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A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate

European Journal of Clinical Pharmacology volume 58, pages 683–688 (2003)Cite this article

Abstract

Objective

NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4.

Methods

Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, α-hydroxymidazolam, were investigated.

Results

Following a single dose of NN703 (day 3), the AUC of both midazolam and α-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas α-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The Cmax values of midazolam and α-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t1/2 of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9.

Conclusion

This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.

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References

  1. Spatzenegger M, Jaeger W (1995) Clinical importance of hepatic cytochrome P-450 in drug metabolism. Drug Metab Rev 23:397–415

    Google Scholar 

  2. Yu DK (1999) The contribution of P-glycoprotein to pharmacokinetic drug–drug interactions. J Clin Pharmacol 39:1203–1211

    CAS  PubMed  Google Scholar 

  3. Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA (1989) Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 36:89–96

    CAS  PubMed  Google Scholar 

  4. Fabre G, Rahmani R, Placidi M, Combalbert J, Covo J, Cano JP, Coulange C, Ducros M, Rampal M (1988) Characterization of midazolam metabolism using human hepatic microsomal fractions and hepatocytes in suspension obtained by perfusing whole human livers. Biochem Pharmacol 37:4389–4397

    CAS  PubMed  Google Scholar 

  5. Gorski JC, Hall SD, Jones DR, VandenBranden M, Wrighton SA (1994) Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol 47:1643–1653

    CAS  PubMed  Google Scholar 

  6. Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR (1999) Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 16:408–414

    CAS  PubMed  Google Scholar 

  7. Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, Wilkinson GR (1996) Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 59:491–502

    Google Scholar 

  8. Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430

    CAS  PubMed  Google Scholar 

  9. Zdravkovic M, Sogaard B, Ynddal L, Christiansen T, Agerso H, Thomsen MS, Falch JE, Ilondo MM (2000) The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers. Growth Horm IGF Res 10:193–198

    Article  CAS  PubMed  Google Scholar 

  10. Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ (1998) The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 54:53–58

    Article  CAS  PubMed  Google Scholar 

  11. von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI (1996) Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J Clin Pharmacol 36:783–791

    PubMed  Google Scholar 

  12. Tsunoda SM, Velez RL, von Moltke LL, Greenblatt DJ (1999) Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in-vivo probe: effect of ketoconazole. Clin Pharmacol Ther 66:461–471

    CAS  PubMed  Google Scholar 

  13. Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S (1995) Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 58:20–28

    CAS  PubMed  Google Scholar 

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Acknowledgements

The study performed complies with local laws and was performed in accordance with Good Clinical Practise.

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Authors and Affiliations

  1. Novo Nordisk A/S, Research and Development, Denmark

    Milan Zdravkovic, Anette K. Olsen, Tina Christiansen, Mitchell E. Taub, Mikael S. Thomsen, Michael H. Rasmussen & Mapoko M. Ilondo

  2. Novo Nordisk A/S, Department of Clinical Drug Development, Krogshøjsvej 53A, DK-2880, Bagsvaerd, Denmark

    Milan Zdravkovic

  3. Quintiles Innovex (Biodesign), Freiburg, Germany

    Rainer Schulz

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  1. Milan Zdravkovic
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  2. Anette K. Olsen
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  3. Tina Christiansen
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  4. Rainer Schulz
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  5. Mitchell E. Taub
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  6. Mikael S. Thomsen
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  7. Michael H. Rasmussen
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  8. Mapoko M. Ilondo
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Correspondence to Milan Zdravkovic.

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Zdravkovic, M., Olsen, A.K., Christiansen, T. et al. A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate. Eur J Clin Pharmacol 58, 683–688 (2003). https://doi.org/10.1007/s00228-002-0539-1

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  • DOI: https://doi.org/10.1007/s00228-002-0539-1

Keywords

  • CYP3A4
  • Interaction
  • Midazolam
  • NN703
  • Clinical study