The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain.
OBJECTIVE
Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated.


METHODS
A pharmacokinetic-pharmacodynamic (PK/PD) model relating pain relief to gabapentin plasma concentrations was derived from a phase 3 study. The PK component of the model was modified to reflect pregabalin PK. The PD component was modified by scaling the gabapentin concentration-effect relationship to reflect pregabalin potency, which was based on preclincal data. Uncertainty about the potency difference and the steepness of the concentration-response slope necessitated simulating a distribution of outcomes for a series of PK/PD models.


RESULTS
Analysis of the simulated data suggested that after accounting for the uncertainty, there was an 80% chance that the dose defining the clinical feature was within 45% of the true value. The likelihood of estimating a dose that was within an acceptable predefined precision range relative to a known value approximated 60%. The minimum dose that should be studied to have a reasonable chance of estimating the dose that caused a one-point change was 300 mg.


CONCLUSIONS
Doses that identify predefined response may be imprecisely estimated, suggesting that replication of a similar outcome may be elusive in a confirmatory study. Quantification of this precision provides a rationale for phase 2 trial design and dose selection for confirmatory studies.
Lockwood
Peter A
PA
Clinical Pharmacokinetics and Pharmacodynamics, Pfizer Global Research and Development, Ann Arbor, MI, USA. peter.lockwood@pfizer.com
Cook
Jack A
JA
Ewy
Wayne E
WE
Mandema
Jaap W
JW
D000085:Acetates / Q000008:administration & dosage; D000588:Amines; D000700:Analgesics / Q000008:administration & dosage*; D002908:Chronic Disease; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003198:Computer Simulation; D003509:Cyclohexanecarboxylic Acids; D003929:Diabetic Neuropathies / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D008956:Models, Chemical; D015233:Models, Statistical; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods*; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin