Drug Res (Stuttg) 2021; 71(06): 326-334
DOI: 10.1055/a-1381-6579
Original Article

Population Pharmacokinetic Analysis of Fevipiprant in Healthy Subjects and Asthma Patients using a Tukey’s g-and-h Distribution

1   Biostatistics & Pharmacometrics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
,
Christian Bartels
2   Biostatistics & Pharmacometrics, Novartis Pharma AG, Basel, Switzerland
,
Swarupa Kulkarni
3   PK Science, Novartis Pharmaceutics Corporation, East Hanover, NJ, USA
,
Ramachandra Sangana
4   PK Science, Novartis Institutes for Biomedical Research, Hyderabad, India
,
Monish Jain
5   PK Science, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
,
Julia Zack
3   PK Science, Novartis Pharmaceutics Corporation, East Hanover, NJ, USA
,
Jing Yu
1   Biostatistics & Pharmacometrics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
› Author Affiliations

Abstract

Aim The objective of this analysis was to characterize the population pharmacokinetics (PK) of fevipiprant in asthma patients and to evaluate the effect of baseline covariates on the PK of fevipiprant.

Methods PK data from 1281 healthy subjects or asthma patients were available after single or once daily dosing of fevipiprant. Population PK analysis was conducted to describe fevipiprant plasma concentration data using a non-linear mixed effect modeling approach.

Results Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. Exploration of fevipiprant PK in the population from the phase III studies revealed an over-dispersed and skewed distribution. This unusual distribution was described using Tukey’s g-and-h distribution (TGH) on the between-subject variability of apparent clearance (CL/F). The model identified a significant impact of disease status on CL/F, with the value in healthy subjects being 62% higher than that in asthma patients. Bodyweight, age and renal function showed statistically significant impact on fevipiprant clearance; however, compared with a typical asthma patient, the simulated difference in steady-state exposure was at most 16%.

Conclusion Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. The TGH distribution was appropriate to describe the over-dispersed and skewed PK data as observed in the current studies. Asthma patients had approximately 37% higher exposure than healthy subjects did. Other covariates changed exposure by at most 16%.

Supplementary Material



Publication History

Received: 12 October 2020

Accepted: 29 January 2021

Article published online:
05 March 2021

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