Model-based bioequivalence approach for sparse pharmacokinetic bioequivalence studies: Model selection or model averaging?
Stat Med
; 43(18): 3403-3416, 2024 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-38847215
ABSTRACT
Conventional pharmacokinetic (PK) bioequivalence (BE) studies aim to compare the rate and extent of drug absorption from a test (T) and reference (R) product using non-compartmental analysis (NCA) and the two one-sided test (TOST). Recently published regulatory guidance recommends alternative model-based (MB) approaches for BE assessment when NCA is challenging, as for long-acting injectables and products which require sparse PK sampling. However, our previous research on MB-TOST approaches showed that model misspecification can lead to inflated type I error. The objective of this research was to compare the performance of model selection (MS) on R product arm data and model averaging (MA) from a pool of candidate structural PK models in MBBE studies with sparse sampling. Our simulation study was inspired by a real case BE study using a two-way crossover design. PK data were simulated using three structural models under the null hypothesis and one model under the alternative hypothesis. MB-TOST was applied either using each of the five candidate models or following MS and MA with or without the simulated model in the pool. Assuming T and R have the same PK model, our simulation shows that following MS and MA, MB-TOST controls type I error rates at or below 0.05 and attains similar or even higher power than when using the simulated model. Thus, we propose to use MS prior to MB-TOST for BE studies with sparse PK sampling and to consider MA when candidate models have similar Akaike information criterion.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Computer Simulation
/
Therapeutic Equivalency
/
Models, Statistical
/
Cross-Over Studies
Limits:
Humans
Language:
En
Journal:
Stat Med
Year:
2024
Type:
Article
Affiliation country:
France