Hostname: page-component-7479d7b7d-767nl Total loading time: 0 Render date: 2024-07-13T11:51:43.129Z Has data issue: false hasContentIssue false

Antiparasitic drugs for paediatrics: systematic review, formulations, pharmacokinetics, safety, efficacy and implications for control

Published online by Cambridge University Press:  24 February 2011

JENNIFER KEISER*
Affiliation:
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH–4002 Basel, Switzerland University of Basel, P.O. Box, CH–4003 Basel, Switzerland
KATRIN INGRAM
Affiliation:
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH–4002 Basel, Switzerland University of Basel, P.O. Box, CH–4003 Basel, Switzerland
JÜRG UTZINGER
Affiliation:
University of Basel, P.O. Box, CH–4003 Basel, Switzerland Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, P.O. Box, CH–4002 Basel, Switzerland
*
*Corresponding author: Jennifer Keiser, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH–4002 Basel, Switzerland. Tel.: +4161 284-8218. Fax: +41 61 284-8105. E-mail: jennifer.keiser@unibas.ch

Summary

Drug development for paediatric applications entails a number of challenges, such as the wide age spectrum covered – from birth to adolescence – and developmental changes in physiology during biological maturation that influence the efficacy and toxicity of drugs. Safe and efficacious antiparasitic drugs for children are of pivotal importance given the large proportion of burden attributable to parasitic diseases in this age group, and growing efforts to administer, as widely as possible, antiparasitic drugs to at-risk populations, such as infants and school-aged children, often without prior diagnosis. The purpose of this review is to investigate whether antiparasitic drugs have been adequately studied for use in paediatrics. We approached this issue through a systematic review using PubMed and the Cochrane Central Register of Trials covering a period of 10 years and 8 months until the end of August 2010 to identify trials that investigated efficacy, safety and pharmacokinetic (PK) parameters of antiparasitic drugs for paediatrics. Overall, 269 clinical drug trials and 17 PK studies met our inclusion criteria. Antimalarial drugs were the most commonly studied medicines (82·6%). Most trials were carried out in Africa and children aged 2–11 years were the age group most often investigated. Additionally, we critically examined available drug formulations for anthelminthics and identified a number of shortcomings that are discussed. Finally, we shed new light on current proposals to expand ‘preventive chemotherapy’ to preschool-aged children and emphasise that new research, including risk-benefit analyses, are needed before such a strategy can be adopted more widely.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Aponte, J. J., Schellenberg, D., Egan, A., Breckenridge, A., Carneiro, I., Critchley, J., Danquah, I., Dodoo, A., Kobbe, R., Lell, B., May, J., Premji, Z., Sanz, S., Sevene, E., Soulaymani-Becheikh, R., Winstanley, P., Adjei, S., Anemana, S., Chandramohan, D., Issifou, S., Mockenhaupt, F., Owusu-Agyei, S., Greenwood, B., Grobusch, M. P., Kremsner, P. G., Macete, E., Mshinda, H., Newman, R. D., Slutsker, L., Tanner, M., Alonso, P. and Menendez, C. (2009). Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials. Lancet 374, 15331542.CrossRefGoogle ScholarPubMed
Barsch, M. and Otte, A. (2010). The legal standards for the radioactive or non radioactive drugs research and approval in the European Community and in Germany after the thalidomide catastrophe. Hellenic Journal of Nuclear Medicine 13, 4551.Google ScholarPubMed
Bethony, J., Brooker, S., Albonico, M., Geiger, S. M., Loukas, A., Diemert, D. and Hotez, P. J. (2006). Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 367, 15211532.CrossRefGoogle ScholarPubMed
Betson, M., Sousa-Figueiredo, J. C., Rowell, C., Kabatereine, N. B. and Stothard, J. R. (2010). Intestinal schistosomiasis in mothers and young children in Uganda: investigation of field-applicable markers of bowel morbidity. American Journal of Tropical Medicine and Hygiene 83, 10481055.CrossRefGoogle Scholar
Black, R. E., Cousens, S., Johnson, H. L., Lawn, J. E., Rudan, I., Bassani, D. G., Jha, P., Campbell, H., , Fischer Walker, , C., Cibulskis, R., Eisele, T., Liu, L., Mathers, C., Child Health Epidemiology Reference Group of WHO and UNICEF (2010). Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 375, 19691987.CrossRefGoogle ScholarPubMed
Boots, I., Sukhai, R. N., Klein, R. H., Holl, R. A., Wit, J. M., Cohen, A. F. and Burggraaf, J. (2007). Stimulation programs for pediatric drug research – do children really benefit? European Journal of Pediatrics 166, 849855.CrossRefGoogle ScholarPubMed
Bosompem, K. M., Bentum, I. A., Otchere, J., Anyan, W. K., Brown, C. A., Osada, Y., Takeo, S., Kojima, S. and Ohta, N. (2004). Infant schistosomiasis in Ghana: a survey in an irrigation community. Tropical Medicine and International Health 9, 917922.CrossRefGoogle Scholar
Breitkreutz, J. (2009). Dosage forms for children. After the EU Reform. Pharmazie unserer Zeit 38, 3037.CrossRefGoogle ScholarPubMed
Breitkreutz, J. and Boos, J. (2007). Paediatric and geriatric drug delivery. Expert Opinion on Drug Delivery 4, 3745.CrossRefGoogle ScholarPubMed
Breitkreutz, J., Tuleu, C. and Solomonidou, D. (2007). Paediatric formulations. In: Guide to Paediatric Clinical Research (ed. Rose, K. and van den Anker, J. N.), pp. 6577. Karger, Basel.Google Scholar
Choonara, I. (2009). Ethical and safety aspects of clinical trials in neonates. Early Human Development 85, S1920.CrossRefGoogle ScholarPubMed
Cohen, J., Dibner, M. S. and Wilson, A. (2010). Development of and access to products for neglected diseases. PLoS One 5, e10610.CrossRefGoogle ScholarPubMed
Conroy, S., McIntyre, J., Choonara, I. and Stephenson, T. (2000). Drug trials in children: problems and the way forward. British Journal Clinical Pharmacology 49, 9397.CrossRefGoogle ScholarPubMed
Doenhoff, M. J., Hagan, P., Cioli, D., Southgate, V., Pica-Mattoccia, L., Botros, S., Coles, G., Tchuem Tchuenté, L. A., Mbaye, A. and Engels, D. (2009). Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs. Parasitology 136, 18251835.CrossRefGoogle ScholarPubMed
European Medicines Agency (2006). Reflection paper: formulations of choice for the paediatric population. European Medicines Agency, London.Google Scholar
Fairweather, I. (2009). Triclabendazole progress report, 2005–2009: an advancement of learning? Journal of Helminthology 83, 139150.CrossRefGoogle ScholarPubMed
Fenwick, A., Webster, J. P., Bosque-Oliva, E., Blair, L., Fleming, F. M., Zhang, Y., Garba, A., Stothard, J. R., Gabrielli, A. F., Clements, A. C. A., Kabatereine, N. B., Toure, S., Dembele, R., Nyandindi, U., Mwansa, J. and Koukounari, A. (2009). The Schistosomiasis Control Initiative (SCI): rationale, development and implementation from 2002–2008. Parasitology 136, 17191730.CrossRefGoogle ScholarPubMed
Fox, L. M. (2006). Ivermectin: uses and impact 20 years on. Current Opinion in Infectious Diseases 19, 588593.CrossRefGoogle Scholar
Garba, A., Barkire, N., Djibo, A., Lamine, M. S., Sofo, B., Gouvras, A. N., Bosque-Oliva, E., Webster, J. P., Stothard, J. R., Utzinger, J. and Fenwick, A. (2010). Schistosomiasis in infants and preschool-aged children: infection in a single Schistosoma haematobium and a mixed S. haematobium-S. mansoni foci of Niger. Acta Tropica 115, 212219.CrossRefGoogle Scholar
Geary, T. G., Woo, K., McCarthy, J. S., Mackenzie, C. D., Horton, J., Prichard, R. K., de Silva, N. R., Olliaro, P. L., Lazdins-Helds, J. K., Engels, D. A. and Bundy, D. A. (2010). Unresolved issues in anthelmintic pharmacology for helminthiases of humans. International Journal for Parasitology 40, 113.CrossRefGoogle ScholarPubMed
Gosling, R. D., Cairns, M. E., Chico, R. M. and Chandramohan, D. (2010). Intermittent preventive treatment against malaria: an update. Expert Reviews of Anti-Infective Therapy 8, 589606.CrossRefGoogle ScholarPubMed
Hotez, P. J., Engels, D., Fenwick, A. and Savioli, L. (2010). Africa is desperate for praziquantel. Lancet 376, 496498.CrossRefGoogle ScholarPubMed
Hotez, P. J., Molyneux, D. H., Fenwick, A., Kumaresan, J., Ehrlich Sachs, S., Sachs, J. D. and Savioli, L. (2007). Control of neglected tropical diseases. New England Journal of Medicine 357, 10181027.CrossRefGoogle ScholarPubMed
Howie, R. C. (2011). Blood sample volumes in child health research: review of safe limits. Bulletin of the World Health Organization 89, 4653.CrossRefGoogle ScholarPubMed
Jordan, P. and Webbe, G. (1969). Human Schistosomiasis. William Heinemann Medical Books Ltd, London.Google Scholar
Kastner, M., Wilczynski, N. L., Walker-Dilks, C., McKibbon, K. A. and Haynes, B. (2006). Age-specific search strategies for Medline. Journal of Medical Internet Research 8, e25.CrossRefGoogle ScholarPubMed
Kayser, O., Olbrich, C., Croft, S. L. and Kiderlen, A. F. (2003). Formulation and biopharmaceutical issues in the development of drug delivery systems for antiparasitic drugs. Parasitology Research 90 (Suppl. 2), S63S70.CrossRefGoogle ScholarPubMed
Kearns, G. L., Abdel-Rahman, S. M., Alander, S. W., Blowey, D. L., Leeder, J. S. and Kauffman, R. E. (2003). Developmental pharmacology – drug disposition, action, and therapy in infants and children. New England Journal of Medicine 349, 11571167.CrossRefGoogle ScholarPubMed
Keiser, J., Engels, D., Büscher, G. and Utzinger, J. (2005). Triclabendazole for the treatment of fascioliasis and paragonimiasis. Expert Opinion on Investigational Drugs 14, 15131526.CrossRefGoogle ScholarPubMed
Keiser, J. and Utzinger, J. (2007). Advances in the discovery and development of trematocidal drugs. Expert Opinion on Drug Discovery 2 (Suppl. 1), S9S23.CrossRefGoogle ScholarPubMed
Keiser, J. and Utzinger, J. (2008). Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA 299, 19371948.CrossRefGoogle ScholarPubMed
Keiser, J. and Utzinger, J. (2010). The drugs we have and the drugs we need against major helminth infections. Advances in Parasitology 73, 197230.CrossRefGoogle ScholarPubMed
Kuepfer, I. and Burri, C. (2009). Reflections on clinical research in sub-Saharan Africa. International Journal for Parasitology 39, 947954.CrossRefGoogle ScholarPubMed
Lippert, C., Gbenado, S., Qiu, C., Lavin, B. and Kovacs, S. J. (2005). The bioequivalence of telithromycin administered orally as crushed tablets versus tablets swallowed whole. Journal of Clinical Pharmacology 45, 10251031.CrossRefGoogle ScholarPubMed
Lunn, P. G. and Northrop-Clewes, C. A. (1993). The impact of gastrointestinal parasites on protein-energy malnutrition in man. Proceedings of the Nutrition Society 52, 101111.CrossRefGoogle ScholarPubMed
Macleod, S. (2010). Therapeutic drug monitoring in paediatrics: how do children differ? Therapeutic Drug Monitoring 32, 253256.CrossRefGoogle ScholarPubMed
Mafiana, C. F., Ekpo, U. F. and Ojo, D. A. (2003). Urinary schistosomiasis in preschool children in settlements around Oyan Reservoir in Ogun State, Nigeria: implications for control. Tropical Medicine and International Health 8, 7882.CrossRefGoogle ScholarPubMed
Mellin, G. W. and Katzenstein, M. (1962). The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. New England Journal of Medicine 267, 12381244.CrossRefGoogle ScholarPubMed
Mennella, J. A. and Beauchamp, G. K. (2008). Optimizing oral medications for children. Clinical Therapy 30, 21202132.CrossRefGoogle ScholarPubMed
Meyer, T., Sekljic, H., Fuchs, S., Bothe, H., Schollmeyer, D. and Miculka, C. (2009). Taste, a new incentive to switch to (R)-praziquantel in schistosomiasis treatment. PLoS Neglected Tropical Diseases 3, e357.CrossRefGoogle Scholar
Michele, T. M., Knorr, B., Vadas, E. B. and Reiss, T. F. (2002). Safety of chewable tablets for children. Journal of Asthma 39, 391403.CrossRefGoogle ScholarPubMed
Milne, C. P. (2009). Pharmaceutical economics and applications to pediatrics: business case development. In Pediatric Drug Development Concepts and Applications (ed. Mulberg, A. E., Silber, S. A. and van den Anker, J. N.) pp. 3957. John Wiley & Sons, Hoboken.Google Scholar
Milne, C. P. and Bruss, J. B. (2008). The economics of paediatric formulation development for off-patent drugs. Clinical Therapy 30, 21332145.CrossRefGoogle ScholarPubMed
Montresor, A., Awasthi, S. and Crompton, D. W. T. (2003). Use of benzimidazoles in children younger than 24 months for the treatment of soil-transmitted helminthiasis. Acta Tropica 86, 223232.CrossRefGoogle ScholarPubMed
Moran, M. (2005). A breakthrough in R&D for neglected diseases: new ways to get the drugs we need. PLoS Medicine 2, e302.CrossRefGoogle Scholar
Moran, M., Guzman, J., Ropars, A. L., McDonald, A., Jameson, N., Omune, B., Ryan, S. and Wu, L. (2009). Neglected disease research and development: how much are we really spending? PLoS Medicine 6, e30.CrossRefGoogle ScholarPubMed
Na Bangchang, K., Karbwang, J., Pungpak, S., Radomyos, B. and Bunnag, D. (1993). Pharmacokinetics of praziquantel in patients with opisthorchiasis. Southeast Asian Journal of Tropical Medicine and Public Health 24, 717723.Google ScholarPubMed
Nor Aripin, K. N. B., Choonara, I. and Sammons, H. M. (2010 b). A systematic review of paediatric randomised controlled drug trials published in 2007. Archives of Disease in Childhood 95, 469473.CrossRefGoogle Scholar
Nor Aripin, K. N. B., Sammons, H. M. and Choonara, I. (2010 a). Published paediatric randomized drug trials in developing countries, 1996–2002. Paediatric Drugs 12, 99103.CrossRefGoogle ScholarPubMed
Nwaka, S., and Hudson, A. (2006). Innovative lead discovery strategies for tropical diseases. Nature Reviews Drug Discovery 5, 941955.CrossRefGoogle ScholarPubMed
Odogwu, S. E., Ramamurthy, N. K., Kabatereine, N. B., Kazibwe, F., Tukahebwa, E., Webster, J. P., Fenwick, A. and Stothard, J. R. (2006). Schistosoma mansoni in infants (aged <3 years) along the Ugandan shoreline of Lake Victoria. Annals of Tropical Medicine and Parasitology 100, 315326.CrossRefGoogle ScholarPubMed
Pandolfini, C. and Bonati, M. (2005). A literature review on off-label drug use in children. European Journal of Pediatrics 164, 552558.CrossRefGoogle ScholarPubMed
Pifferi, G. and Restani, P. (2003). The safety of pharmaceutical excipients. Farmaco 58, 541550.CrossRefGoogle ScholarPubMed
Rakhmanina, N. Y. and van den Anker, J. N. (2009). Developmental pharmacology issues: neonates, infants and children. In Pediatric Drug Development Concepts and Applications (ed. Mulberg, A. E., Silber, S. A. and van den Anker, J. N.), pp. 231242. John Wiley & Sons, Hoboken.Google Scholar
Rose, K. (2009). European perspective. In Pediatric Drug Development Concepts and Applications (ed. Mulberg, A. E., Silber, S. A. and van den Anker, J. N.), pp. 137152. John Wiley & Sons, Hoboken.Google Scholar
Sammons, H. M. and Choonara, I. (2005). Clinical trials of medication in children, 1996–2002. European Journal of Clinical Pharmacology 61, 165167.CrossRefGoogle ScholarPubMed
Savioli, L., Gabrielli, A. F., Montresor, A., Chitsulo, L. and Engels, D. (2009). Schistosomiasis control in Africa: 8 years after World Health Assembly Resolution 54·19. Parasitology 136, 16771681.CrossRefGoogle ScholarPubMed
Schachter, A. D. and Ramoni, M. F. (2007). Paediatric drug development. Nature Reviews Drug Discovery 6, 429430.CrossRefGoogle ScholarPubMed
Schwartz, C., Issanchou, S. and Nicklaus, S. (2009). Developmental changes in the acceptance of the five basic tastes in the first year of life. British Journal of Nutrition 102, 13751385.CrossRefGoogle ScholarPubMed
Sousa-Figueiredo, J. C., Day, M., Betson, M., Kabatereine, N. B. and Stothard, J. R. (2010 a). An inclusive dose pole for treatment of schistosomiasis in infants and preschool children with praziquantel. Transaction of the Royal Society of Tropical Medicine and Hygiene 104, 740742.CrossRefGoogle ScholarPubMed
Sousa-Figueiredo, J. C., Pleasant, J., Day, M., Betson, M., Rollinson, D., Montresor, A., Kazibwe, F., Kabatereine, N. B. and Stothard, J. R. (2010 b). Treatment of intestinal schistosomiasis in Ugandan preschool children: best diagnosis, treatment efficacy and side-effects, and an extended praziquantel dosing pole. International Health 2, 103113.CrossRefGoogle Scholar
Standing, J. F. and Tuleu, C. (2005). Paediatric formulations – getting to the heart of the problem. International Journal of Pharmacy 300, 5666.CrossRefGoogle Scholar
Stothard, J. R. and Gabrielli, A. F. (2007). Schistosomiasis in African infants and preschool children: to treat or not to treat? Trends in Parasitology 23, 8386.CrossRefGoogle ScholarPubMed
Stothard, J. R., Sousa-Figuereido, J. C., Betson, M., Adriko, M., Arinaitwe, M., Rowell, C., Besiyge, F. and Kabatereine, N. B. (2011). Schistosoma mansoni infections in young children: when are schistosome antigens in urine, eggs in stool and antibodies to eggs first detectable? PLoS Neglected Tropical Diseases 5, e938.CrossRefGoogle ScholarPubMed
Stötter, H. (2007). Paediatric drug development – historical background of regulatory initiatives. In Guide to Paediatric Clinical Research (ed. Rose, K. and van den Anker, J. N.), pp. 2532. Karger, Basel.Google Scholar
Strolin Benedetti, M., Whomsley, R. and Baltes, E. L. (2005). Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opinion on Drug Metabolism and Toxicology 1, 447471.CrossRefGoogle ScholarPubMed
Taylor, M. J., Hoerauf, A. and Bockarie, M. (2010). Lymphatic filariasis and onchocerciasis. Lancet 376, 11751185.CrossRefGoogle ScholarPubMed
United Nations (2009). World Population Prospects: The 2008 Revision. United Nations, Department of Economic and Social Affairs Population Division, New York.Google Scholar
Utzinger, J., Raso, G., Brooker, S., de Savigny, D., Tanner, M., Ørnbjerg, N., Singer, B. H. and N'Goran, E. K. (2009). Schistosomiasis and neglected tropical diseases: towards integrated and sustainable control and a word of caution. Parasitology 136, 18591874.CrossRefGoogle Scholar
WHO (1985). The control of schistosomiasis: report of a WHO expert committee. WHO Technical Report Series 728, 1113.Google Scholar
WHO (2002 a). Report of the WHO Informal Consultation on the Use of Praziquantel during Pregnancy/Lactation and Albendazole/Mebendazole in Children under 24 Months. World Health Organization, Geneva.Google Scholar
WHO (2002 b). Prevention and control of schistosomiasis and soil-transmitted helminthiasis: report of a WHO expert committee. WHO Technical Report Series 912, 157.Google Scholar
WHO (2006). Preventive Chemotherapy in Human Helminthiasis: Coordinated Use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. World Health Organization, Geneva.Google Scholar
WHO (2007 a). Promoting Safety of Medicines for Children. World Health Organization, Geneva.Google Scholar
WHO (2007 b). The Selection and Use of Essential Medicines. World Health Institution, Geneva.Google Scholar
WHO (2008 a). The Global Burden of Disease: 2004 Update. World Health Organization, Geneva.Google Scholar
WHO (2008 b). Soil-transmitted helminthiasis. Progress report on number of children treated with anthelminthic drugs: an update towards the 2010 global target. Weekly Epidemiological Records 82, 237252.Google Scholar
WHO (2010 a). Working to Overcome the Global Impact of Neglected Tropical Diseases. First WHO Report on Neglected Tropical Diseases. World Health Organization, Geneva.Google Scholar
WHO (2010 b). Schistosomiasis. Weekly Epidemiological Records 85, 158164.Google Scholar
WHO (2010 c). Soil-transmitted helminthiasis. Weekly Epidemiological Records 85, 141147.Google Scholar
Wu, M. H., Wei, C. C., Xu, Z. Y., Yuan, H. C., Lian, W. N., Yang, Q. J., Chen, M., Jiang, Q. W., Wang, C. Z., Zhang, S. J., Liu, Z. D., Wei, R. M., Yuan, S. J., Hu, L. S. and Wu, Z. S. (1991). Comparison of the therapeutic efficacy and side effects of a single dose of levo-praziquantel with mixed isomer praziquantel in 278 cases of schistosomiasis japonica. American Journal Tropical Medicine and Hygiene 45, 345349.CrossRefGoogle ScholarPubMed