Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety.
Pharm Res
; 38(4): 593-605, 2021 Apr.
Article
in En
| MEDLINE
| ID: mdl-33733372
ABSTRACT
PURPOSE:
Pharmacometric models provide useful tools to aid the rational design of clinical trials. This study evaluates study design-, drug-, and patient-related features as well as analysis methods for their influence on the power to demonstrate a benefit of pharmacogenomics (PGx)-based dosing regarding myelotoxicity.METHODS:
Two pharmacokinetic and one myelosuppression model were assembled to predict concentrations of irinotecan and its metabolite SN-38 given different UGT1A1 genotypes (poor metabolizers CLSN-38 -36%) and neutropenia following conventional versus PGx-based dosing (350 versus 245 mg/m2 (-30%)). Study power was assessed given diverse scenarios (n = 50-400 patients/arm, parallel/crossover, varying magnitude of CLSN-38, exposure-response relationship, inter-individual variability) and using model-based data analysis versus conventional statistical testing.RESULTS:
The magnitude of CLSN-38 reduction in poor metabolizers and the myelosuppressive potency of SN-38 markedly influenced the power to show a difference in grade 4 neutropenia (<0.5·109 cells/L) after PGx-based versus standard dosing. To achieve >80% power with traditional statistical analysis (χ2/McNemar's test, α = 0.05), 220/100 patients per treatment arm/sequence (parallel/crossover study) were required. The model-based analysis resulted in considerably smaller total sample sizes (n = 100/15 given parallel/crossover design) to obtain the same statistical power.CONCLUSIONS:
The presented findings may help to avoid unfeasible trials and to rationalize the design of pharmacogenetic studies.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Research Design
/
Glucuronosyltransferase
/
Irinotecan
/
Neutropenia
Type of study:
Clinical_trials
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Pharm Res
Year:
2021
Document type:
Article
Affiliation country:
Suecia