1521-0081/71/1/89–122$35.00 https://doi.org/10.1124/pr.118.015750 PHARMACOLOGICAL REVIEWS Pharmacol Rev 71:89–122, January 2019 Copyright © 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: GUNNAR SCHULTE Dose-Response-Time Data Analysis: An Underexploited Trinity Johan Gabrielsson, Robert Andersson, Mats Jirstrand, and Stephan Hjorth Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden (J.G.); Fraunhofer-Chalmers Centre, Gothenburg, Sweden (R.A., M.J.); Pharmacilitator AB, Vallda, Sweden (S.H.); and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.) Abstract. .................................................................................... 90 I. Introduction. .............................................................................. 90 II. Methods and Models ........................................................................ 92 A. What Can Be Learned from Response-Time Data Patterns? .............................. 92 B. How Is the Biophase Typically Defined?. ................................................ 93 C. The Drug “Mechanism” Function. ...................................................... 94 D. Structure of the Pharmacodynamic Model ................................................ 95 Downloaded from E. Response-Time Patterns Impact Model Structure......................................... 95 III. Case Studies . .............................................................................. 96 A. Case Study 1: Dose-Response-Time Analysis of Nociceptive Response . ................... 96 1. Background . ........................................................................ 96 2. Models, Equations, and Exploratory Analysis ......................................... 96 by guest on September 30, 2021 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. ............. 99 4. Pharmacodynamic Interpretation and Comments ..................................... 99 B. Case Study 2: Dose-Response-Time Analysis of Locomotor Stimulation. ................... 99 1. Background . ........................................................................ 99 2. Models, Equations, and Exploratory Analysis ......................................... 99 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............101 4. Pharmacodynamic Interpretation and Comments .....................................101 C. Case Study 3: Dose-Response-Time Analysis of Functional Adaptation . ...................102 1. Background . ........................................................................102 2. Models, Equations, and Exploratory Analysis .........................................102 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............103 4. Pharmacodynamic Interpretation and Comment . .....................................103 D. Case Study 4: Dose-Response-Time Analysis of Antipsychotic Effects (Brief Psychiatric Rating Scale Scores) . ..................................................................103 1. Background . ........................................................................103 2. Models, Equations, and Exploratory Analysis .........................................104 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............105 4. Pharmacodynamic Interpretation and Comments .....................................106 E. Case Study 5: Dose-Response-Time Analysis of Bacterial Count . .........................106 1. Background . ........................................................................106 2. Models, Equations, and Exploratory Analysis .........................................106 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............106 Address correspondence to: Johan Gabrielsson, Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7028, SE-750 07 Uppsala, Sweden. E-mail: johan. [email protected] This work was funded in part through the Marie Curie Seventh Framework Programme People Initial Training Networks European Industrial Doctorate Project [Innovative Modeling for Pharmacological Advances through Collaborative Training Grant No. 316736] and by the Swedish Foundation for Strategic Research [(both to R.A. and M.J.)]. https://doi.org/10.1124/pr.118.015750. 89 90 Gabrielsson et al. 4. Pharmacodynamic Interpretation and Comments .....................................107 F. Case Study 6: Dose-Response-Time Analysis of Cortisol–Adrenocorticotropic Hormone Action...................................................................................107 1. Background . ........................................................................107 2. Models, Equations, and Exploratory Analysis .........................................107 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............107 4. Pharmacodynamic Interpretation and Comments .....................................108 G. Case Study 7: Dose-Response-Time Analysis of Miotic Effects.............................108 1. Background . ........................................................................108 2. Models, Equations, and Exploratory Analysis .........................................109 3. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............109 4. Pharmacodynamic Interpretation and Comments .....................................109 H. Case Study 8: Meta-Analysis of Dose-Response-Time Data. ...............................110 1. Background . ........................................................................110 2. Results and Conclusions with Respect to Dose-Response-Time Analysis. .............110 3. Pharmacodynamic Interpretation and Comments .....................................111 I. Overall Conclusions of the Case Studies. ................................................111 IV. Discussion ..................................................................................112 A. Background .............................................................................112 B. What Do Different Doses, Routes, and Rates of Input Add? ...............................112 C. Drug Delivery by Means of Iontophoresis ................................................119 D. Permutations of Smolen’s Model: The Kinetic-dynamic K-PD Rate of Change Model.......120 E. General Conclusions . ..................................................................120 References ..................................................................................120 Abstract——Themostcommonapproachtoinvivo direct assay method for the drug and has the pharmacokinetic and pharmacodynamic analyses additional advantage of being applicable to cases involves sequential analysis of the plasma concen- of local drug administration close to its intended tration- and response-time data, such that the targets in the immediate vicinity of target, or when plasma kinetic model provides an independent func- target precedes systemic plasma concentrations. tion, driving the dynamics. However, in situations This review exemplifies the potential of biophase when plasma sampling may jeopardize the effect functions in pharmacodynamic analyses in both measurements or is scarce, nonexistent, or unlinked preclinical and clinical studies, with the purpose to the effect (e.g., in intensive care units, pediatric of characterizing response data and optimizing or frail elderly populations, or drug discovery), subsequent study protocols. This article illustrates focusing on the response-time course alone may be crucial determinants to the success of modeling an adequate alternative for pharmacodynamic analyses. dose-response-time (DRT) data, such as the dose Response-time data inherently contain useful information selection, repeated dosing, and different input about the turnover characteristics of response (target rates and routes. Finally, a literature search was also turnover rate, half-life of response), as well as the drug’s performed to gauge how frequently this technique has biophase kinetics (biophase availability, absorption been applied in preclinical and clinical studies. This half-life, and disposition half-life) pharmacodynamic review highlights situations in which DRT should be properties (potency, efficacy). The use of pharmacodynamic carefully scrutinized and discusses future perspectives time-response data circumvents the need for a of the field. I. Introduction pharmacological response when information about the drug concentration is scarce or even totally lacking Pharmacological time-series data are typically rich in (Levy, 1971; Smolen, 1971a,b, 1976a,b, 1978; Smolen information. However, response-time series are often et al., 1972; Smolen and Weigand, 1973). Usually, compared with plasma or blood exposure prior to any plasma or tissue concentrations of drug are used as analysis of the connection between dose, response, and the “driver” of the pharmacological response. However, time data per se. Dose-response-time (DRT) data anal- plasma concentrations may be of marginal value ysis is therefore an underexplored approach for quan- in situations with difficult or unethical sampling (e.g., tification of the onset, intensity,