TABLE 12

Overview of case studies, mechanisms involved, design features and suggested improvements of design with respect to DRT analyses

No.Case StudyComments on MechanismFeatures of DataDesign FeaturesSuggested Improvements to Design
1Tail flickAnalgetic drug actions may involve central (spinal, supraspinal) as well as peripheral componentsBaseline, peak shift, saturation, absorption rate–limited duration of response, time series of response, multiple dose and route challenges3 and 10 µg i.v. boluses and 10, 50, and 100 µg s.c.; 10-µg dose same for i.v. and s.c. dosingF needs i.v. and s.c. data
Ka may require better resolution of both onset and offset of response
K requires better resolution of the offset of response
kin requires robust baseline data
kout determines onset and offset of response
SD50 determines duration and offset of response
Smax determines intensity of response
nH will impact the steepness of the rise and decline of response
2Locomotor activity stimulationIndirect-acting dopamine receptor stimulant (releaser); psychostimulantNo baseline, peak shift, zero-order rise and decline of response, saturation of buildup and loss, high-resolution response-time series3.12 and 5.82 µg/kg given i.p.F biophase availability needs i.v. and i.p. data
K’ needs i.v. and i.p. data to discriminate between absorption and disposition rate-limited processes
kout needs reasonable resolution during onset
kM needs reasonable resolution of low response data
SD50 requires robust data on the offset of response
Smax requires data at maximum response
nH requires robust data at the time of rapid rise and decline
The present design may suffice for assessment of the acute locomotor response. To capture chronic patterns in the response, extended test compound exposure during several days is needed, which in turn may also require adjustment of the model if functional adaptation occurs (see case study 8)
3Fatty acid responseAntilipolyticBaseline, saturation, rebound, tolerance, multiple interventionsMultiple i.v. infusions plus washoutK requires robust data on the onset and offset of response
R0 requires robust data at baseline
kout requires robust data at onset and offset of response
ktol requires robust data during extended exposure to drug
ID50 requires robust data on the offset of response
nH requires robust data at the time of rapid rise and decline
The present design may suffice for assessment of the acute antilipolytic response. To capture chronic patterns in the response, extended exposure to test compound during several days is needed, which also requires adjustment of the model (see case study 8)
4Psychosis score (BPRS)Central dopamine receptor antagonismBaseline, time to PD steady state, categorizing responders, onset of action120–600 mg daily p.o. dosingkin requires robust data at baseline
kout requires robust data at onset
Imax requires data at maximum response
Extended data beyond the observational time range may cast light on potential functional adaptation. Baseline data of BPRS and placebo comparisons are also necessary for correct assessment of pure drug-induced response independently of concentration-driven or DRT approach
5Bacterial growth and killAntimicrobialBaseline, growth limit, saturation, first-order growth/killMultiple i.v. doseskg requires robust vehicle control data
kk requires kill and regrowth data from two or more doses
6Cortisol release during and after exposure to ACTHPhysiologic interplay in the cortisol axis. Suggested mechanisms may also involve changes in cortisol hydroxylation, and/or other unknown actions of ACTH on steroidogenesisBaseline, rebound, tolerance turnover, endogenous agonist, square wave of ACTH interventionExperimental model of ACTH exposure driving the release rate of cortisolkin requires robust data at baseline
kout requires robust data at onset
SD50 requires data during offset of response
Smax requires data at maximum intensity
nH requires robust data at the time of rapid rise and decline
Long-term adaptation requires extended exposure to test compound over time. Oscillatory behavior in experimental data may need a model extension similar to Ahlström et al. (2011)
7Miotic response in the cat eyeProstenoid F receptor interaction in the smooth muscle of the irisBaseline, partial inhibition, saturation, rapid equilibrium modelThree doses (0.1, 1.0, and 10 µg latanoprost) given topicallyKa requires robust data at onset and offset
K requires robust data at onset and offset
tlag requires robust data at onset
ID50 requires data on the offset
Imax requires data at maximum intensity
nH requires robust data at the time of rapid rise and decline
Long-term adaptation of the pharmacological response requires extended exposure to test compound over time
8Meta-analysis of fatty acid and insulin response to multiple NiAc provocations (NLME analysis)AntilipolyticBaseline, saturation, rebound, tolerance turnover, multiple biomarkers, multiple drug provocations, endogenous agonist, input-stimulated washout profileMultiple i.v. and s.c. doses, rates, and modes of NiAc plus washout; multiple, intertwined, biomarker responsesFor a thorough description model and suggestions about experimental design and identifiability of KaM, Vmax, K, kin, kout, SD50, Smax and nH, see Andersson et al. (2017). System parameters after DRT analysis are still reasonably consistent with estimates from a concentration-driven analysis
  • NLME, nonlinear mixed effects.