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Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects

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Abstract

Purpose

The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker.

Methods

Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at −2, −1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3–7.

Results

The geometric mean ratio and 90 % confidence interval of Cmax and AUC of acetaminophen were within 80–125 % suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food.

Conclusion

In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ∼1.25 h without affecting Cmax or AUC.

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Acknowledgments

This study was supported by Novartis Pharma AG, Basel, Switzerland. Authors would like to thank Sushma Molugu and Pravin Bolshete (Novartis Healthcare Pvt. Ltd., Hyderabad, India) for medical writing support and subsequent revisions based on authors’ feedback.

Conflict of interest

SA, DM, PK, AS, SR, GS, and JC are full time employees of Novartis. TM was a full time employee of Novartis during the study conduct. Currently, TM is a full time employee of Alcon Laboratories, Inc. Fort Worth, TX, USA.

Authors’ contributions

SA, DM, and JC contributed to the study design and data interpretation. AS participated in study design and statistical analysis. PK conducted the study, and TM conducted bioanalysis. SA and JC drafted and revised the manuscript. SR and GS assisted with data interpretation and manuscript composition. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

    Surya Ayalasomayajula, Phillip Koo, Tapan Majumdar, Sam Rebello, Gangadhar Sunkara & Jin Chen

  2. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Dan Meyers

  3. Novartis Healthcare Pvt. Ltd, Hyderabad, India

    Atish Salunke

Authors
  1. Surya Ayalasomayajula
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  2. Dan Meyers
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  3. Phillip Koo
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  4. Atish Salunke
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  5. Tapan Majumdar
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  6. Sam Rebello
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  7. Gangadhar Sunkara
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  8. Jin Chen
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Corresponding author

Correspondence to Jin Chen.

Additional information

Study Highlights

What is the current knowledge on the topic?

Gastric emptying impacts absorption of orally administered medicines. Administration of drugs that impact gastric motility may potentially impact the absorption of coadministered medicines. It was shown that both pramlintide and exenatide delay gastric motility (demonstrated by administering acetaminophen at various time intervals, References 9 and 10). The prescription information for these products suggest dose spacing with co-medication that have similar absorption kinetics as that of acetaminophen.

What question does this study address?

This study was conducted to determine the impact of pradigastat (formerly LCQ908), a diacylglycerol acyltransferase-1 (DGAT1) inhibitor on the pharmacokinetic of acetaminophen, a probe to evaluate gastric motility.

What this study adds to our knowledge

The pharmacokinetics of acetaminophen or other drugs that require rapid gastric emptying for rapid absorption is unlikely to be altered when coadministered with pradigastat.

How this might change clinical pharmacology and therapeutics

Our results confirm that coadministration of these agents has no clinically relevant effect and patients receiving pradigastat may also be given acetaminophen or other agents whose pharmacokinetic exposure may be impacted by gastric motility.

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Ayalasomayajula, S., Meyers, D., Koo, P. et al. Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects. Eur J Clin Pharmacol 71, 425–432 (2015). https://doi.org/10.1007/s00228-015-1822-2

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  • DOI: https://doi.org/10.1007/s00228-015-1822-2

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