G Model IJP 13921 No. of Pages 3
International Journal of Pharmaceutics xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Note
Paediatric biopharmaceutics classification system: Current status and future decisions Hannah Batchelor * on behalf of the European Paediatric Formulation Initiative (EUPFI) Pharmacy, Pharmacology and Therapeutics Section, Medical School Building, University of Birmingham, Birmingham, B15 2TT, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 December 2013 Received in revised form 28 February 2014 Accepted 28 February 2014 Available online xxx
Biopharmaceutical methods are routinely used in the design of medicines to predict in vivo absorption and hence guide the development of new products. Differences in anatomy and physiology of paediatric patients require adaptation of existing biopharmaceutical methods to ensure that in vivo predictions are relevant for this population. The biopharmaceutics classification system is a tool used in drug development to guide formulation selection and manufacture from early clinical studies through to product launch. The applicability of the biopharmaceutics system to paediatric product development has yet to be explored; this note brings together some key issues in direct extrapolation from adults into paediatric populations. ã 2014 Published by Elsevier B.V.
Keywords: Paediatric Biopharmaceutics Solubility Dose number
Paediatric biopharmaceutics is recognised as an under-researched area where there several accepted knowledge gaps have been highlighted by both the European and United States of America Paediatric Formulation Initiatives (EuPFI and USPFI) (Abdel-Rahman et al., 2012; Batchelor et al., 2013). One notable knowledge gap is the limitations of the biopharmaceutics classification system and its use in the development of paediatric medicines. The biopharmaceutics classification system (BCS) was introduced in 1995 (Amidon et al.,1995) and allows drugs to be classified on the basis of their in vitro solubility and intestinal permeability. There has been limited work to develop a paediatric biopharmaceutics classification system to recognise the differences between paediatric and adult populations (Abdel-Rahman et al., 2012). A molecule is classified as highly permeable according to the BCS where greater than 85–90% of the administered drug is absorbed (EMA 2010; WHO, 2005; Amidon et al., 1995). Several previous papers have correlated in vivo permeability measurement to simpler in vitro methods for example Caco-2 cell lines or even log D or log P values (e.g. Kasim et al., 2004; Lennernäs,1998). It is difficult to predict differences in permeability between paediatric populations and adults as there are limited accurate measures of intestinal permeability in paediatric populations. It is generally accepted that permeability in children above the age of 2 is equivalent to that observed in adults (Batchelor et al., 2013).
* Corresponding author. Tel.: +44 121 414 3717. E-mail address: [email protected] (H. Batchelor).
Highly soluble drugs are those where the highest dose (or dose unit) is soluble in 250 mL aqueous liquid at a relevant pH range. The dose number of a drug is used to normalise solubility measurements of drugs to account for the differences in dose administered. The dose number is calculated as the maximum dose (Mo) divided by the saturated solubility (Cs) multiplied by the initial gastric volume (Vo) (Amidon et al., 1995). Do ¼
Mo Cs V o
In adults a value of 250 mL is used for Vo, this value was derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water of a volume equal to 250 mL (e.g. FDA, 2003). Alternative values have been used in adaptations made to the BCS for alternative populations, for example in Japanese Guidelines for bioequivalence studies the dose number calculation is made using a volume of 150 mL (Japanese Pharmaceutical and Food Safety Bureau, 1997). Typically the dose (Mo) is also reduced in Japanese populations therefore the overall effect on Do was reported to be minimal with very few drugs changing BCS classification between a European/United States of America population and a Japanese population (Dahan et al., 2009). The relative relationship between dose reduction in children and the initial gastric volume (Vo) is less predictable. Paediatric doses are often calculated using allometric scaling, although more recently there have been moves towards scaling for function rather than size (e.g. Abernethy and Burckart, 2010) as well as the use of modelling (e.g. Salazar et al., 2012). The initial gastric volume in children has yet to be determined. A value of 25 mL has been
http://dx.doi.org/10.1016/j.ijpharm.2014.02.046 0378-5173/ã 2014 Published by Elsevier B.V.
Please cite this article in press as: Batchelor, H., Paediatric biopharmaceutics classification system: Current status and future decisions, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.02.046
G Model IJP 13921 No. of Pages 3
2
H. Batchelor / International Journal of Pharmaceutics xxx (2014) xxx–xxx
proposed for children, with no further subdivision based on age, by the United States of America, National Institute of Child Health and Human Development Pediatric Biopharmaceutics Classification System Working Group (Abdel-Rahman et al., 2012). This value may be more appropriate for younger children; as a ten-fold reduction in Vo needs to be matched with a ten-fold reduction in dose (Mo) for the dose number to remain unchanged. A paediatric patient may be classified as a child from 2 to 11 years based on the ICH guidance (EMA, 2001); this represents a very broad population in terms of weight, body surface area etc. associated with a considerable dose range across this population. A drug dosed on a mg/kg scale would vary at least three-fold over the range 2–11 years (Joint Formulary Committee, 2012–2013); therefore the dose number would also increase three-fold if Vo is maintained at a single value. Literature reports on the volume of gastric fluids in the fasted state in children range from a value of approximately 0.4 mL/kg (Meakin et al., 1987; Schwartz et al., 1998) up to a higher value of 0.56 mL/kg (Crawford et al., 1990). These values equate to an adult value of 28.0–37.1 mL (assuming a 70 kg fasted male). The fasted gastric volume typically reported in adults is 40 mL (Goetze et al., 2009). An alternative means to extrapolate the 250 mL Vo value used in the adult BCS classification system to a paediatric population is to ratio this based on the 0.56 mL/kg value to provide a range of Vo representative of the boundaries of each patient population. For example in a 10 year old child weighing of 32 kg; the gastric volume is calculated to be 18 mL (32 0.56); this can be extrapolated to a Vo value of 121 mL ((18/37.1) 250). To explore how a paediatric BCS may differ to that in adults key references were combined to create a database of drugs where paediatric formulations exist (Pediatric Formulations Platform, 2012) and where biopharmaceutics measurements, solubility (converted to dose number) and permeability data (as CLogP values, where high permeability was classified as CLogP 1.35) were readily available (Kasim et al., 2004). The highest dose used in paediatric populations was taken from the British National Formulary for children (Joint Formulary Committee, 2012–2013). In total 56 drugs were identified and Fig.1 shows the spread of these drugs according to their BCS classification based on existing criteria
as well as following recalculation of the dose number for children. The dose number of these 56 drugs were recalculated based on the maximum dose used in a 10 year old child; with associated Vo values of 121 mL as extrapolated based on the relationship of 0.56 mL/kg (based on BNFC data (Joint Formulary Committee, 2012–2013)) and 25 mL as previously proposed (Abdel-Rahman et al., 2012). The resulting spread of compounds by BCS classification is shown in Fig. 1. As anticipated there is a shift in the dose number that reflects the difference in Vo values used within the calculation. The discrepancy in the linearity in the relationship between dose adjustment and dose number adjustment in children results in a change in BCS classification of certain drugs; this is illustrated in Fig. 2. For dose numbers calculated in the traditional manner for adults there are fewer compounds classified as poorly soluble (BCS2 and 4). The consequences of this difference in biopharmaceutics classification are significant in terms of the development of paediatric formulations of existing compounds. BCS1 drugs are eligible for biowaivers which can negate the need for a clinical study to demonstrate bioequivalence between two formulations of the same drug (FDA, 2000). Existing guidance allows bioequivalence studies on alternative formulations intended for paediatric use to be conducted in adults; however, this may not reflect potential differences in pharmacokinetics in the target paediatric population (EMA, 2001; FDA, 2013). Bioequivalence studies conducted where the dose number experienced in paediatric populations is replicated in adults is one alternative to predict the likely pharmacokinetic profile in children and young people although this may be limited by the maximum dose to be tested in adults. However, additional research is required to determine a relevant Vo value to use in paediatric populations. It is apparent that there is a need to establish an age specific biopharmaceutic classification system for children to ensure that development work is relevant in producing age appropriate medicines for children. In addition, standardisation in conducting bioequivalence studies for paediatric products both in adult and in paediatric populations would assist in understanding how medicines perform across wide age bands. The current regulations that
Fig. 1. BCS classification of 56 drugs used in paediatric populations. The dose number calculations reflect adults (diamonds); and children aged 10 years with Vo values of 25 mL (crosses) and 121 mL (squares).
Please cite this article in press as: Batchelor, H., Paediatric biopharmaceutics classification system: Current status and future decisions, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.02.046
G Model IJP 13921 No. of Pages 3
H. Batchelor / International Journal of Pharmaceutics xxx (2014) xxx–xxx
3
Fig. 2. Comparison of BCS classification for the 56 drugs investigated by age and Vo value.
allow interchange of products for BCS1 compounds may not be appropriate in paediatric populations. Acknowledgements The author would like to thank the National Institute for Health Research Medicines for Children Research Network for their support for this research. References Abdel-Rahman, S.M., Amidon, G.L., Kaul, A., Lukacova, V., Vinks, A.A., Knipp, G.T., 2012. Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group. Clinical Therapeutics 34, S11–S24. Abernethy, D.R., Burckart, G.J., 2010. Pediatric dose selection. Clinical Pharmacology and Therapeutics 87, 270–271. Amidon, G.L., Lennernas, H., Shah, V.P., Crison, J.R., 1995. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research 12, 413–420. Batchelor, H., Kendall, R., Desset-Brethes, S., Alex, R., Ernest, T.B., 2013. Application of in-vitro biopharmaceutic methods in development of immediate release oral dosage forms intended for paediatric patients. European Journal of Pharmaceutics and Biopharmaceutics http://dx.doi.org/10.1016/j.ejpb.2013.04.015 (in press, e-pub ahead of print). Crawford, M., Lerman, J., Christensen, S., Farrow-Gillespie, A., 1990. Effects of duration of fasting on gastric fluid pH and volume in healthy children. Anesthesia and Analgesia 71, 400–403. Dahan, A., Miller, J., Amidon, G., 2009. Prediction of Solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. The AAPS Journal 11, 740–746. EMA, 2001. ICH Topic E11. Clinical Investigation of Medicinal Products in the Paediatric Population. CPMP/ICH/2711/99. http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2009/09/WC500002926 pdf [accessed 7/11/2013]. EMA, 2010. Guideline on the Investigation of Bioequivalence. CPMP/EWP/QWP/ 1401/98. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf [accessed 28/02/2014]. FDA, 2000. Guidance for Industry. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville MD, USA http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM070246.pdf [accessed 7/11/2013].
FDA, 2003. Guidance for Industry. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville MD, USA http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM070124.pdf [accessed 7/11/2013]. FDA, 2013. Draft Guidance for Industry and Review Staff: Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling. U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville MD, USA http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM341394.pdf [accessed 7/11 /2013]. Goetze, O., Treier, R., Fox, M., Steingoetter, A., Fried, M., Boesiger, P., Schwizer, W., 2009. The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging. Neurogastroenterology & Motility 21, 725–e742. Japanese Pharmaceutical and Food Safety Bureau, 1997. English translation of Attachment 1 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau, dated February 29, 2012 Guideline for Bioequivalence Studies of Generic Products. http://www.nihs.go.jp/drug/be-guide(e)/Generic/ be97E.pdf [accessed 7/11/2013]. Joint Formulary Committee, 2012–2013. British National Formulary (online). BMJ Group and Pharmaceutical Press, London. [accessed30/06/2013]. Kasim, N.A., Whitehouse, M., Ramachandran, C., Bermejo, M., Lennernäs, H., Hussain, A.S., Junginger, H.E., Stavchansky, S.A., Midha, K.K., Shah, V.P., Amidon, G.L., 2004. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Molecular Pharmacology 1, 85–96. Lennernäs, H., 1998. Human intestinal permeability. Journal of Pharmaceutical Sciences 87, 403–410. Meakin, G., Dingwall, A.E., Addison, G.M., 1987. Effects of fasting and oral premedication on the pH and volume of gastric aspirate in children. British Journal of Anaesthesia 59, 678–682. Pediatric Formulations Platform, 2012. Intra-Agency Agreement Between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the U.S. Food and Drug Administration (FDA) Oral Formulations Platform—Report 1. http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/ upload/Formulations_Table_for_Web_11-02-11. pdf [accessed 7/11/2013]. Salazar, D.E., Song, S.H., Shi, J., Rohatagi, S., Heyrman, R., Wada, D.R., Carrothers, T.J., 2012. The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects. Clinical Pharmacology and Therapeutics 91, 250–256. Schwartz, D.A., Connelly, N.R., Theroux, C.A., Gibson, C.S., Ostrom, D.N., Dunn, S.M., Hirsch, B.Z., Angelides, A.G., 1998. Gastric contents in children presenting for upper endoscopy. Anesthesia and Analgesia 87, 757–760. WHO, 2005. Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. Working document QAS/04.093. http://www.who.int/medicines/services/expertcommittees/ pharmprep/QAS04_093Rev4_final.pdf [accessed 28/02/2014].
Please cite this article in press as: Batchelor, H., Paediatric biopharmaceutics classification system: Current status and future decisions, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.02.046
International Journal of Pharmaceutics xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Note
Paediatric biopharmaceutics classification system: Current status and future decisions Hannah Batchelor * on behalf of the European Paediatric Formulation Initiative (EUPFI) Pharmacy, Pharmacology and Therapeutics Section, Medical School Building, University of Birmingham, Birmingham, B15 2TT, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 December 2013 Received in revised form 28 February 2014 Accepted 28 February 2014 Available online xxx
Biopharmaceutical methods are routinely used in the design of medicines to predict in vivo absorption and hence guide the development of new products. Differences in anatomy and physiology of paediatric patients require adaptation of existing biopharmaceutical methods to ensure that in vivo predictions are relevant for this population. The biopharmaceutics classification system is a tool used in drug development to guide formulation selection and manufacture from early clinical studies through to product launch. The applicability of the biopharmaceutics system to paediatric product development has yet to be explored; this note brings together some key issues in direct extrapolation from adults into paediatric populations. ã 2014 Published by Elsevier B.V.
Keywords: Paediatric Biopharmaceutics Solubility Dose number
Paediatric biopharmaceutics is recognised as an under-researched area where there several accepted knowledge gaps have been highlighted by both the European and United States of America Paediatric Formulation Initiatives (EuPFI and USPFI) (Abdel-Rahman et al., 2012; Batchelor et al., 2013). One notable knowledge gap is the limitations of the biopharmaceutics classification system and its use in the development of paediatric medicines. The biopharmaceutics classification system (BCS) was introduced in 1995 (Amidon et al.,1995) and allows drugs to be classified on the basis of their in vitro solubility and intestinal permeability. There has been limited work to develop a paediatric biopharmaceutics classification system to recognise the differences between paediatric and adult populations (Abdel-Rahman et al., 2012). A molecule is classified as highly permeable according to the BCS where greater than 85–90% of the administered drug is absorbed (EMA 2010; WHO, 2005; Amidon et al., 1995). Several previous papers have correlated in vivo permeability measurement to simpler in vitro methods for example Caco-2 cell lines or even log D or log P values (e.g. Kasim et al., 2004; Lennernäs,1998). It is difficult to predict differences in permeability between paediatric populations and adults as there are limited accurate measures of intestinal permeability in paediatric populations. It is generally accepted that permeability in children above the age of 2 is equivalent to that observed in adults (Batchelor et al., 2013).
* Corresponding author. Tel.: +44 121 414 3717. E-mail address: [email protected] (H. Batchelor).
Highly soluble drugs are those where the highest dose (or dose unit) is soluble in 250 mL aqueous liquid at a relevant pH range. The dose number of a drug is used to normalise solubility measurements of drugs to account for the differences in dose administered. The dose number is calculated as the maximum dose (Mo) divided by the saturated solubility (Cs) multiplied by the initial gastric volume (Vo) (Amidon et al., 1995). Do ¼
Mo Cs V o
In adults a value of 250 mL is used for Vo, this value was derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water of a volume equal to 250 mL (e.g. FDA, 2003). Alternative values have been used in adaptations made to the BCS for alternative populations, for example in Japanese Guidelines for bioequivalence studies the dose number calculation is made using a volume of 150 mL (Japanese Pharmaceutical and Food Safety Bureau, 1997). Typically the dose (Mo) is also reduced in Japanese populations therefore the overall effect on Do was reported to be minimal with very few drugs changing BCS classification between a European/United States of America population and a Japanese population (Dahan et al., 2009). The relative relationship between dose reduction in children and the initial gastric volume (Vo) is less predictable. Paediatric doses are often calculated using allometric scaling, although more recently there have been moves towards scaling for function rather than size (e.g. Abernethy and Burckart, 2010) as well as the use of modelling (e.g. Salazar et al., 2012). The initial gastric volume in children has yet to be determined. A value of 25 mL has been
http://dx.doi.org/10.1016/j.ijpharm.2014.02.046 0378-5173/ã 2014 Published by Elsevier B.V.
Please cite this article in press as: Batchelor, H., Paediatric biopharmaceutics classification system: Current status and future decisions, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.02.046
G Model IJP 13921 No. of Pages 3
2
H. Batchelor / International Journal of Pharmaceutics xxx (2014) xxx–xxx
proposed for children, with no further subdivision based on age, by the United States of America, National Institute of Child Health and Human Development Pediatric Biopharmaceutics Classification System Working Group (Abdel-Rahman et al., 2012). This value may be more appropriate for younger children; as a ten-fold reduction in Vo needs to be matched with a ten-fold reduction in dose (Mo) for the dose number to remain unchanged. A paediatric patient may be classified as a child from 2 to 11 years based on the ICH guidance (EMA, 2001); this represents a very broad population in terms of weight, body surface area etc. associated with a considerable dose range across this population. A drug dosed on a mg/kg scale would vary at least three-fold over the range 2–11 years (Joint Formulary Committee, 2012–2013); therefore the dose number would also increase three-fold if Vo is maintained at a single value. Literature reports on the volume of gastric fluids in the fasted state in children range from a value of approximately 0.4 mL/kg (Meakin et al., 1987; Schwartz et al., 1998) up to a higher value of 0.56 mL/kg (Crawford et al., 1990). These values equate to an adult value of 28.0–37.1 mL (assuming a 70 kg fasted male). The fasted gastric volume typically reported in adults is 40 mL (Goetze et al., 2009). An alternative means to extrapolate the 250 mL Vo value used in the adult BCS classification system to a paediatric population is to ratio this based on the 0.56 mL/kg value to provide a range of Vo representative of the boundaries of each patient population. For example in a 10 year old child weighing of 32 kg; the gastric volume is calculated to be 18 mL (32 0.56); this can be extrapolated to a Vo value of 121 mL ((18/37.1) 250). To explore how a paediatric BCS may differ to that in adults key references were combined to create a database of drugs where paediatric formulations exist (Pediatric Formulations Platform, 2012) and where biopharmaceutics measurements, solubility (converted to dose number) and permeability data (as CLogP values, where high permeability was classified as CLogP 1.35) were readily available (Kasim et al., 2004). The highest dose used in paediatric populations was taken from the British National Formulary for children (Joint Formulary Committee, 2012–2013). In total 56 drugs were identified and Fig.1 shows the spread of these drugs according to their BCS classification based on existing criteria
as well as following recalculation of the dose number for children. The dose number of these 56 drugs were recalculated based on the maximum dose used in a 10 year old child; with associated Vo values of 121 mL as extrapolated based on the relationship of 0.56 mL/kg (based on BNFC data (Joint Formulary Committee, 2012–2013)) and 25 mL as previously proposed (Abdel-Rahman et al., 2012). The resulting spread of compounds by BCS classification is shown in Fig. 1. As anticipated there is a shift in the dose number that reflects the difference in Vo values used within the calculation. The discrepancy in the linearity in the relationship between dose adjustment and dose number adjustment in children results in a change in BCS classification of certain drugs; this is illustrated in Fig. 2. For dose numbers calculated in the traditional manner for adults there are fewer compounds classified as poorly soluble (BCS2 and 4). The consequences of this difference in biopharmaceutics classification are significant in terms of the development of paediatric formulations of existing compounds. BCS1 drugs are eligible for biowaivers which can negate the need for a clinical study to demonstrate bioequivalence between two formulations of the same drug (FDA, 2000). Existing guidance allows bioequivalence studies on alternative formulations intended for paediatric use to be conducted in adults; however, this may not reflect potential differences in pharmacokinetics in the target paediatric population (EMA, 2001; FDA, 2013). Bioequivalence studies conducted where the dose number experienced in paediatric populations is replicated in adults is one alternative to predict the likely pharmacokinetic profile in children and young people although this may be limited by the maximum dose to be tested in adults. However, additional research is required to determine a relevant Vo value to use in paediatric populations. It is apparent that there is a need to establish an age specific biopharmaceutic classification system for children to ensure that development work is relevant in producing age appropriate medicines for children. In addition, standardisation in conducting bioequivalence studies for paediatric products both in adult and in paediatric populations would assist in understanding how medicines perform across wide age bands. The current regulations that
Fig. 1. BCS classification of 56 drugs used in paediatric populations. The dose number calculations reflect adults (diamonds); and children aged 10 years with Vo values of 25 mL (crosses) and 121 mL (squares).
Please cite this article in press as: Batchelor, H., Paediatric biopharmaceutics classification system: Current status and future decisions, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.02.046
G Model IJP 13921 No. of Pages 3
H. Batchelor / International Journal of Pharmaceutics xxx (2014) xxx–xxx
3
Fig. 2. Comparison of BCS classification for the 56 drugs investigated by age and Vo value.
allow interchange of products for BCS1 compounds may not be appropriate in paediatric populations. Acknowledgements The author would like to thank the National Institute for Health Research Medicines for Children Research Network for their support for this research. References Abdel-Rahman, S.M., Amidon, G.L., Kaul, A., Lukacova, V., Vinks, A.A., Knipp, G.T., 2012. Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group. Clinical Therapeutics 34, S11–S24. Abernethy, D.R., Burckart, G.J., 2010. Pediatric dose selection. Clinical Pharmacology and Therapeutics 87, 270–271. Amidon, G.L., Lennernas, H., Shah, V.P., Crison, J.R., 1995. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research 12, 413–420. Batchelor, H., Kendall, R., Desset-Brethes, S., Alex, R., Ernest, T.B., 2013. Application of in-vitro biopharmaceutic methods in development of immediate release oral dosage forms intended for paediatric patients. European Journal of Pharmaceutics and Biopharmaceutics http://dx.doi.org/10.1016/j.ejpb.2013.04.015 (in press, e-pub ahead of print). Crawford, M., Lerman, J., Christensen, S., Farrow-Gillespie, A., 1990. Effects of duration of fasting on gastric fluid pH and volume in healthy children. Anesthesia and Analgesia 71, 400–403. Dahan, A., Miller, J., Amidon, G., 2009. Prediction of Solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. The AAPS Journal 11, 740–746. EMA, 2001. ICH Topic E11. Clinical Investigation of Medicinal Products in the Paediatric Population. CPMP/ICH/2711/99. http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2009/09/WC500002926 pdf [accessed 7/11/2013]. EMA, 2010. Guideline on the Investigation of Bioequivalence. CPMP/EWP/QWP/ 1401/98. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf [accessed 28/02/2014]. FDA, 2000. Guidance for Industry. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville MD, USA http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM070246.pdf [accessed 7/11/2013].
FDA, 2003. Guidance for Industry. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville MD, USA http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM070124.pdf [accessed 7/11/2013]. FDA, 2013. Draft Guidance for Industry and Review Staff: Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling. U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville MD, USA http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM341394.pdf [accessed 7/11 /2013]. Goetze, O., Treier, R., Fox, M., Steingoetter, A., Fried, M., Boesiger, P., Schwizer, W., 2009. The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging. Neurogastroenterology & Motility 21, 725–e742. Japanese Pharmaceutical and Food Safety Bureau, 1997. English translation of Attachment 1 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau, dated February 29, 2012 Guideline for Bioequivalence Studies of Generic Products. http://www.nihs.go.jp/drug/be-guide(e)/Generic/ be97E.pdf [accessed 7/11/2013]. Joint Formulary Committee, 2012–2013. British National Formulary (online). BMJ Group and Pharmaceutical Press, London. [accessed30/06/2013]. Kasim, N.A., Whitehouse, M., Ramachandran, C., Bermejo, M., Lennernäs, H., Hussain, A.S., Junginger, H.E., Stavchansky, S.A., Midha, K.K., Shah, V.P., Amidon, G.L., 2004. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Molecular Pharmacology 1, 85–96. Lennernäs, H., 1998. Human intestinal permeability. Journal of Pharmaceutical Sciences 87, 403–410. Meakin, G., Dingwall, A.E., Addison, G.M., 1987. Effects of fasting and oral premedication on the pH and volume of gastric aspirate in children. British Journal of Anaesthesia 59, 678–682. Pediatric Formulations Platform, 2012. Intra-Agency Agreement Between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the U.S. Food and Drug Administration (FDA) Oral Formulations Platform—Report 1. http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/ upload/Formulations_Table_for_Web_11-02-11. pdf [accessed 7/11/2013]. Salazar, D.E., Song, S.H., Shi, J., Rohatagi, S., Heyrman, R., Wada, D.R., Carrothers, T.J., 2012. The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects. Clinical Pharmacology and Therapeutics 91, 250–256. Schwartz, D.A., Connelly, N.R., Theroux, C.A., Gibson, C.S., Ostrom, D.N., Dunn, S.M., Hirsch, B.Z., Angelides, A.G., 1998. Gastric contents in children presenting for upper endoscopy. Anesthesia and Analgesia 87, 757–760. WHO, 2005. Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. Working document QAS/04.093. http://www.who.int/medicines/services/expertcommittees/ pharmprep/QAS04_093Rev4_final.pdf [accessed 28/02/2014].
Please cite this article in press as: Batchelor, H., Paediatric biopharmaceutics classification system: Current status and future decisions, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.02.046
