PERSPECTIVES patients. An estimated 100,000 emergency hospitalizations for adverse drug events in US adults 65 years of age or older occurred each year from 2007 through 2009; nearly two-thirds were due to unintentional overdoses.10 PGx has the potential to assist older patients taking a number of medications by identifying optimal medications and dosages and reducing the likelihood of ADR. Genetic tests are being developed faster than the value can be evaluated. Special attention to gathering the evidence base for PGx testing should be prioritized. In summary, the FDA’s warning letter to 23andMe relaunched the academic discourse around DTC-GT into mainstream conversation, and called on proponents and opponents to defend their positions along the spectrum of arguments from patient harm to patient ownership, from utility to privacy. The pendulum has nudged steadily toward the acceptance of DTC-GT in the regulatory and medical communities, including the FDA’s reclassification of carrier tests as Class II devices (February, 2015) and the National Society of Genetic Counselors’ revised position that people have every right to pursue DTG-GT, with the caveat that DTC companies have a responsibility to offer consumers easy access and/or referrals to appropriate resources and
qualified genetics professionals (June, 2015). Where do we go from here? In the presence of growing agreement and in the absence of evidence of harm, the public is best served by the FDA focusing on negligent actors in the DTC-GT space while permitting the private sector to pursue responsible efforts. We feel the best path forward for using personal genetic information is through an expert physician intermediary. However, DTC-GT options represent an imperfect but reasonable alternative in the absence of expert physicians. Given the potential for genetic information to inform decision-making from preventive medicine to drug and therapy response, we must temper the exalted promise of precision medicine with determined access across patient populations. It’s an exciting time in medicine and progress such as PGx should inform as many health outcomes as possible. CONFLICT OF INTEREST The authors declare no conflicts of interest. C 2015 ASCPT V
1.
2.
23andMe. What the FDA decision means for 23andMe customers. 23andMe Blog (2015). Peterson, J.F. et al. Attitudes of clinicians following large-scale pharmacogenomics
Therapeutic Drug Monitoring: A Patient Management Tool for Precision Medicine SH Jang1, Z Yan1 and JA Lazor1 The precision medicine initiative is designed to better understand the causes of disease, to develop target therapies, and to identify patients that would benefit from treatment. Prescribing the right dose, which is not always the same to all patients, is needed for a successful outcome. The purpose of this commentary is to discuss the role of dose individualization based on therapeutic drug monitoring as a clinical patient management tool in the application of precision medicine.
implementation. Pharmacogenom. J. (2015); e-pub ahead of print. 3. Phillips, K.A., Veenstra, D.L., Oren, E., Lee, J.K. & Sadee, W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286, 2270–2279 (2001). 4. Gollust, S.E. et al. Motivations and perceptions of early adopters of personalized genomics: perspectives from research participants. Public Health Genomics 15, 22–30 (2012). 5. Diseati, L. et al. Common genetic risk for melanoma encourages preventive behavior change. J. Pers. Med. 5, 36–49 (2015). 6. Ostergren, J.E. et al. How well do customers of direct-to-consumer personal genomic testing services comprehend genetic test results? Findings from the Impact of Personal Genomics Study. Public Health Genomics 18, 216–224 (2015). 7. Francke, U. et al. Dealing with the unexpected: consumer responses to directaccess BRCA mutation testing. PeerJ 1, e8 (2013). 8. Green, R.C. et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N. Engl. J. Med. 361, 245–254 (2009). 9. Powell, K. et al. Educational needs of primary care physicians regarding direct-toconsumer genetic testing. J. Genet. Counsel. 21, 469–478 (2012). 10. Budnitz, D.S., Lovegrove, M.C., Shehab, N. & Richards, C.L. Emergency hospitalizations for adverse drug events in older Americans. N. Engl. J. Med. 365, 2002–2012 (2011).
An understanding of individual patient variability is an element of the precision medicine strategies.1,2 One component of individual variability is the wide range of drug exposures that result from a given dose. Determining the dose that will provide individual patients with the best probability of a successful outcome is a key component of therapeutics that should be addressed during drug development. Most drugs are developed as “one size fits all” for the general patient population, with the same dose given to all patients. Depending on the exposure-response relationship and the variability in the pharmacokinetics of the drug, a given dose may result in vastly different exposures across patients and marked differences in response. It is possible that factors could be identified to help
The views expressed in this article are those of the authors and do not necessarily reflect the official views of the US Food and Drug Administration. 1
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA. Correspondence: SH Jang ([email protected]) doi:10.1002/cpt.298
148
VOLUME 99 NUMBER 2 | FEBRUARY 2016 | www.wileyonlinelibrary/cpt
PERSPECTIVES explain pharmacokinetic variability, which then could be used in dose selection. However, dosing based on factors, such as weight, body surface area, or organ impairment, may not always be sufficient to overcome the variability. In some cases, a more individualized approach is needed to yield a positive balance of efficacy and safety. Although the use of pharmacogenomics has advanced during the last two decades as a tool for dose individualization, therapeutic drug monitoring (TDM) should not be neglected for dose individualization that can ultimately contribute to precision medicine. TDM can achieve target drug concentrations in individual patients more precisely than what genotyping of drug metabolizing enzymes or transporters can do. However, the two approaches are complementary rather than exclusive. Genotyping of drug metabolizing enzymes or transporters may be useful to select drug and initial dose, whereas TDM will be useful to adjust subsequent doses according to drug concentrations or pharmacodynamic measures in individual patients. The clinical uses of some psychiatry drugs and warfarin are based on both TDM and genotyping of drug metabolizing enzymes or transporters.3,4 TDM has evolved to be an important patient management tool for drugs such as antiarrhythmic drugs, anticonvulsants, psychiatric drugs, anticancer drugs, immunosuppressive drugs, and antifungal drugs.5 TDM could be useful for drugs with high pharmacokinetic variability when it is important to achieve a target plasma drug concentration range to provide the best opportunity for efficacy and to prevent toxicity, to achieve a minimal concentration that is required for a greater probability of success, or to avoid a high concentration to prevent adverse events. The use of TDM requires an association between exposure and response (efficacy and/or adverse events), an assay to measure drug concentrations, target concentration(s), a practical measure of exposure that can be used in clinical practice, and the marketing of multiple dose strengths of oral products to allow for dose adjustment. TDM can be a useful patient management tool for dose individualization for the general patient population and also for specific populations or circumstances. During
drug development, the pharmacokinetics of a drug may not be evaluated in patients who are critically ill and require intensive care. Patients who are critically ill may have physiological changes that may affect a drug’s absorption, distribution, metabolism, or excretion, or they may be receiving medical interventions, such as renal replacement therapy.6,7 These changes could result in alterations in the drug’s pharmacokinetics, which may lead to loss of efficacy or toxicity without dose adjustments. Patient factors, such as drug metabolism enzyme polymorphism or organ function, may not be sufficient to explain pharmacokinetic variability in critically ill patients. TDM based on a drug exposure or a pharmacodynamic measure could be useful to further individualize the doses given in these patients. Some drug products display high interpatient variability because of extrinsic factors that alter exposure. For example, posaconazole suspension is highly dependent on food intake to attain adequate exposure. With the high interpatient variability in the exposure of posaconazole, TDM could be a useful tool to help ensure that patients are receiving adequate dosing.8 Without achieving sufficient systemic drug concentrations, the drug will not be efficacious and the patient will not benefit from the drug. TDM could also be important to assess intrapatient changes in drug exposure over time. The reasons for intrapatient variability in drug exposure are various and often not clear. After initiation of drug therapy, pathophysiological changes may occur with disease progression, which could result in altered drug exposure that may alter a patient’s response to the drug. Knowing the exposure of the drug could help explain observed changes in response and could serve as the basis for adjusting the dose to obtain the desired response. Drug labeling may include dose recommendations for specific populations and for drug interactions. However, it is difficult to provide dosing recommendations for complex situations in which a combination of factors need to be considered. In those situations, TDM could be a useful tool to determine drug exposure and assess whether a dose adjustment is required to achieve the desired result. Even though the
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 99 NUMBER 2 | FEBRUARY 2016
right drug is prescribed to the right patient at the right dose, the drug will not have its expected benefit if the drug is not taken. TDM can be used as a patient management tool to assess patient adherence and to understand why a patient is not showing benefit. In other cases in which a patient is exhibiting adverse events, TDM could also be used to assess whether a patient was taking several times the prescribed dose. Although drugs are not usually approved with recommendations for individualization of dosing using TDM, the usefulness of such a tool to determine the right dose is often identified postapproval with expanded use of the drug in clinical practice. The outgrowth of TDM as part of clinical practice often results in differing opinions in its clinical utility or differing concentration targets because the benefit of TDM has not been well studied. Since the approval of Vfend (voriconazole), a growing body of evidence from retrospective analyses has revealed the utility of TDM for individualizing voriconazole dosing. A prospective, randomized, controlled study to evaluate the clinical utility of TDM in voriconazole therapy showed that routine TDM of voriconazole reduced drug discontinuations because of adverse events and improved the treatment response in patients with invasive fungal infections.9 This study sheds light on the value of prospectively evaluating the use of TDM for dose individualization. For investigational drugs that have unpredictable pharmacokinetics and a well-characterized exposureresponse relationship, the need for dose individualization using TDM should be explored during drug development. This approach can lead to better dosing guidelines and TDM instruction in labeling, so all patients receive the right dose. Unlike voriconazole, the evidence of the clinical benefit of TDM is not sufficiently established for most drugs, although the need of dose individualization is supported by other pharmacological evidence, such as the relationship between a drug’s pharmacokinetics and its variability, and the relationship of dose, exposure, and effect. The lack of evidence of clinical benefit of TDM limits clinical use of TDM for dose individualization. Conducting clinical trials to provide solid evidence for a TDM-based approach remains a challenge. It should be 149
PERSPECTIVES noted that prospective randomized clinical trials to assess the advantage of TDM vs. “one size fits all” dose may not always be successful because the number of patients who would benefit from TDM is relatively small in these trials. The interpretation of drug concentrations measured in individual patients is another strong challenge in the application of TDM. When drug concentrations in an individual patient are measured, the decision for whether dose adjustment is needed is dependent upon comparing the drug concentration measured in individual patients with the predetermined target concentrations, which are derived from the patient population. This approach has been acceptable for TDM in general. However, for some drugs, the target concentrations determined from the patient population are not always right for all patients. For instance, some patients may experience efficacy failure at concentrations higher than the upper limit of the target concentration range or adverse events at concentrations lower than the lower limit of the target concentration range. The circumstances could lead to the application of “individualized” target concentrations for TDM by monitoring drug response (either efficacy or toxicity, or both) as well as drug concentrations in individual patients.10 This practice has been used for
some drugs, such as psychotropic drugs and immunosuppressive drugs. Application of “individualized” target concentrations is one step closer to an individualized approach when it is needed. Precision medicine is a global initiative to identify the right target for drug effect and to align the patient’s disease characteristics to the identified target to prescribe the right drug. If the patient is not receiving the right dose, then the benefits of precision medicine at the patient level is jeopardized. TDM could be a useful patient management tool to individualize the dose and help ensure the best possible outcome for each patient. ACKNOWLEDGMENT We thank Dr. Kellie S. Reynolds for providing valuable editorial comments.
CONFLICT OF INTEREST The authors declared no conflict of interest. C 2015 ASCPT V
1.
2.
The Precision Medicine Initiative Cohort Program-Building a Research Foundation for 21st Century Medicine. Precision Medicine Initiative (PMI) Working Group Report to the Advisory Committee to the Director, NIH. . Collins, F.S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).
Microdosing of Protein Drugs M Rowland1 Poor pharmacokinetics (PK) can seriously limit clinical utility. Knowing early whether a new compound is likely to have the desired PK profile at therapeutic doses is therefore important. One approach, microdosing,1 has shown high success with small molecular weight compounds,2 despite early skepticism. Vlaming et al.3 report the first, and successful, clinical application of a microdose of a humanized recombinant protein. But what is the likely success for this class of drugs more generally?
€qvist, F. & Eliasson, E. The convergence Sjo of conventional therapeutic drug monitoring and pharmacogenetic testing in personalized medicine: focus on antidepressants. Clin. Pharmacol. Ther. 81, 899–902 (2007). 4. Mahajan, P., Meyer, K.S., Wall, G.C. & Price, H.J. Clinical applications of pharmacogenomics guided warfarin dosing. Int. J. Clin. Pharm. 35, 359–368 (2013). 5. Kang, J.S. & Lee, M.H. Overview of therapeutic drug monitoring. Korean J. Intern. Med. 24, 1–10 (2009). 6. Jamal, J.A., Mueller, B.A., Choi, G.Y., Lipman, J. & Roberts, J.A. How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy? Diagn. Microbiol. Infect. Dis. 82, 92–103 (2015). 7. Parker, D.L., Sime, F.B. & Roberts, J.A. Optimizing dosing of antibiotics in critically ill patients. Curr. Opin. Infect. Dis. 28, 497– 504 (2015). 8. Jang, S.H., Colangelo, P.M. & Gobburu, J.V. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin. Pharmacol. Ther. 88, 115– 119 (2010). 9. Park, W.B. et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin. Infect. Dis. 55, 1080–1087 (2012). 10. Bengtsson, F. Therapeutic drug monitoring of psychotropic drugs. TDM “nouveau”. Ther. Drug Monit. 26, 145–151 (2004).
3.
The point in favor of human microdosing of protein drugs is that for humanized proteins information gained from animals may not reflect well behavior in human, due in part to immunological incompatibility that, through antibody formation, alters the PK of the molecule. A view against microdosing of proteins could be taken based on the relatively common situation, especially with monoclonal antibodies, of target mediated disposition (TDM), in which the disposition kinetics is nonlinear at low doses, only becoming linear at higher doses, when the TDM mechanism becomes saturated. However, TDM may
1
University of Manchester, Manchester, UK. Correspondence: M Rowland ([email protected])
doi:10.1002/cpt.275 150
VOLUME 99 NUMBER 2 | FEBRUARY 2016 | www.wileyonlinelibrary/cpt
qualified genetics professionals (June, 2015). Where do we go from here? In the presence of growing agreement and in the absence of evidence of harm, the public is best served by the FDA focusing on negligent actors in the DTC-GT space while permitting the private sector to pursue responsible efforts. We feel the best path forward for using personal genetic information is through an expert physician intermediary. However, DTC-GT options represent an imperfect but reasonable alternative in the absence of expert physicians. Given the potential for genetic information to inform decision-making from preventive medicine to drug and therapy response, we must temper the exalted promise of precision medicine with determined access across patient populations. It’s an exciting time in medicine and progress such as PGx should inform as many health outcomes as possible. CONFLICT OF INTEREST The authors declare no conflicts of interest. C 2015 ASCPT V
1.
2.
23andMe. What the FDA decision means for 23andMe customers. 23andMe Blog (2015). Peterson, J.F. et al. Attitudes of clinicians following large-scale pharmacogenomics
Therapeutic Drug Monitoring: A Patient Management Tool for Precision Medicine SH Jang1, Z Yan1 and JA Lazor1 The precision medicine initiative is designed to better understand the causes of disease, to develop target therapies, and to identify patients that would benefit from treatment. Prescribing the right dose, which is not always the same to all patients, is needed for a successful outcome. The purpose of this commentary is to discuss the role of dose individualization based on therapeutic drug monitoring as a clinical patient management tool in the application of precision medicine.
implementation. Pharmacogenom. J. (2015); e-pub ahead of print. 3. Phillips, K.A., Veenstra, D.L., Oren, E., Lee, J.K. & Sadee, W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286, 2270–2279 (2001). 4. Gollust, S.E. et al. Motivations and perceptions of early adopters of personalized genomics: perspectives from research participants. Public Health Genomics 15, 22–30 (2012). 5. Diseati, L. et al. Common genetic risk for melanoma encourages preventive behavior change. J. Pers. Med. 5, 36–49 (2015). 6. Ostergren, J.E. et al. How well do customers of direct-to-consumer personal genomic testing services comprehend genetic test results? Findings from the Impact of Personal Genomics Study. Public Health Genomics 18, 216–224 (2015). 7. Francke, U. et al. Dealing with the unexpected: consumer responses to directaccess BRCA mutation testing. PeerJ 1, e8 (2013). 8. Green, R.C. et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N. Engl. J. Med. 361, 245–254 (2009). 9. Powell, K. et al. Educational needs of primary care physicians regarding direct-toconsumer genetic testing. J. Genet. Counsel. 21, 469–478 (2012). 10. Budnitz, D.S., Lovegrove, M.C., Shehab, N. & Richards, C.L. Emergency hospitalizations for adverse drug events in older Americans. N. Engl. J. Med. 365, 2002–2012 (2011).
An understanding of individual patient variability is an element of the precision medicine strategies.1,2 One component of individual variability is the wide range of drug exposures that result from a given dose. Determining the dose that will provide individual patients with the best probability of a successful outcome is a key component of therapeutics that should be addressed during drug development. Most drugs are developed as “one size fits all” for the general patient population, with the same dose given to all patients. Depending on the exposure-response relationship and the variability in the pharmacokinetics of the drug, a given dose may result in vastly different exposures across patients and marked differences in response. It is possible that factors could be identified to help
The views expressed in this article are those of the authors and do not necessarily reflect the official views of the US Food and Drug Administration. 1
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA. Correspondence: SH Jang ([email protected]) doi:10.1002/cpt.298
148
VOLUME 99 NUMBER 2 | FEBRUARY 2016 | www.wileyonlinelibrary/cpt
PERSPECTIVES explain pharmacokinetic variability, which then could be used in dose selection. However, dosing based on factors, such as weight, body surface area, or organ impairment, may not always be sufficient to overcome the variability. In some cases, a more individualized approach is needed to yield a positive balance of efficacy and safety. Although the use of pharmacogenomics has advanced during the last two decades as a tool for dose individualization, therapeutic drug monitoring (TDM) should not be neglected for dose individualization that can ultimately contribute to precision medicine. TDM can achieve target drug concentrations in individual patients more precisely than what genotyping of drug metabolizing enzymes or transporters can do. However, the two approaches are complementary rather than exclusive. Genotyping of drug metabolizing enzymes or transporters may be useful to select drug and initial dose, whereas TDM will be useful to adjust subsequent doses according to drug concentrations or pharmacodynamic measures in individual patients. The clinical uses of some psychiatry drugs and warfarin are based on both TDM and genotyping of drug metabolizing enzymes or transporters.3,4 TDM has evolved to be an important patient management tool for drugs such as antiarrhythmic drugs, anticonvulsants, psychiatric drugs, anticancer drugs, immunosuppressive drugs, and antifungal drugs.5 TDM could be useful for drugs with high pharmacokinetic variability when it is important to achieve a target plasma drug concentration range to provide the best opportunity for efficacy and to prevent toxicity, to achieve a minimal concentration that is required for a greater probability of success, or to avoid a high concentration to prevent adverse events. The use of TDM requires an association between exposure and response (efficacy and/or adverse events), an assay to measure drug concentrations, target concentration(s), a practical measure of exposure that can be used in clinical practice, and the marketing of multiple dose strengths of oral products to allow for dose adjustment. TDM can be a useful patient management tool for dose individualization for the general patient population and also for specific populations or circumstances. During
drug development, the pharmacokinetics of a drug may not be evaluated in patients who are critically ill and require intensive care. Patients who are critically ill may have physiological changes that may affect a drug’s absorption, distribution, metabolism, or excretion, or they may be receiving medical interventions, such as renal replacement therapy.6,7 These changes could result in alterations in the drug’s pharmacokinetics, which may lead to loss of efficacy or toxicity without dose adjustments. Patient factors, such as drug metabolism enzyme polymorphism or organ function, may not be sufficient to explain pharmacokinetic variability in critically ill patients. TDM based on a drug exposure or a pharmacodynamic measure could be useful to further individualize the doses given in these patients. Some drug products display high interpatient variability because of extrinsic factors that alter exposure. For example, posaconazole suspension is highly dependent on food intake to attain adequate exposure. With the high interpatient variability in the exposure of posaconazole, TDM could be a useful tool to help ensure that patients are receiving adequate dosing.8 Without achieving sufficient systemic drug concentrations, the drug will not be efficacious and the patient will not benefit from the drug. TDM could also be important to assess intrapatient changes in drug exposure over time. The reasons for intrapatient variability in drug exposure are various and often not clear. After initiation of drug therapy, pathophysiological changes may occur with disease progression, which could result in altered drug exposure that may alter a patient’s response to the drug. Knowing the exposure of the drug could help explain observed changes in response and could serve as the basis for adjusting the dose to obtain the desired response. Drug labeling may include dose recommendations for specific populations and for drug interactions. However, it is difficult to provide dosing recommendations for complex situations in which a combination of factors need to be considered. In those situations, TDM could be a useful tool to determine drug exposure and assess whether a dose adjustment is required to achieve the desired result. Even though the
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 99 NUMBER 2 | FEBRUARY 2016
right drug is prescribed to the right patient at the right dose, the drug will not have its expected benefit if the drug is not taken. TDM can be used as a patient management tool to assess patient adherence and to understand why a patient is not showing benefit. In other cases in which a patient is exhibiting adverse events, TDM could also be used to assess whether a patient was taking several times the prescribed dose. Although drugs are not usually approved with recommendations for individualization of dosing using TDM, the usefulness of such a tool to determine the right dose is often identified postapproval with expanded use of the drug in clinical practice. The outgrowth of TDM as part of clinical practice often results in differing opinions in its clinical utility or differing concentration targets because the benefit of TDM has not been well studied. Since the approval of Vfend (voriconazole), a growing body of evidence from retrospective analyses has revealed the utility of TDM for individualizing voriconazole dosing. A prospective, randomized, controlled study to evaluate the clinical utility of TDM in voriconazole therapy showed that routine TDM of voriconazole reduced drug discontinuations because of adverse events and improved the treatment response in patients with invasive fungal infections.9 This study sheds light on the value of prospectively evaluating the use of TDM for dose individualization. For investigational drugs that have unpredictable pharmacokinetics and a well-characterized exposureresponse relationship, the need for dose individualization using TDM should be explored during drug development. This approach can lead to better dosing guidelines and TDM instruction in labeling, so all patients receive the right dose. Unlike voriconazole, the evidence of the clinical benefit of TDM is not sufficiently established for most drugs, although the need of dose individualization is supported by other pharmacological evidence, such as the relationship between a drug’s pharmacokinetics and its variability, and the relationship of dose, exposure, and effect. The lack of evidence of clinical benefit of TDM limits clinical use of TDM for dose individualization. Conducting clinical trials to provide solid evidence for a TDM-based approach remains a challenge. It should be 149
PERSPECTIVES noted that prospective randomized clinical trials to assess the advantage of TDM vs. “one size fits all” dose may not always be successful because the number of patients who would benefit from TDM is relatively small in these trials. The interpretation of drug concentrations measured in individual patients is another strong challenge in the application of TDM. When drug concentrations in an individual patient are measured, the decision for whether dose adjustment is needed is dependent upon comparing the drug concentration measured in individual patients with the predetermined target concentrations, which are derived from the patient population. This approach has been acceptable for TDM in general. However, for some drugs, the target concentrations determined from the patient population are not always right for all patients. For instance, some patients may experience efficacy failure at concentrations higher than the upper limit of the target concentration range or adverse events at concentrations lower than the lower limit of the target concentration range. The circumstances could lead to the application of “individualized” target concentrations for TDM by monitoring drug response (either efficacy or toxicity, or both) as well as drug concentrations in individual patients.10 This practice has been used for
some drugs, such as psychotropic drugs and immunosuppressive drugs. Application of “individualized” target concentrations is one step closer to an individualized approach when it is needed. Precision medicine is a global initiative to identify the right target for drug effect and to align the patient’s disease characteristics to the identified target to prescribe the right drug. If the patient is not receiving the right dose, then the benefits of precision medicine at the patient level is jeopardized. TDM could be a useful patient management tool to individualize the dose and help ensure the best possible outcome for each patient. ACKNOWLEDGMENT We thank Dr. Kellie S. Reynolds for providing valuable editorial comments.
CONFLICT OF INTEREST The authors declared no conflict of interest. C 2015 ASCPT V
1.
2.
The Precision Medicine Initiative Cohort Program-Building a Research Foundation for 21st Century Medicine. Precision Medicine Initiative (PMI) Working Group Report to the Advisory Committee to the Director, NIH. . Collins, F.S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).
Microdosing of Protein Drugs M Rowland1 Poor pharmacokinetics (PK) can seriously limit clinical utility. Knowing early whether a new compound is likely to have the desired PK profile at therapeutic doses is therefore important. One approach, microdosing,1 has shown high success with small molecular weight compounds,2 despite early skepticism. Vlaming et al.3 report the first, and successful, clinical application of a microdose of a humanized recombinant protein. But what is the likely success for this class of drugs more generally?
€qvist, F. & Eliasson, E. The convergence Sjo of conventional therapeutic drug monitoring and pharmacogenetic testing in personalized medicine: focus on antidepressants. Clin. Pharmacol. Ther. 81, 899–902 (2007). 4. Mahajan, P., Meyer, K.S., Wall, G.C. & Price, H.J. Clinical applications of pharmacogenomics guided warfarin dosing. Int. J. Clin. Pharm. 35, 359–368 (2013). 5. Kang, J.S. & Lee, M.H. Overview of therapeutic drug monitoring. Korean J. Intern. Med. 24, 1–10 (2009). 6. Jamal, J.A., Mueller, B.A., Choi, G.Y., Lipman, J. & Roberts, J.A. How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy? Diagn. Microbiol. Infect. Dis. 82, 92–103 (2015). 7. Parker, D.L., Sime, F.B. & Roberts, J.A. Optimizing dosing of antibiotics in critically ill patients. Curr. Opin. Infect. Dis. 28, 497– 504 (2015). 8. Jang, S.H., Colangelo, P.M. & Gobburu, J.V. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin. Pharmacol. Ther. 88, 115– 119 (2010). 9. Park, W.B. et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin. Infect. Dis. 55, 1080–1087 (2012). 10. Bengtsson, F. Therapeutic drug monitoring of psychotropic drugs. TDM “nouveau”. Ther. Drug Monit. 26, 145–151 (2004).
3.
The point in favor of human microdosing of protein drugs is that for humanized proteins information gained from animals may not reflect well behavior in human, due in part to immunological incompatibility that, through antibody formation, alters the PK of the molecule. A view against microdosing of proteins could be taken based on the relatively common situation, especially with monoclonal antibodies, of target mediated disposition (TDM), in which the disposition kinetics is nonlinear at low doses, only becoming linear at higher doses, when the TDM mechanism becomes saturated. However, TDM may
1
University of Manchester, Manchester, UK. Correspondence: M Rowland ([email protected])
doi:10.1002/cpt.275 150
VOLUME 99 NUMBER 2 | FEBRUARY 2016 | www.wileyonlinelibrary/cpt
