JPPT Editorial Characterizing the Impact of Development on the Dose-ExposureResponse Relationship: Challenge or Opportunity? Mary Jayne Kennedy, PharmD Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia INDEX TERMS: development, pharmacokinetics, pharmacodynamics J Pediatr Pharmacol Ther 2014;19(4):260–261
It is an exciting time in the field of Pediatric Clinical Pharmacology. In just under 2 decades, the discipline has undergone a significant transformation ignited by legislative initiatives designed to improve pediatric drug labeling. see related article on page 262
Increased funding for pediatric research has expanded opportunities for investigating the impact of growth and development on the dose-exposure-response relationship. Creation of research networks such as the Eunice Kennedy Shriver National Institute of Child Health and Human Development-funded Specialized Centers in Research in Pediatric and Developmental Pharmacology has provided a national infrastructure to support conduct of clinical pharmacology studies across the age spectrum. Collectively, these initiatives have directly facilitated the evaluation of 189 drugs under the pediatric exclusivity program from 1998 to 2012 and resulted in the addition of pediatric labeling in 92% of evaluated agents.1 Developmental roadmaps have also been completed for many of the underlying physiologic processes that influence drug exposure. In this issue of the journal, Lu and colleagues review the field of developmental pharmacokinetics and discuss the current state of the art with respect to the design of age-specific dosing regimens. The impact of normal growth and development on the processes of drug absorption, distribution, metabolism, and elimination has been well characterized and can be used to predict agespecific changes in systemic drug exposure. This developmental pharmacokinetic information 260
can also be used to develop dosing guidelines to achieve a target level of systemic exposure and, theoretically, response in a pediatric patient. This assumes, however, that the dose-exposureresponse relationship remains constant across the age spectrum—an assumption that may not always be correct. This is because the processes of normal and growth and development may alter the expression and/or activity of therapeutic targets that ultimately determine drug response. As pointed out in the accompanying review, data regarding the pharmacodynamic behavior of drugs in the pediatric population are limited. However, there are several examples where developmental differences in target enzymes, receptors, and/or physiologic systems clearly alter the dose-exposure-response relationship. The immature immune system is more sensitive to cyclosporine-induced immunosuppression, and target exposure levels are therefore lower in infants and young children relative to adults.2 Similarly, the International Normalized Ratio values in prepubertal children are significantly higher than those in postpubertal children and adults at comparable levels of warfarin exposure.3 These examples highlight the fact that biologic systems constantly change from birth to adulthood and reinforce why extrapolation of adult-derived pharmacodynamic data is often ineffective at predicting response even when the principles of developmental pharmacokinetics are applied. Emerging data from the pediatric exclusivity program also suggest that there are underlying age-specific differences in disease pathophysiology and/or response indicators that may influJ Pediatr Pharmacol Ther 2014 Vol. 19 No. 4 • www.jppt.org
JPPT
Development and the Exposure-Response Relationship
ence therapeutic efficacy and our ability to detect a positive treatment outcome.1 Over 40% of drugs studied under this program failed to demonstrate efficacy in the pediatric population, and efficacy rates varied significantly by therapeutic group. A new pediatric safety signal was also identified in one quarter of the drugs granted pediatric exclusivity highlighting the fact that we cannot assume that a product with proven safety and efficacy in adults will perform similarly in children. Given the significant heterogeneity in disease pathophysiology and clinical presentation across the developmental continuum, we also cannot assume that the therapeutic target and/or end points are equivalent in children and adults. Children are obviously the best model for evaluating drug safety and efficacy in the pediatric population. Given the ethical and practical constraints of conducting studies in this patient population, however, this is easier said than done. Characterizing the impact of development on the expression and functional activity of target receptors, transporters, and enzymes requires collection of healthy tissues from normal, healthy children using invasive sampling techniques. In vitro and animal models may be appropriate surrogates for evaluating developmental pharmacodynamics in the absence of pediatric subjects or tissues although the availability of age-specific correlates is somewhat limited particularly in the neonatal population. There are certainly many challenges to overcome. With challenge comes opportunity, however, and our discipline has been given a tremendous opportunity in the area of developmental pharmacodynamics. Albert Einstein said that “We cannot solve our problems with the same level of thinking that
J Pediatr Pharmacol Ther 2014 Vol. 19 No. 4 • www.jppt.org
created them,” and this could not be truer for the discipline of Pediatric Clinical Pharmacology. Understanding the impact of growth and development on the dose-exposure-response relationship will require a concerted effort to develop novel and innovative models to evaluate changes in the expression and functional activity of target receptors, enzymes, and receptors and to identify age-specific response indicators. We have come a long way but we have a long way to go. Are you up for the challenge? Disclosure The author declares no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Correspondence Mary Jayne Kennedy, PharmD, Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, PO Box 980533, Richmond, VA 23298-0533, email: [email protected]
REFERENCES 1.
2. 3.
Wharton GT, Murphy MD, Avant D, et al. Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy. Pediatrics. 2014;134(2):e512-e518. Marshall JD, Kearns GL. Developmental pharmacodynamics of cyclosporine. Clin Pharmacol Ther. 1999;66(1):66-75. Takahashi H, Ishikawa S, Nomoto S, et al. Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children. Clin Pharmacol Ther. 2000;68(5):541-555.
261
It is an exciting time in the field of Pediatric Clinical Pharmacology. In just under 2 decades, the discipline has undergone a significant transformation ignited by legislative initiatives designed to improve pediatric drug labeling. see related article on page 262
Increased funding for pediatric research has expanded opportunities for investigating the impact of growth and development on the dose-exposure-response relationship. Creation of research networks such as the Eunice Kennedy Shriver National Institute of Child Health and Human Development-funded Specialized Centers in Research in Pediatric and Developmental Pharmacology has provided a national infrastructure to support conduct of clinical pharmacology studies across the age spectrum. Collectively, these initiatives have directly facilitated the evaluation of 189 drugs under the pediatric exclusivity program from 1998 to 2012 and resulted in the addition of pediatric labeling in 92% of evaluated agents.1 Developmental roadmaps have also been completed for many of the underlying physiologic processes that influence drug exposure. In this issue of the journal, Lu and colleagues review the field of developmental pharmacokinetics and discuss the current state of the art with respect to the design of age-specific dosing regimens. The impact of normal growth and development on the processes of drug absorption, distribution, metabolism, and elimination has been well characterized and can be used to predict agespecific changes in systemic drug exposure. This developmental pharmacokinetic information 260
can also be used to develop dosing guidelines to achieve a target level of systemic exposure and, theoretically, response in a pediatric patient. This assumes, however, that the dose-exposureresponse relationship remains constant across the age spectrum—an assumption that may not always be correct. This is because the processes of normal and growth and development may alter the expression and/or activity of therapeutic targets that ultimately determine drug response. As pointed out in the accompanying review, data regarding the pharmacodynamic behavior of drugs in the pediatric population are limited. However, there are several examples where developmental differences in target enzymes, receptors, and/or physiologic systems clearly alter the dose-exposure-response relationship. The immature immune system is more sensitive to cyclosporine-induced immunosuppression, and target exposure levels are therefore lower in infants and young children relative to adults.2 Similarly, the International Normalized Ratio values in prepubertal children are significantly higher than those in postpubertal children and adults at comparable levels of warfarin exposure.3 These examples highlight the fact that biologic systems constantly change from birth to adulthood and reinforce why extrapolation of adult-derived pharmacodynamic data is often ineffective at predicting response even when the principles of developmental pharmacokinetics are applied. Emerging data from the pediatric exclusivity program also suggest that there are underlying age-specific differences in disease pathophysiology and/or response indicators that may influJ Pediatr Pharmacol Ther 2014 Vol. 19 No. 4 • www.jppt.org
JPPT
Development and the Exposure-Response Relationship
ence therapeutic efficacy and our ability to detect a positive treatment outcome.1 Over 40% of drugs studied under this program failed to demonstrate efficacy in the pediatric population, and efficacy rates varied significantly by therapeutic group. A new pediatric safety signal was also identified in one quarter of the drugs granted pediatric exclusivity highlighting the fact that we cannot assume that a product with proven safety and efficacy in adults will perform similarly in children. Given the significant heterogeneity in disease pathophysiology and clinical presentation across the developmental continuum, we also cannot assume that the therapeutic target and/or end points are equivalent in children and adults. Children are obviously the best model for evaluating drug safety and efficacy in the pediatric population. Given the ethical and practical constraints of conducting studies in this patient population, however, this is easier said than done. Characterizing the impact of development on the expression and functional activity of target receptors, transporters, and enzymes requires collection of healthy tissues from normal, healthy children using invasive sampling techniques. In vitro and animal models may be appropriate surrogates for evaluating developmental pharmacodynamics in the absence of pediatric subjects or tissues although the availability of age-specific correlates is somewhat limited particularly in the neonatal population. There are certainly many challenges to overcome. With challenge comes opportunity, however, and our discipline has been given a tremendous opportunity in the area of developmental pharmacodynamics. Albert Einstein said that “We cannot solve our problems with the same level of thinking that
J Pediatr Pharmacol Ther 2014 Vol. 19 No. 4 • www.jppt.org
created them,” and this could not be truer for the discipline of Pediatric Clinical Pharmacology. Understanding the impact of growth and development on the dose-exposure-response relationship will require a concerted effort to develop novel and innovative models to evaluate changes in the expression and functional activity of target receptors, enzymes, and receptors and to identify age-specific response indicators. We have come a long way but we have a long way to go. Are you up for the challenge? Disclosure The author declares no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Correspondence Mary Jayne Kennedy, PharmD, Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, PO Box 980533, Richmond, VA 23298-0533, email: [email protected]
REFERENCES 1.
2. 3.
Wharton GT, Murphy MD, Avant D, et al. Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy. Pediatrics. 2014;134(2):e512-e518. Marshall JD, Kearns GL. Developmental pharmacodynamics of cyclosporine. Clin Pharmacol Ther. 1999;66(1):66-75. Takahashi H, Ishikawa S, Nomoto S, et al. Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children. Clin Pharmacol Ther. 2000;68(5):541-555.
261
