 mg unit, (five dosing categories, mean dose 51.1 mg/kg, lowest dose a ½ tablet, highest dose two tablets) (Figure 1b).

Table 1. Range of body weights for the age range 3–72 months for females and males in sub-Saharan Africa and Brazil within the 10th and 90th centiles
Age (months)10th centile Female/Africa90th centile Male/Africa10th centile Female/Brazil90th centile Male/Brazil
33.97.34.97.6
65.08.86.29.5
126.410.37.911.4
187.511.58.712.7
248.312.69.513.9
309.013.910.315.2
369.615.011.116.5
4210.316.111.917.8
4810.917.112.719.0
5411.618.013.520.2
6012.318.914.321.5
6613.019.815.222.8
7213.720.716.124.2
image

Figure 1. Dosing of praziquantel (PZQ) in mg/kg body weight for the weight range with 150 mg (a) units (a quarter of a 600-mg tablet) and 300 mg (b) units (half of a 600-mg tablet).

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Based on these calculations, it was possible to propose a weight-based administration, which will have all children weighing 5 kg or more receive 40–60 mg/kg using PZQ formulations allowing for 150 mg units; and a common dosing for children weighing 11 kg or more with any formulations – that is, using ½ 600-mg tablets, whether scored to allow for 150 mg quarters or 300 mg halves (Table 2).

Table 2. Practical dosing for children weighing 4–25 kg with 600-mg tablets scored to give 150 or 300 mg dosing unitsThumbnail image of

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References

In the absence of a paediatric formulation of praziquantel, dosing young children with schistosomiasis accurately may be challenging. Tablets such as those currently available are scored to allow a dosing unit of 150 mg (i.e. ¼ tablet) or 300 mg (i.e. ½ tablet). In this article, we assessed whether sufficient accuracy could be obtained by 150 or 300 mg increments, calculated on body weight. Then, to improve acceptability by small children and reduce the risk of potential chocking, the tablet fraction so calculated could be crushed and dissolved if need be.

Using tablets that can be divided into four 150 mg units, children weighing 5 kg and more are correctly dosed; with tablets that can be divided in two 300 mg units, it is practically possible to dose consistently children weighing 10 kg or more. From 11 kg upwards, the same dosing can be applied using either presentations. Two weight categories (5 and 10 kg body weight) will receive the upper limit of the dosing range (60 mg/kg) with the 300 mg unit; and the 5 kg children also with the 150 mg unit. Children weighing 4 kg given 150 mg will be slightly underdosed (37.5 mg/kg, or ca. 6% less than the minimum dose, 40 mg). Very small children should be treated on individual basis in healthcare settings.

In comparison, the extended pole proposed by Sousa-Figueiredo et al. (2012), using 150 mg dosing units will provide 40–60 mg/kg to approximately 51% of subjects, with approximately 47% receiving less than 40 mg/kg. Differently from our study, the therapeutic range targeted in those calculations was 30–60 mg/kg. As for the target dose range, one should consider that there are considerably fewer trials in younger children than in older children and adults, and that pharmacokinetic data are scarce and limited to (mostly healthy) adults. In order ‘to determine the optimal dose of praziquantel for the treatment of schistosomiasis in children, a pharmacokinetic study is warranted’ (World Health Organization 2010). Dosing young children based on body weight should be generally feasible; almost all children under 5 years of age in Schistosoma-endemic areas are routinely weighed for growth monitoring in child health programmes.

A paediatric formulation would facilitate the administration of praziquantel to young children and avoid the need for crushing tablets. Studies have been conducted with a liquid formulation (World Health Organization 2010), but this product is not currently manufactured according to international standards. Furthermore, solid oral forms are preferred. A consortium has been formed to work on this issue (Pharma 2013), and it is hoped that it will deliver a product soon.

With the currently available praziquantel 600-mg tablets, formulations that can be divided in four 150 mg dosing units are preferred for children weighing 5–10 kg; the same dosing scheme can be applied using either formulations than can be divided in four or two from 11 kg body weight.

Disclaimer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References

Piero L. Olliaro, Lester Chitsulo and Antonio Montresor are staff members of WHO; the authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy or views of WHO.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclaimer
  8. References
  • van Buuren S, Hayes DJ, Stasinopoulos DM, Rigby RA, ter Kuile FO & Terlouw DJ (2009) Estimating regional centile curves from mixed data sources and countries. Statistics in Medicine 28, 28912911. Epub 2009/08/20.
  • Danso-Appiah A, Utzinger J, Liu J & Olliaro P (2008) Drugs for treating urinary schistosomiasis. Cochrane Database of Systematic Review CD000053. Epub 2008/07/23.
  • Danso-Appiah A, Olliaro PL, Donegan S, Sinclair D & Utzinger J (2013) Drugs for treating Schistosoma mansoni infection. Cochrane Database of Systematic Review 2, CD000528. Epub 2013/03/02.
  • Hayes DJ (2011) Development of Age and Height Based Dosing Regimens for Antimalarials as Alternatives to Weight-Based Dose Regimens [Doctoral Thesis]. Liverpool School of Tropical Medicine, Liverpool.
  • Montresor A, Engels D, Chitsulo L, Bundy DA, Brooker S & Savioli L (2001) Development and validation of a ‘tablet pole’ for the administration of praziquantel in sub-Saharan Africa. Transactions of the Royal Society Tropical Medicine and Hygiene 95, 542544. Epub 2001/11/15.
  • Pharma TI (2013) Schistosomiasis Treatment for Preschool Children. Leiden [cited 2013 05/04/2013]. Available from: http://www.tipharma.com/pharmaceutical-research-projects/infectious-diseases/schistosomiasis.html.
  • Sousa-Figueiredo JC, Betson M & Stothard JR (2012) Treatment of schistosomiasis in African infants and preschool-aged children: downward extension and biometric optimization of the current praziquantel dose pole. International Health 4, 95102. Epub 2012/08/10.
  • Stothard JR & Gabrielli AF (2007) Schistosomiasis in African infants and preschool children: to treat or not to treat? Trends in Parasitology 23, 8386. Epub 2007/01/24.
  • Stothard JR, Sousa-Figueiredo JC, Betson M, Bustinduy A & Reinhard-Rupp J (2013) Schistosomiasis in African infants and preschool children: let them now be treated! Trends in Parasitology 29, 197205. Epub 2013/03/08.
  • World Health Organization (2006) Preventive Chemotherapy in Human Helminthiasis: Coordinated Use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. WHO, Geneva.
  • World Health Organization (2010) Report of a Meeting to Review the Results of Studies on the Treatment of Schistosomiasis in Pre-School-Age Children. 13–14 September 2010. Report No, Geneva, Switzerland.