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Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects

  • Pharmacokinetics and Disposition
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Abstract

Purpose

The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (~70%) metabolized via CYP2C9.

Methods

This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method.

Results

The administration of nateglinide in combination with sulfinpyrazone resulted in ~28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20–1.39) with no differences in mean peak plasma concentration (Cmax; 90% CI test-reference ratio: 0.86–1.12) compared with nateglinide-alone treatment. The time to reach Cmax (tmax) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated.

Conclusions

Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.

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Authors and Affiliations

  1. Exploratory Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ 07936-1080, USA

    Helene Sabia, Gangadhar Sunkara, Monica Ligueros-Saylan, Yibin Wang, Harold Smith, James McLeod & Pratapa Prasad

Authors
  1. Helene Sabia
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  2. Gangadhar Sunkara
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  3. Monica Ligueros-Saylan
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  4. Yibin Wang
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  5. Harold Smith
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  6. James McLeod
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  7. Pratapa Prasad
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Corresponding author

Correspondence to Gangadhar Sunkara.

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Sabia, H., Sunkara, G., Ligueros-Saylan, M. et al. Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects. Eur J Clin Pharmacol 60, 407–412 (2004). https://doi.org/10.1007/s00228-004-0778-4

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  • DOI: https://doi.org/10.1007/s00228-004-0778-4

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