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Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK

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Abstract

Purpose

To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution.

Methods

Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B).

Results

TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect.

Conclusions

Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

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Data Availability

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com

Abbreviations

API:

Active pharmaceutical ingredient

AUC:

Area under the curve

Cmax :

Maximum blood concentration

CI:

Confidence interval

DC:

Direct compression

DNX:

Danirixin

FaSSIF:

Fasted state simulated intestinal fluid

FB:

Free base

FeSSIF:

Fed state simulated intestinal fluid

HBr:

Hydrobromide

HPLC:

High performance liquid chromatography

HPMC:

Hydroxypropyl methylcellulose

OMP:

Omeprazole

PBPK:

Physiologically-based pharmacokinetic

PK:

Pharmacokinetic

PPI:

Proton pump inhibitor

RC:

Roller compaction

SD:

Standard deviation

SGF:

Simulated gastric fluid

TIM-1:

TNO/Triskelion intestinal model 1

tmax :

Time of occurrence of maximum blood concentration

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ACKNOWLEDGEMENTS AND DISCLOSURES

The authors would like to thank the staff of Quintiles, Inc. and, most importantly, the volunteers for their participation in the clinical study which was funded by GlaxoSmithKline (ClinicalTrials.gov identifier NCT03457727). The authors would also like to thank the staff of Pozlab sp. z o.o for performing the in-vitro TIM experiments.

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Authors and Affiliations

  1. Medicinal Science and Technology, GlaxoSmithKline R&D, Park Road, Hertfordshire, UK

    Richard S. Lloyd, Martin I. Hingle, Jackie C. Bloomer, Stephen J. Charles, James M. Butler & Alan Paul

  2. Medicinal Science and Technology, GlaxoSmithKline R&D, Collegeville, Pennsylvania, USA

    Xiaofeng Zhu

  3. Respiratory Therapy Area Unit, GlaxoSmithKline R&D, King of Prussia, Pennsylvania, USA

    Bruce Miller, Donald D’Amico & Alison Donald

  4. Medical Innovation, GlaxoSmithKline R&D, Collegeville, Pennsylvania, USA

    Ruth Tal-Singer

  5. Clinical Pharmacology and Modelling Simulation, GlaxoSmithKline R&D, 980 Great West Road, TW8 9GS, Brentford, UK

    Claire Ambery

Authors
  1. Richard S. Lloyd
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  2. Martin I. Hingle
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  3. Jackie C. Bloomer
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  6. Alan Paul
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  7. Xiaofeng Zhu
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  8. Bruce Miller
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  10. Alison Donald
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  11. Ruth Tal-Singer
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  12. Claire Ambery
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Corresponding author

Correspondence to Claire Ambery.

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Conflict of Interest

RSL reports employment and shareholder status at GlaxoSmithKline; MIH reports former employment and shareholder status at GlaxoSmithKline; SJC former employment status, pension and shareholder status at GlaxoSmithKline; AP reports employment and shareholder status at GlaxoSmithKline; JCB reports employment and shareholder status at GlaxoSmithKline; XZ reports employment and shareholder status at GlaxoSmithKline; BM reports employment and shareholder status at GlaxoSmithKline; DD reports former employment and shareholder status at GlaxoSmithKline; AD reports employment and shareholder status at GlaxoSmithKline; RTS reports former employment and shareholder status at GlaxoSmithKline; CA reports employment and shareholder status at GlaxoSmithKline.

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Lloyd, R.S., Hingle, M.I., Bloomer, J.C. et al. Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK. Pharm Res 37, 233 (2020). https://doi.org/10.1007/s11095-020-02948-z

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