Population pharmacokinetic modelling and simulation of tafamidis in healthy subjects and patients with transthyretin amyloidosis

Aims Since the first approval for transthyretin amyloid polyneuropathy patients, new formulations and different strength of tafamidis have been developed and tested in a different population (transthyretin amyloid cardiomyopathy). The objective of this analysis was to develop a unified population ph...

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Published inBritish journal of clinical pharmacology Vol. 87; no. 9; pp. 3574 - 3587
Main Authors Huh, Yeamin, Riley, Steve, Harnisch, Lutz, Nicholas, Timothy
Format Journal Article
LanguageEnglish
Published England 01.09.2021
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ISSN0306-5251
1365-2125
1365-2125
DOI10.1111/bcp.14773

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Summary:Aims Since the first approval for transthyretin amyloid polyneuropathy patients, new formulations and different strength of tafamidis have been developed and tested in a different population (transthyretin amyloid cardiomyopathy). The objective of this analysis was to develop a unified population pharmacokinetic (PK) model of tafamidis, which can describe the PK of various different formulations in healthy subjects as well as patients with TTR amyloidosis, and to understand effects of intrinsic and extrinsic factors on the PK variability. Methods Pooled data from 23 clinical studies (17 Phase 1 and 6 Phase 2/3 studies) were used for the analysis. The plasma concentration–time data were analysed using a nonlinear mixed effects modelling methodology. Covariate analysis was performed using a stepwise covariate model building procedure. Results The final model was a 2‐compartment model with first‐order absorption and elimination coupled with an absorption lag time for nonsolution formations. Body weight, food and tafamidis formulations were incorporated as structural covariates on PK parameters. Covariate analysis further identified age ≥65 years (14.5% decrease) and moderate hepatic impairment effects (57.6% increase) on apparent clearance and transthyretin amyloid polyneuropathy effect (17.3% decrease) on F. However, model‐based clinical trial simulation results indicated that tafamidis steady‐state exposure changes were not clinically meaningful under the tested conditions. Conclusions The unified population PK model of tafamidis was developed based on 23 studies. Subsequent clinical trial simulations indicated that no significant changes in tafamidis exposure necessitating a dose modification are expected due to either extrinsic or intrinsic factors. The model was used to support labelling statements for dose recommendations in special populations.
Bibliography:Funding information
This is a pooled analysis of previously conducted clinical trials. All clinical trials were conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. None of the authors of this manuscript were a Principal Investigator for those clinical trials and no new clinical investigations on human subjects were conducted for this analysis.
Pfizer Inc.
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content type line 23
ISSN:0306-5251
1365-2125
1365-2125
DOI:10.1111/bcp.14773