G Model IJP 14882 No. of Pages 3
International Journal of Pharmaceutics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Rapid communication
Developmental pharmacology: A moving target Janko Samardzic a, * , Karel Allegaert b , Milica Bajcetic a,c a
Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Serbia Department of Development and Regeneration, KU Leuven and Neonatal Intensive Care Unit, University Hospitals Leuven, Belgium c Clinical Pharmacology Unit, University Children’s Hospital, Belgrade, Serbia b
A R T I C L E I N F O
A B S T R A C T
Article history: Available online xxx
The main characteristic of pediatric and neonatal pharmacotherapy still is the insufficient availability of drugs with confirmed efficacy and safety data in children. Children differ from adults in the physiological, psychological and developmental terms and this subsequently results in differences in anticipated drug potency, efficacy and toxicity. This paper is focused on the most prominent issues of the contemporary developmental pharmacology. Child’s age and development can significantly affect drug pharmacokinetics (PK) processes. The dosage of drugs for children must be based on the physiological characteristics, as well as PK parameters of the drug obtained from the clinical trials with children. While knowledge about the impact of developmental changes on drug PK is increasing, information regarding pharmacodynamics (PD) is still more limited. The examples from clinical and animal data on ontogeny of receptors resulted in strong evidence for changes in drug response during development, in addition to but independent from PK alterations. In order to improve the use of medicines in children, it is essentially to know the complex processes of growth and development into the pediatric drug development programs. This is because absence of PK/PD data leads to increased risk of over- or under-dosing, adverse reactions or inefficiency. ã 2015 Elsevier B.V. All rights reserved.
Keywords: Children Drugs Developmental pharmacology GABA
The main characteristic of contemporary pediatric and neonatal pharmacotherapy still is the insufficient availability of drugs with confirmed efficacy and safety data in children. This setting is the result of: The stringent ethical and legal frameworks, as well as problems
with the definition of minimal risk in pediatric research. Insufficient presence of tools and methods to study these drugs,
such as non-invasive or highly sensitive methods, specific study designs and the lack of special formulations of medicines for children and methods for monitoring adverse effects. Financial issues, because these studies last longer are very expensive and do not have a big market for sale. Consequently, this is perceived to be financially insufficient attractive. Children are a special and vulnerable group of patients and they differ from adults in the physiological, psychological and developmental terms. The growth and development are very
* Corresponding author at: Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia. Tel.: +381 641212849. E-mail address: [email protected] (J. Samardzic).
dynamic, interrelated processes and they can significantly affect both pharmacokinetics and pharmacodynamics of drugs. This subsequently results in differences in anticipated potency, efficacy and toxicity. The pharmacokinetics (PK) processes generally considered are drug absorption, distribution, metabolism and excretion (ADME), while pharmacodynamics (PD) refers to the exposure – effect relation of a drug. These general principles of clinical pharmacology also apply to neonates or children, but their specific characteristics require a more integrated, challenging approach. This is because effective and safe pharmacotherapy in children likely cannot be based on simple linear extrapolation of adult concepts but needs integration of the impact of maturational aspects on PK and PD (i.e. developmental pharmacology (Fig. 1). From birth to adolescence, children go through at least four specific periods of development (premature neonates, neonates, infants, children and adolescents), each requiring tailored pharmacotherapy (Allegaert et al., 2013). The dosage of drugs for children must be based on the physiological characteristics of the child and the pharmacokinetic parameters of the drug obtained from the clinical trials with children. Child’s age and development can significantly affect drug ADME processes (Kearns et al., 2003; Yaffe and Aranda, 2011). The absorption of drugs is affected by age, changed-pathological state of the organism, dose, route drug of administration as well as food and other drugs that can interact. In
http://dx.doi.org/10.1016/j.ijpharm.2015.05.012 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: J. Samardzic, et al., Developmental pharmacology: A moving target, Int J Pharmaceut (2015), http://dx.doi. org/10.1016/j.ijpharm.2015.05.012
G Model IJP 14882 No. of Pages 3
2
J. Samardzic et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx
Fig. 1. Developmental pharmacology and PK-PD interface. A: it is essentially to explore first PK and afterwards PD. B: developmental PD shows changes in GABA signaling and intracellular chloride concentration [Cl]i ! depolarization & excitation of immature neurons vs. hyperpolarization & inhibition of adult neurons.
Table 1 Physiological differences, characteristic for different age groups of children, that have pharmacokinetic and clinical implications in the use of drugs. Physiological system
Trends related to age
Pharmacokinetic implication
Clinical implications
Gastrointestinal tract
Neonates and young infants: reduced and irregular peristalsis followed by slow gastric emptying Neonates: increased gastric pH (>4) in relation to infants
Slower absorption of the drug (e.g., elevated Tmax)
Possible sustained action after oral administration of the drug
Infants: increased motility of the lower gastrointestinal tract
The possibility of altered bioavailability Faster absorption of acid labile drugs e.g., penicillin G, erythromycin- Reduced absorption of weak-acid drugs e.g., phenobarbital, phenytoin The possibility of reduced bioavailability after Decreased retention of suppositories rectal administration of the drug
Skin
Neonates and young infants: a thinner stratum corneum (neonates), increased skin perfusion, increased water content and higher body surface area-to-weight ration
Increased rate and extent of absorption of the drug through the skin during the first year of life A higher relative exposure to drugs for topical use in relation to adults, e.g., corticosteroids
Muscle tissue
Neonates: reduction in muscle perfusion, decreased muscle contractility Infants: higher density of capillaries in skeletal muscles
Neonates: poor perfusion limits the absorption, Neonates: avoid intramuscular administration unpredictable pharmacokinetics of drugs Infants: increased absorption Infants: effectiveness of drugs applied IM is higher e.g., epinephrine
Increased bioavailability and potential toxicity of drugs applied topically By the end of the second month of life it is dangerous to apply the drug topically! The need for a reduced amount of the drug applied to the skin
Neonates: increased volume of distribution for Spatial Neonates and infants: lower proportion of compartments adipose tissue (10%), decreased muscle mass, an water-soluble drugs (e.g., gentamicin), and a
Please cite this article in press as: J. Samardzic, et al., Developmental pharmacology: A moving target, Int J Pharmaceut (2015), http://dx.doi. org/10.1016/j.ijpharm.2015.05.012
G Model IJP 14882 No. of Pages 3
J. Samardzic et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx
3
Table 1 (Continued) Physiological system
Trends related to age
Pharmacokinetic implication
increased amount of water related to the body weight (80%), an increased proportion of the extracellular fluid (45%) as compared to the intracellular fluid
reduced volume of distribution of drugs which It is necessary to adjust the loading/ are bind to the muscles and adipose tissue (e.g., maintenance dosing (mg/kg) to achieve vancomycin, diazepam) therapeutic concentrations of drug in plasma
Clinical implications
Plasma protein binding
Increased plasma concentration of unbound Neonates: reduced concentrations of albumin and a-1 acid glycoprotein, with a decreased drug drug, with increased volume of distribution and protein-binding affinity relative to children and the possibility of occurrence of toxic effects adults
Drug metabolism
Neonates and young infants: immature isoform of cytochrome P450 and phase II enzymes with harsh developmental expression Children aged 1–6 years: apparent increased activity of certain enzymes over the normal values for adults (allometrics)
Neonates and young infants: reduced hepatic drug metabolism, with increase in half-life
Neonates and young infants: increase dosage interval of drug and/or reduce maintenance dose
Children aged 1–6 years: enhanced drug clearance (e.g., decrease in half-life) for the specific pharmacological substrates
Children aged 1–6 years: for certain drugs is necessary to increase the dose and/or reduce the dosage interval compared to recommended adult dose
Neonates and young infants: decreased level of glomerular filtration rate (first 6 months) and active tubular secretion (first 12 months). Adult values are achieved by the 24th month of life
Neonates and young infants: the accumulation Neonates and young infants: increase dosage of drugs that are secreted via the kidneys and/or interval drug and/or reduce maintenance dose the active metabolite, with a decrease in plasma during the first three months of life clearance and increase in half-life (the greatest during the first three months of life)
Renal drug excretion
neonatal and pediatric patients differences in the distribution of the drug are influenced by the ratio of body fluids and fatty tissue and muscle, the extent of plasma protein binding, as well as an underdeveloped liver function, and blood-brain barrier. Underdevelopment of liver enzymes, primarily in neonates and infants, significantly affects the drug metabolism and excretion (Table 1). While knowledge about the impact of developmental changes on drug PK is increasing, information regarding ontogeny (age-related maturation) on drug effects (PD) is still more limited (Smits and Allegaert, 2011). The examples from clinical and animal data on ontogeny of receptors resulted in strong evidence for changes in drug response during development, in addition to but independent from PK alterations (Yaffe and Aranda, 2011). To illustrate this, gamma-aminobutyric acid (GABA) mediated effects during the first weeks of life are different compared to older age. While GABA is the main inhibitory neurotransmitter in the adult brain (Samardzic et al., 2012), it is the principal excitatory transmitter during early development. Changes in the GABAA receptor subunit composition with a decrease in intracellular chloride concentration occur at 1–2 weeks after birth in rats (Fig. 1). It is not fully understood when this occurs in humans (Ben-Ari et al., 2007; Mulla, 2010). Furthermore, some diseases occur exclusively in children, and etiology and pathophysiology of some diseases in children are different and more diverse than in the adults. For example, cardiac insufficiency in children has its pathophysiological specificity, requiring different therapeutic and diagnostic approach as compared to the adults (Bajcetic et al., 2014). Contractile function of the myocardium at an early age is underdeveloped, while the most common causes of heart failure are congenital-structural defects and genetic-metabolic defects. Thus, such diseases require specially designed medications for use in neonatology and pediatrics. Clinical pharmacology has the intention to predict drug effects, beneficial and toxic, based on PK and PD. These general principles also apply to children, but one should take into account that fast developmental changes result in extensive individual variability,
For drugs with high binding affinity for proteins (e.g., >70%), it is necessary to adjust the dose to maintain the drug levels in the plasma close to the lower limit of the recommended therapeutic range
making both clinical care and research in neonatal and pediatric population more challenging. In order to improve the use of medicines in children, it is essentially to know the complex processes of growth and development into the pediatric drug development programs. This is because absence of PK/PD data leads to increased risk of over- or under-dosing, adverse reactions or inefficiency, although these drugs in the correct dose can be very effective in pediatrics.
Acknowledgements Janko Samardzic is supported by ERAWEB II scholarship for post doctoral program at the KU Leuven, Belgium, Karel Allegaert by the Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800214N). The work is supported in part by Ministry of Education, Science and Technological Development of the Republic of Serbia (project No. 173014). References Allegaert, K., Langhendries, J.P., van den Anker, J.N., 2013. Educational paper: do we need neonatal clinical pharmacologists? Eur. J. Pediatr. 172, 429–435. Bajcetic, M., Uzelac, T.V., Jovanovic, I., 2014. Heart failure pharmacotherapy: differences between adult and paediatric patients. Curr. Med. Chem. 21, 3108–3120. Ben-Ari, Y., Gaiarsa, J.L., Tyzio, R., Khazipov, R., 2007. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87, 1215–1284. Kearns, G.L., Abdel-Rahman, S.B., Alander, S.W., Blowey, D.L., Leeder, J.S., Kauffman, R.E., 2003. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N. Eng. J. Med. 349, 1157–1167. Mulla, H., 2010. Understanding developmental pharmacodynamics: importance for drug development and clinical practice. Paediatr. Drugs 12, 223–233. Samardzic, J., Strac, D.S., Obradovic, M., Opric, D., Obradovic, D.I., 2012. DMCM a benzodiazepine site inverse agonist, improves active avoidance and motivation in the rat. Behav. Brain Res. 235, 195–199. Smits, A., Allegaert, K., 2011. Perinatal pharmacology: applications for neonatal neurology. Eur. J. Paediatr. Neurol. 15, 478–486. Yaffe, S.J., Aranda, J.V., 2011. Neonatal and Pediatric Pharmacology. Therapeutic Principles in Practice, fourth ed. Wolters Kluwer Lippincot Williams and Wilkins.
Please cite this article in press as: J. Samardzic, et al., Developmental pharmacology: A moving target, Int J Pharmaceut (2015), http://dx.doi. org/10.1016/j.ijpharm.2015.05.012
International Journal of Pharmaceutics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Rapid communication
Developmental pharmacology: A moving target Janko Samardzic a, * , Karel Allegaert b , Milica Bajcetic a,c a
Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Serbia Department of Development and Regeneration, KU Leuven and Neonatal Intensive Care Unit, University Hospitals Leuven, Belgium c Clinical Pharmacology Unit, University Children’s Hospital, Belgrade, Serbia b
A R T I C L E I N F O
A B S T R A C T
Article history: Available online xxx
The main characteristic of pediatric and neonatal pharmacotherapy still is the insufficient availability of drugs with confirmed efficacy and safety data in children. Children differ from adults in the physiological, psychological and developmental terms and this subsequently results in differences in anticipated drug potency, efficacy and toxicity. This paper is focused on the most prominent issues of the contemporary developmental pharmacology. Child’s age and development can significantly affect drug pharmacokinetics (PK) processes. The dosage of drugs for children must be based on the physiological characteristics, as well as PK parameters of the drug obtained from the clinical trials with children. While knowledge about the impact of developmental changes on drug PK is increasing, information regarding pharmacodynamics (PD) is still more limited. The examples from clinical and animal data on ontogeny of receptors resulted in strong evidence for changes in drug response during development, in addition to but independent from PK alterations. In order to improve the use of medicines in children, it is essentially to know the complex processes of growth and development into the pediatric drug development programs. This is because absence of PK/PD data leads to increased risk of over- or under-dosing, adverse reactions or inefficiency. ã 2015 Elsevier B.V. All rights reserved.
Keywords: Children Drugs Developmental pharmacology GABA
The main characteristic of contemporary pediatric and neonatal pharmacotherapy still is the insufficient availability of drugs with confirmed efficacy and safety data in children. This setting is the result of: The stringent ethical and legal frameworks, as well as problems
with the definition of minimal risk in pediatric research. Insufficient presence of tools and methods to study these drugs,
such as non-invasive or highly sensitive methods, specific study designs and the lack of special formulations of medicines for children and methods for monitoring adverse effects. Financial issues, because these studies last longer are very expensive and do not have a big market for sale. Consequently, this is perceived to be financially insufficient attractive. Children are a special and vulnerable group of patients and they differ from adults in the physiological, psychological and developmental terms. The growth and development are very
* Corresponding author at: Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia. Tel.: +381 641212849. E-mail address: [email protected] (J. Samardzic).
dynamic, interrelated processes and they can significantly affect both pharmacokinetics and pharmacodynamics of drugs. This subsequently results in differences in anticipated potency, efficacy and toxicity. The pharmacokinetics (PK) processes generally considered are drug absorption, distribution, metabolism and excretion (ADME), while pharmacodynamics (PD) refers to the exposure – effect relation of a drug. These general principles of clinical pharmacology also apply to neonates or children, but their specific characteristics require a more integrated, challenging approach. This is because effective and safe pharmacotherapy in children likely cannot be based on simple linear extrapolation of adult concepts but needs integration of the impact of maturational aspects on PK and PD (i.e. developmental pharmacology (Fig. 1). From birth to adolescence, children go through at least four specific periods of development (premature neonates, neonates, infants, children and adolescents), each requiring tailored pharmacotherapy (Allegaert et al., 2013). The dosage of drugs for children must be based on the physiological characteristics of the child and the pharmacokinetic parameters of the drug obtained from the clinical trials with children. Child’s age and development can significantly affect drug ADME processes (Kearns et al., 2003; Yaffe and Aranda, 2011). The absorption of drugs is affected by age, changed-pathological state of the organism, dose, route drug of administration as well as food and other drugs that can interact. In
http://dx.doi.org/10.1016/j.ijpharm.2015.05.012 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: J. Samardzic, et al., Developmental pharmacology: A moving target, Int J Pharmaceut (2015), http://dx.doi. org/10.1016/j.ijpharm.2015.05.012
G Model IJP 14882 No. of Pages 3
2
J. Samardzic et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx
Fig. 1. Developmental pharmacology and PK-PD interface. A: it is essentially to explore first PK and afterwards PD. B: developmental PD shows changes in GABA signaling and intracellular chloride concentration [Cl]i ! depolarization & excitation of immature neurons vs. hyperpolarization & inhibition of adult neurons.
Table 1 Physiological differences, characteristic for different age groups of children, that have pharmacokinetic and clinical implications in the use of drugs. Physiological system
Trends related to age
Pharmacokinetic implication
Clinical implications
Gastrointestinal tract
Neonates and young infants: reduced and irregular peristalsis followed by slow gastric emptying Neonates: increased gastric pH (>4) in relation to infants
Slower absorption of the drug (e.g., elevated Tmax)
Possible sustained action after oral administration of the drug
Infants: increased motility of the lower gastrointestinal tract
The possibility of altered bioavailability Faster absorption of acid labile drugs e.g., penicillin G, erythromycin- Reduced absorption of weak-acid drugs e.g., phenobarbital, phenytoin The possibility of reduced bioavailability after Decreased retention of suppositories rectal administration of the drug
Skin
Neonates and young infants: a thinner stratum corneum (neonates), increased skin perfusion, increased water content and higher body surface area-to-weight ration
Increased rate and extent of absorption of the drug through the skin during the first year of life A higher relative exposure to drugs for topical use in relation to adults, e.g., corticosteroids
Muscle tissue
Neonates: reduction in muscle perfusion, decreased muscle contractility Infants: higher density of capillaries in skeletal muscles
Neonates: poor perfusion limits the absorption, Neonates: avoid intramuscular administration unpredictable pharmacokinetics of drugs Infants: increased absorption Infants: effectiveness of drugs applied IM is higher e.g., epinephrine
Increased bioavailability and potential toxicity of drugs applied topically By the end of the second month of life it is dangerous to apply the drug topically! The need for a reduced amount of the drug applied to the skin
Neonates: increased volume of distribution for Spatial Neonates and infants: lower proportion of compartments adipose tissue (10%), decreased muscle mass, an water-soluble drugs (e.g., gentamicin), and a
Please cite this article in press as: J. Samardzic, et al., Developmental pharmacology: A moving target, Int J Pharmaceut (2015), http://dx.doi. org/10.1016/j.ijpharm.2015.05.012
G Model IJP 14882 No. of Pages 3
J. Samardzic et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx
3
Table 1 (Continued) Physiological system
Trends related to age
Pharmacokinetic implication
increased amount of water related to the body weight (80%), an increased proportion of the extracellular fluid (45%) as compared to the intracellular fluid
reduced volume of distribution of drugs which It is necessary to adjust the loading/ are bind to the muscles and adipose tissue (e.g., maintenance dosing (mg/kg) to achieve vancomycin, diazepam) therapeutic concentrations of drug in plasma
Clinical implications
Plasma protein binding
Increased plasma concentration of unbound Neonates: reduced concentrations of albumin and a-1 acid glycoprotein, with a decreased drug drug, with increased volume of distribution and protein-binding affinity relative to children and the possibility of occurrence of toxic effects adults
Drug metabolism
Neonates and young infants: immature isoform of cytochrome P450 and phase II enzymes with harsh developmental expression Children aged 1–6 years: apparent increased activity of certain enzymes over the normal values for adults (allometrics)
Neonates and young infants: reduced hepatic drug metabolism, with increase in half-life
Neonates and young infants: increase dosage interval of drug and/or reduce maintenance dose
Children aged 1–6 years: enhanced drug clearance (e.g., decrease in half-life) for the specific pharmacological substrates
Children aged 1–6 years: for certain drugs is necessary to increase the dose and/or reduce the dosage interval compared to recommended adult dose
Neonates and young infants: decreased level of glomerular filtration rate (first 6 months) and active tubular secretion (first 12 months). Adult values are achieved by the 24th month of life
Neonates and young infants: the accumulation Neonates and young infants: increase dosage of drugs that are secreted via the kidneys and/or interval drug and/or reduce maintenance dose the active metabolite, with a decrease in plasma during the first three months of life clearance and increase in half-life (the greatest during the first three months of life)
Renal drug excretion
neonatal and pediatric patients differences in the distribution of the drug are influenced by the ratio of body fluids and fatty tissue and muscle, the extent of plasma protein binding, as well as an underdeveloped liver function, and blood-brain barrier. Underdevelopment of liver enzymes, primarily in neonates and infants, significantly affects the drug metabolism and excretion (Table 1). While knowledge about the impact of developmental changes on drug PK is increasing, information regarding ontogeny (age-related maturation) on drug effects (PD) is still more limited (Smits and Allegaert, 2011). The examples from clinical and animal data on ontogeny of receptors resulted in strong evidence for changes in drug response during development, in addition to but independent from PK alterations (Yaffe and Aranda, 2011). To illustrate this, gamma-aminobutyric acid (GABA) mediated effects during the first weeks of life are different compared to older age. While GABA is the main inhibitory neurotransmitter in the adult brain (Samardzic et al., 2012), it is the principal excitatory transmitter during early development. Changes in the GABAA receptor subunit composition with a decrease in intracellular chloride concentration occur at 1–2 weeks after birth in rats (Fig. 1). It is not fully understood when this occurs in humans (Ben-Ari et al., 2007; Mulla, 2010). Furthermore, some diseases occur exclusively in children, and etiology and pathophysiology of some diseases in children are different and more diverse than in the adults. For example, cardiac insufficiency in children has its pathophysiological specificity, requiring different therapeutic and diagnostic approach as compared to the adults (Bajcetic et al., 2014). Contractile function of the myocardium at an early age is underdeveloped, while the most common causes of heart failure are congenital-structural defects and genetic-metabolic defects. Thus, such diseases require specially designed medications for use in neonatology and pediatrics. Clinical pharmacology has the intention to predict drug effects, beneficial and toxic, based on PK and PD. These general principles also apply to children, but one should take into account that fast developmental changes result in extensive individual variability,
For drugs with high binding affinity for proteins (e.g., >70%), it is necessary to adjust the dose to maintain the drug levels in the plasma close to the lower limit of the recommended therapeutic range
making both clinical care and research in neonatal and pediatric population more challenging. In order to improve the use of medicines in children, it is essentially to know the complex processes of growth and development into the pediatric drug development programs. This is because absence of PK/PD data leads to increased risk of over- or under-dosing, adverse reactions or inefficiency, although these drugs in the correct dose can be very effective in pediatrics.
Acknowledgements Janko Samardzic is supported by ERAWEB II scholarship for post doctoral program at the KU Leuven, Belgium, Karel Allegaert by the Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800214N). The work is supported in part by Ministry of Education, Science and Technological Development of the Republic of Serbia (project No. 173014). References Allegaert, K., Langhendries, J.P., van den Anker, J.N., 2013. Educational paper: do we need neonatal clinical pharmacologists? Eur. J. Pediatr. 172, 429–435. Bajcetic, M., Uzelac, T.V., Jovanovic, I., 2014. Heart failure pharmacotherapy: differences between adult and paediatric patients. Curr. Med. Chem. 21, 3108–3120. Ben-Ari, Y., Gaiarsa, J.L., Tyzio, R., Khazipov, R., 2007. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87, 1215–1284. Kearns, G.L., Abdel-Rahman, S.B., Alander, S.W., Blowey, D.L., Leeder, J.S., Kauffman, R.E., 2003. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N. Eng. J. Med. 349, 1157–1167. Mulla, H., 2010. Understanding developmental pharmacodynamics: importance for drug development and clinical practice. Paediatr. Drugs 12, 223–233. Samardzic, J., Strac, D.S., Obradovic, M., Opric, D., Obradovic, D.I., 2012. DMCM a benzodiazepine site inverse agonist, improves active avoidance and motivation in the rat. Behav. Brain Res. 235, 195–199. Smits, A., Allegaert, K., 2011. Perinatal pharmacology: applications for neonatal neurology. Eur. J. Paediatr. Neurol. 15, 478–486. Yaffe, S.J., Aranda, J.V., 2011. Neonatal and Pediatric Pharmacology. Therapeutic Principles in Practice, fourth ed. Wolters Kluwer Lippincot Williams and Wilkins.
Please cite this article in press as: J. Samardzic, et al., Developmental pharmacology: A moving target, Int J Pharmaceut (2015), http://dx.doi. org/10.1016/j.ijpharm.2015.05.012
