No. | Case Study | Comments on Mechanism | Features of Data | Design Features | Suggested Improvements to Design |
---|---|---|---|---|---|
1 | Tail flick | Analgetic drug actions may involve central (spinal, supraspinal) as well as peripheral components | Baseline, peak shift, saturation, absorption rate–limited duration of response, time series of response, multiple dose and route challenges | 3 and 10 µg i.v. boluses and 10, 50, and 100 µg s.c.; 10-µg dose same for i.v. and s.c. dosing | F 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 | |||||
2 | Locomotor activity stimulation | Indirect-acting dopamine receptor stimulant (releaser); psychostimulant | No baseline, peak shift, zero-order rise and decline of response, saturation of buildup and loss, high-resolution response-time series | 3.12 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) | |||||
3 | Fatty acid response | Antilipolytic | Baseline, saturation, rebound, tolerance, multiple interventions | Multiple i.v. infusions plus washout | K 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) | |||||
4 | Psychosis score (BPRS) | Central dopamine receptor antagonism | Baseline, time to PD steady state, categorizing responders, onset of action | 120–600 mg daily p.o. dosing | kin 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 | |||||
5 | Bacterial growth and kill | Antimicrobial | Baseline, growth limit, saturation, first-order growth/kill | Multiple i.v. doses | kg requires robust vehicle control data |
kk requires kill and regrowth data from two or more doses | |||||
6 | Cortisol release during and after exposure to ACTH | Physiologic interplay in the cortisol axis. Suggested mechanisms may also involve changes in cortisol hydroxylation, and/or other unknown actions of ACTH on steroidogenesis | Baseline, rebound, tolerance turnover, endogenous agonist, square wave of ACTH intervention | Experimental model of ACTH exposure driving the release rate of cortisol | kin 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) | |||||
7 | Miotic response in the cat eye | Prostenoid F receptor interaction in the smooth muscle of the iris | Baseline, partial inhibition, saturation, rapid equilibrium model | Three doses (0.1, 1.0, and 10 µg latanoprost) given topically | Ka 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 | |||||
8 | Meta-analysis of fatty acid and insulin response to multiple NiAc provocations (NLME analysis) | Antilipolytic | Baseline, saturation, rebound, tolerance turnover, multiple biomarkers, multiple drug provocations, endogenous agonist, input-stimulated washout profile | Multiple i.v. and s.c. doses, rates, and modes of NiAc plus washout; multiple, intertwined, biomarker responses | For 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.