Development
nature publishing group
Therapeutic Drug Monitoring as a Component of Personalized Medicine: Applications in Pediatric Drug Development JD Momper1 and JA Wagner2 Therapeutic drug monitoring (TDM) is foundational to the concept of personalized medicine. TDM transformed drug therapy by affording the ability to characterize sources of variability in drug disposition and response to individualize drug dosing. Initially, TDM formed the key conceptual basis for personalized medicine, which has evolved to include pharmacogenomic and other biomarker-driven strategies for patient segmentation. Currently, TDM is an attractive option for personalized medicine and, under the right conditions, can facilitate drug development. In the drug development setting, TDM may be particularly valuable for use in pediatric patients, a population in which identifying safe and effective doses has consistently been a challenge. Recent legislation in the United States and Europe has both stimulated and required pediatric drug development programs, and the pharmaceutical industry now devotes significant resources toward these efforts. Efforts to both streamline and improve pediatric drug development have often involved modeling and simulation and the use of tools such as physiologically based pharmacokinetic modeling. However, despite the application of these resources, approximately one-third of completed pediatric trials have failed to result in a labeled pediatric indication. Poor dose selection and failure to test a range of doses have been postulated to be major contributing factors to pediatric trial failures. Pharmacokinetic variability is a major confounding factor in traditional weight-based dosing or fixed-dose pediatric trials. Interindividual variability in pharmacokinetic variables, including drug absorption, distribution, metabolism, and excretion, in the pediatric population is typically greater in comparison with that in adults because of the effects of developmental changes and maturation on drug disposition. Therefore, these dosing strategies often lead to drug concentrations outside of the targeted range in a subset of pediatric patients, which poses a challenge in demonstrating efficacy, safety, or a dose–response
relationship. This variability becomes a significant concern particularly for any drug with a narrow therapeutic range. For drugs with both high pharmacokinetic variability and a narrow therapeutic range, the application of TDM principles to clinical trials in children addresses the limitations of conventional dose-controlled trials by allowing the dose to vary in order to attain drug exposure within a prespecified range in individual patients. Applied prospectively during drug development, TDM may address a key need in selected situations by producing generalized pharmacokinetic–pharmacodynamic knowledge that can allow investigators to refine and optimize drug dosing at the population level. An expanded form of the TDM-based clinical trial is the randomized concentration–controlled trial, first proposed by Carl Peck more than 20 years ago.1 This design fundamentally combines TDM with the randomization of patients to defined concentration ranges. During a randomized concentration–controlled trial, an algorithm is used to continually adjust each patient’s dose, if necessary, to maintain a prespecified exposure. A benefit of the randomized concentration–controlled trial is improved sample size efficiency, which is an important practical and ethical consideration in pediatric trials. Target concentration intervention has also emerged as a method to extend TDM principles by using population pharmacokinetic and pharmacodynamic models to optimize dosing to a specific concentration instead of a target range and may also be valuable in the clinical trial setting. Despite the potential to enhance trial efficiency and increase the probability of establishing a pediatric indication, TDM-based designs remain largely underused in drug development. THE TDM ASSAY AS A COMPANION DIAGNOSTIC DEVICE
Important considerations related to incorporating TDM into the pediatric drug development program include the concurrent development of a robust, validated bioanalytical assay in conjunction with the pediatric study plan. In many
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA; 2Merck, Whitehouse Station, New Jersey, USA.
Correspondence: JD Momper ([email protected])
Received 16 September 2013; accepted 11 November 2013; advance online publication 8 January 2014. doi:10.1038/clpt.2013.227 138
VOLUME 95 NUMBER 2 | fEBRUARY 2014 | www.nature.com/cpt
Development circumstances, a TDM assay would probably constitute a companion in vitro diagnostic, to the extent that the testing is essential for the safe and effective use of the therapeutic product. 2 Such in vitro diagnostics are medical devices that are subject to regulation by the US Food and Drug Administration. Although no TDM tests have been approved as companion diagnostics to date, if the drug assay is considered essential for the safe and effective use of the drug, it could be considered a companion diagnostic test for the purpose of performing TDM and dosage adjustment. For TDM to be effective, such assays must be readily available in a multitude of clinical environments, and information must be provided to clinicians in a manner that is interpretable and actionable for the purposes of guiding dosage adjustments. Pediatric drug development may benefit from codevelopment of the therapeutic agent with TDM assays, although many barriers exist. The cost and complexity of codeveloping a test to manage patients is a major challenge, given the need for rapid turnaround and broad accessibility. Moreover, in the clinic, TDM approaches could require additional blood draws and patient follow-up to ensure that appropriate doses are administered. This can be a perceived barrier to adoption, although new analytical methods, which use saliva or dried blood spots, are likely to make TDM more feasible for •
pediatric patients. Nonetheless, the potential benefit of avoiding toxicity while maintaining efficacy in a population for whom individualizing therapy is critical could outweigh the added burden, as demonstrated in recent examples of these programs. RECENT EXAMPLES OF PEDIATRIC TDM
Pediatric drug treatment and development is notably challenging when a wide range of pediatric age groups are included and the ontogeny of metabolic enzymes and/or drug transporters significantly affects drug disposition. Dosing in children is further complicated by the large heterogeneity of pediatric patients, in which covariates such as body size and metabolic function can vary widely even within age-defined subpopulations. To address these challenges, TDM is already used to individualize treatment in clinical practice in neonates and young infants, particularly in the intensive care setting.3 The pharmacokinetic parameters of absorption, distribution, metabolism, and excretion are variable and undergo rapid maturational change in neonates. In addition to maturational factors, neonates demonstrate wide interindividual pharmacokinetic variability, which is often unexplained. Neonatal intensive care interventions, including therapeutic hypothermia and extracorporeal membrane oxygenation, may further increase pharmacokinetic variability. TDM has proven
Does an established concentration–effect relationship exist in adults for safety and/or efficacy? Yes
Does the drug have a narrow therapeutic range and exhibit high pharmacokinetic variability?
No
No
TDM unnecessary
Yes
Is extrapolation of efficacy applied?
Yes
Consider incorporating TDM into pediatric trials
No
Establish PK–PD relationship in pediatric patients
Figure 1 Proposed decision tree for the incorporation of therapeutic drug monitoring (TDM) into pediatric drug development programs. PK–PD, pharmacokinetic–pharmacodynamic. Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 2 | fEBRUARY 2014
139
Development especially useful with agents such as aminoglycosides, anticonvulsants, caffeine, digoxin, and vancomycin. In drug development, a recent illustration of the utility of TDM is everolimus for the treatment of pediatric patients with subependymal giant cell astrocytoma associated with tuberous sclerosis, which was recently approved by the Food and Drug Administration.4 This application of TDM was adopted from its use in transplant recipients to reduce variability in everolimus exposure. Several factors contribute to high interindividual variability in everolimus disposition in pediatric patients. First, wide ranges of ages and body sizes were included in the clinical study. In addition, trough plasma concentration (Cmin) normalized to the body surface area-adjusted dose was lower in the younger patients, which could possibly be attributed to age-related differences in CYP3A4 functional activity. Finally, patients with tuberous sclerosis–associated subependymal giant cell astrocytoma often require coadministration of enzymeinducing antiepileptic drugs, which may decrease everolimus blood concentrations. A target range of everolimus exposure was supported by an exposure–response (E–R) analysis for efficacy and safety, which supported the adaptation of TDM for pediatric patients. An Emax logistic regression model demonstrated that subependymal giant cell astrocytoma tumor response reached a plateau when Cmin > 5 ng/ml, whereas the E–R profile for safety indicated no safety concern when the Cmin was
nature publishing group
Therapeutic Drug Monitoring as a Component of Personalized Medicine: Applications in Pediatric Drug Development JD Momper1 and JA Wagner2 Therapeutic drug monitoring (TDM) is foundational to the concept of personalized medicine. TDM transformed drug therapy by affording the ability to characterize sources of variability in drug disposition and response to individualize drug dosing. Initially, TDM formed the key conceptual basis for personalized medicine, which has evolved to include pharmacogenomic and other biomarker-driven strategies for patient segmentation. Currently, TDM is an attractive option for personalized medicine and, under the right conditions, can facilitate drug development. In the drug development setting, TDM may be particularly valuable for use in pediatric patients, a population in which identifying safe and effective doses has consistently been a challenge. Recent legislation in the United States and Europe has both stimulated and required pediatric drug development programs, and the pharmaceutical industry now devotes significant resources toward these efforts. Efforts to both streamline and improve pediatric drug development have often involved modeling and simulation and the use of tools such as physiologically based pharmacokinetic modeling. However, despite the application of these resources, approximately one-third of completed pediatric trials have failed to result in a labeled pediatric indication. Poor dose selection and failure to test a range of doses have been postulated to be major contributing factors to pediatric trial failures. Pharmacokinetic variability is a major confounding factor in traditional weight-based dosing or fixed-dose pediatric trials. Interindividual variability in pharmacokinetic variables, including drug absorption, distribution, metabolism, and excretion, in the pediatric population is typically greater in comparison with that in adults because of the effects of developmental changes and maturation on drug disposition. Therefore, these dosing strategies often lead to drug concentrations outside of the targeted range in a subset of pediatric patients, which poses a challenge in demonstrating efficacy, safety, or a dose–response
relationship. This variability becomes a significant concern particularly for any drug with a narrow therapeutic range. For drugs with both high pharmacokinetic variability and a narrow therapeutic range, the application of TDM principles to clinical trials in children addresses the limitations of conventional dose-controlled trials by allowing the dose to vary in order to attain drug exposure within a prespecified range in individual patients. Applied prospectively during drug development, TDM may address a key need in selected situations by producing generalized pharmacokinetic–pharmacodynamic knowledge that can allow investigators to refine and optimize drug dosing at the population level. An expanded form of the TDM-based clinical trial is the randomized concentration–controlled trial, first proposed by Carl Peck more than 20 years ago.1 This design fundamentally combines TDM with the randomization of patients to defined concentration ranges. During a randomized concentration–controlled trial, an algorithm is used to continually adjust each patient’s dose, if necessary, to maintain a prespecified exposure. A benefit of the randomized concentration–controlled trial is improved sample size efficiency, which is an important practical and ethical consideration in pediatric trials. Target concentration intervention has also emerged as a method to extend TDM principles by using population pharmacokinetic and pharmacodynamic models to optimize dosing to a specific concentration instead of a target range and may also be valuable in the clinical trial setting. Despite the potential to enhance trial efficiency and increase the probability of establishing a pediatric indication, TDM-based designs remain largely underused in drug development. THE TDM ASSAY AS A COMPANION DIAGNOSTIC DEVICE
Important considerations related to incorporating TDM into the pediatric drug development program include the concurrent development of a robust, validated bioanalytical assay in conjunction with the pediatric study plan. In many
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA; 2Merck, Whitehouse Station, New Jersey, USA.
Correspondence: JD Momper ([email protected])
Received 16 September 2013; accepted 11 November 2013; advance online publication 8 January 2014. doi:10.1038/clpt.2013.227 138
VOLUME 95 NUMBER 2 | fEBRUARY 2014 | www.nature.com/cpt
Development circumstances, a TDM assay would probably constitute a companion in vitro diagnostic, to the extent that the testing is essential for the safe and effective use of the therapeutic product. 2 Such in vitro diagnostics are medical devices that are subject to regulation by the US Food and Drug Administration. Although no TDM tests have been approved as companion diagnostics to date, if the drug assay is considered essential for the safe and effective use of the drug, it could be considered a companion diagnostic test for the purpose of performing TDM and dosage adjustment. For TDM to be effective, such assays must be readily available in a multitude of clinical environments, and information must be provided to clinicians in a manner that is interpretable and actionable for the purposes of guiding dosage adjustments. Pediatric drug development may benefit from codevelopment of the therapeutic agent with TDM assays, although many barriers exist. The cost and complexity of codeveloping a test to manage patients is a major challenge, given the need for rapid turnaround and broad accessibility. Moreover, in the clinic, TDM approaches could require additional blood draws and patient follow-up to ensure that appropriate doses are administered. This can be a perceived barrier to adoption, although new analytical methods, which use saliva or dried blood spots, are likely to make TDM more feasible for •
pediatric patients. Nonetheless, the potential benefit of avoiding toxicity while maintaining efficacy in a population for whom individualizing therapy is critical could outweigh the added burden, as demonstrated in recent examples of these programs. RECENT EXAMPLES OF PEDIATRIC TDM
Pediatric drug treatment and development is notably challenging when a wide range of pediatric age groups are included and the ontogeny of metabolic enzymes and/or drug transporters significantly affects drug disposition. Dosing in children is further complicated by the large heterogeneity of pediatric patients, in which covariates such as body size and metabolic function can vary widely even within age-defined subpopulations. To address these challenges, TDM is already used to individualize treatment in clinical practice in neonates and young infants, particularly in the intensive care setting.3 The pharmacokinetic parameters of absorption, distribution, metabolism, and excretion are variable and undergo rapid maturational change in neonates. In addition to maturational factors, neonates demonstrate wide interindividual pharmacokinetic variability, which is often unexplained. Neonatal intensive care interventions, including therapeutic hypothermia and extracorporeal membrane oxygenation, may further increase pharmacokinetic variability. TDM has proven
Does an established concentration–effect relationship exist in adults for safety and/or efficacy? Yes
Does the drug have a narrow therapeutic range and exhibit high pharmacokinetic variability?
No
No
TDM unnecessary
Yes
Is extrapolation of efficacy applied?
Yes
Consider incorporating TDM into pediatric trials
No
Establish PK–PD relationship in pediatric patients
Figure 1 Proposed decision tree for the incorporation of therapeutic drug monitoring (TDM) into pediatric drug development programs. PK–PD, pharmacokinetic–pharmacodynamic. Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 2 | fEBRUARY 2014
139
Development especially useful with agents such as aminoglycosides, anticonvulsants, caffeine, digoxin, and vancomycin. In drug development, a recent illustration of the utility of TDM is everolimus for the treatment of pediatric patients with subependymal giant cell astrocytoma associated with tuberous sclerosis, which was recently approved by the Food and Drug Administration.4 This application of TDM was adopted from its use in transplant recipients to reduce variability in everolimus exposure. Several factors contribute to high interindividual variability in everolimus disposition in pediatric patients. First, wide ranges of ages and body sizes were included in the clinical study. In addition, trough plasma concentration (Cmin) normalized to the body surface area-adjusted dose was lower in the younger patients, which could possibly be attributed to age-related differences in CYP3A4 functional activity. Finally, patients with tuberous sclerosis–associated subependymal giant cell astrocytoma often require coadministration of enzymeinducing antiepileptic drugs, which may decrease everolimus blood concentrations. A target range of everolimus exposure was supported by an exposure–response (E–R) analysis for efficacy and safety, which supported the adaptation of TDM for pediatric patients. An Emax logistic regression model demonstrated that subependymal giant cell astrocytoma tumor response reached a plateau when Cmin > 5 ng/ml, whereas the E–R profile for safety indicated no safety concern when the Cmin was
