Clinical Therapeutics/Volume 37, Number 2, 2015
Editor-in-Chief’s Note Pharmacokinetics: The View From Clinical Therapeutics When I began to write this piece, I smiled because of this thought: “Pharmacokinetics is in my blood.” It was 42 years ago when my longtime friend and colleague Dr. David Greenblatt and I began our first pharmacokinetic (PK) research. We studied the PK behavior of single doses of the benzodiazepine chlordiazepoxide (CDX), initially marketed as Libriums (Hoffmann–La Roche Ltd, Nutley, New Jersey) in 1960. We were our own first subjects, drawing blood from each other on Saturdays and Sundays. Our first PK article was generated in part from this work and was published in 1974.1 In that same year, we were able to show that oral CDX produced faster and higher blood levels than intramuscular CDX.2 This finding was clinically important because intramuscular CDX was commonly used when rapid sedation was needed. We continued our collaboration, studying many other drugs from different perspectives and exploring such variables as diet, age, Richard I. Shader, MD sex, obesity, drug interactions, and pharmacogenetics. Thirty years ago, we published a primer on PK that contained ideas, examples, and discussions that are still useful.3 What that primer lacked is current knowledge about pharmacogenomics and about the roles of transporters in absorption and barrier passage. For an up-to-date perspective about pharmacogenomics in drug development, the 2014 guidance from the US Food and Drug Administration is a good place to start.4 In this issue, Dr. John S. Markowitz, our Topic Editor for Pharmacology, Pharmacokinetics, and Pharmacodynamics, has assembled a collection of representative articles.5–10 Absent are any articles dealing with bioequivalence between innovator and generic small molecules. This absence reflects the policy we adopted in 2014 to omit such studies, as we do not view them as valuable for our clinician/scientist readership.11 What PK areas are of particular interest to us at Clinical Therapeutics? The following are the types of studies we consider important, both to the early phases of drug development and to the later stages of a drug’s life cycle, particularly when it is used in previously unstudied populations. Let us start our discussion with a new chemical entity (NCE). The first PK question is: What does the body do to the NCE? This process begins with route of administration and the release characteristics of the delivery system before the NCE is absorbed. By following the concentrations of the NCE over time in the relevant compartment (usually blood), it is then possible to determine the t½ of absorption, Tmax, Cmax, and the t½ of the elimination phase; AUC values are also calculated. From these values, the intrinsic clearance of an NCE can be determined. Once absorption begins, drug distribution starts. Distribution is affected by many factors such as ionization and protein binding, and it is sometimes passive; pumps and transporters may also affect distribution (eg, across the blood–brain barrier). Some drugs are partitioned into fat, and others may be sequestered into specific sites or tissues. At some point during distribution, metabolism or biotransformation begins. Where and how drugs are biotransformed is important early knowledge, and the route of elimination (eg, feces, urine, bile) must also be determined. The next important concern is which populations and contexts are to be studied. Major factors to consider are sex, age (eg, youth, adults, elderly, “old–old”), food intake, obesity, pregnancy and lactation, renal impairment, hepatic impairment, drug interactions, and genetic differences in metabolism. When an NCE is marketed in a new country, PK studies may be required. When such studies are submitted to Clinical Therapeutics, they should take
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Volume 37 Number 2
Editor-in-Chief’s Note any known genetic variations into account. How the body and specific target tissues are affected by the NCE is not a PK property, however; these responses are considered pharmacodynamics. Richard I. Shader, MD Editor-in-Chief
REFERENCES 1. Greenblatt DJ, Shader RI, Koch-Weser J. Pharmacokinetic determinants of the response to single doses of chlordiazepoxide. Am J Psychiatry. 1974;131:1395–1397. 2. Greenblatt DJ, Shader RI, Koch-Weser J. Slow absorption of intramuscular chlordiazepoxide. N Engl J Med. 1974;291:1116–1118. 3. Greenblatt DJ, Shader RI. Pharmacokinetics in Clinical Practice. Philadelphia: W.B. Saunders Co; 1985. 4. FDA Guidance for Industry. Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM337169.pdf. Accessed December 29, 2014. 5. Nam Y, Lim CH, Lee HS, et al. Randomized, single dose, 2-way crossover, open study to compare the pharmacokinetics profile of Etravils (amitriptyline hydrochloride) tablet 10 mg and 25 mg after a single oral administration in healthy Korean male volunteers. Clin Ther. 2015;37:302–310. 6. Chen C, Upward J, Arumugham T, et al. Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind randomized pharmacokinetic and tolerability comparison. Clin Ther. 2015;37:349–357. 7. Darwish M, Bond M, Yang R, et al. Evaluation of the potential for pharmacokinetic drug–drug interaction between armodafinil and carbamazepine in healthy adults. Clin Ther. 2015;37:325–337. 8. Turncliff R, DiPetrillo L, Silverman B, Ehrich E. Single and multiple dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers. Clin Ther. 2015;37:338–348. 9. Barbier AJ, Hilhorst M, Van Vliet A, et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending dose and bioavailability studies. Clin Ther. 2015;37:311–324. 10. Gurley BJ, Steelman SC, Thomas SL. Multi-ingredient, caffeine-containing dietary supplements: history, safety, and efficacy. Clin Ther. 2015;37:275–301. 11. Shader RI. Phase 1 trials. Clin Ther. 2014;36:459.
Specialty Updates Specialty Updates are special themed sections published in each monthly issue of the journal. Each Update highlights new or controversial research within a specific therapeutic area or medical discipline. All articles in an Update are provided as FREE ACCESS content online on the Clinical Therapeutics website.
February 2015
269
Editor-in-Chief’s Note Pharmacokinetics: The View From Clinical Therapeutics When I began to write this piece, I smiled because of this thought: “Pharmacokinetics is in my blood.” It was 42 years ago when my longtime friend and colleague Dr. David Greenblatt and I began our first pharmacokinetic (PK) research. We studied the PK behavior of single doses of the benzodiazepine chlordiazepoxide (CDX), initially marketed as Libriums (Hoffmann–La Roche Ltd, Nutley, New Jersey) in 1960. We were our own first subjects, drawing blood from each other on Saturdays and Sundays. Our first PK article was generated in part from this work and was published in 1974.1 In that same year, we were able to show that oral CDX produced faster and higher blood levels than intramuscular CDX.2 This finding was clinically important because intramuscular CDX was commonly used when rapid sedation was needed. We continued our collaboration, studying many other drugs from different perspectives and exploring such variables as diet, age, Richard I. Shader, MD sex, obesity, drug interactions, and pharmacogenetics. Thirty years ago, we published a primer on PK that contained ideas, examples, and discussions that are still useful.3 What that primer lacked is current knowledge about pharmacogenomics and about the roles of transporters in absorption and barrier passage. For an up-to-date perspective about pharmacogenomics in drug development, the 2014 guidance from the US Food and Drug Administration is a good place to start.4 In this issue, Dr. John S. Markowitz, our Topic Editor for Pharmacology, Pharmacokinetics, and Pharmacodynamics, has assembled a collection of representative articles.5–10 Absent are any articles dealing with bioequivalence between innovator and generic small molecules. This absence reflects the policy we adopted in 2014 to omit such studies, as we do not view them as valuable for our clinician/scientist readership.11 What PK areas are of particular interest to us at Clinical Therapeutics? The following are the types of studies we consider important, both to the early phases of drug development and to the later stages of a drug’s life cycle, particularly when it is used in previously unstudied populations. Let us start our discussion with a new chemical entity (NCE). The first PK question is: What does the body do to the NCE? This process begins with route of administration and the release characteristics of the delivery system before the NCE is absorbed. By following the concentrations of the NCE over time in the relevant compartment (usually blood), it is then possible to determine the t½ of absorption, Tmax, Cmax, and the t½ of the elimination phase; AUC values are also calculated. From these values, the intrinsic clearance of an NCE can be determined. Once absorption begins, drug distribution starts. Distribution is affected by many factors such as ionization and protein binding, and it is sometimes passive; pumps and transporters may also affect distribution (eg, across the blood–brain barrier). Some drugs are partitioned into fat, and others may be sequestered into specific sites or tissues. At some point during distribution, metabolism or biotransformation begins. Where and how drugs are biotransformed is important early knowledge, and the route of elimination (eg, feces, urine, bile) must also be determined. The next important concern is which populations and contexts are to be studied. Major factors to consider are sex, age (eg, youth, adults, elderly, “old–old”), food intake, obesity, pregnancy and lactation, renal impairment, hepatic impairment, drug interactions, and genetic differences in metabolism. When an NCE is marketed in a new country, PK studies may be required. When such studies are submitted to Clinical Therapeutics, they should take
268
Volume 37 Number 2
Editor-in-Chief’s Note any known genetic variations into account. How the body and specific target tissues are affected by the NCE is not a PK property, however; these responses are considered pharmacodynamics. Richard I. Shader, MD Editor-in-Chief
REFERENCES 1. Greenblatt DJ, Shader RI, Koch-Weser J. Pharmacokinetic determinants of the response to single doses of chlordiazepoxide. Am J Psychiatry. 1974;131:1395–1397. 2. Greenblatt DJ, Shader RI, Koch-Weser J. Slow absorption of intramuscular chlordiazepoxide. N Engl J Med. 1974;291:1116–1118. 3. Greenblatt DJ, Shader RI. Pharmacokinetics in Clinical Practice. Philadelphia: W.B. Saunders Co; 1985. 4. FDA Guidance for Industry. Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM337169.pdf. Accessed December 29, 2014. 5. Nam Y, Lim CH, Lee HS, et al. Randomized, single dose, 2-way crossover, open study to compare the pharmacokinetics profile of Etravils (amitriptyline hydrochloride) tablet 10 mg and 25 mg after a single oral administration in healthy Korean male volunteers. Clin Ther. 2015;37:302–310. 6. Chen C, Upward J, Arumugham T, et al. Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind randomized pharmacokinetic and tolerability comparison. Clin Ther. 2015;37:349–357. 7. Darwish M, Bond M, Yang R, et al. Evaluation of the potential for pharmacokinetic drug–drug interaction between armodafinil and carbamazepine in healthy adults. Clin Ther. 2015;37:325–337. 8. Turncliff R, DiPetrillo L, Silverman B, Ehrich E. Single and multiple dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers. Clin Ther. 2015;37:338–348. 9. Barbier AJ, Hilhorst M, Van Vliet A, et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending dose and bioavailability studies. Clin Ther. 2015;37:311–324. 10. Gurley BJ, Steelman SC, Thomas SL. Multi-ingredient, caffeine-containing dietary supplements: history, safety, and efficacy. Clin Ther. 2015;37:275–301. 11. Shader RI. Phase 1 trials. Clin Ther. 2014;36:459.
Specialty Updates Specialty Updates are special themed sections published in each monthly issue of the journal. Each Update highlights new or controversial research within a specific therapeutic area or medical discipline. All articles in an Update are provided as FREE ACCESS content online on the Clinical Therapeutics website.
February 2015
269
