Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

  • Natacha Lenuzza
  • Xavier Duval
  • Grégory Nicolas
  • Etienne Thévenot
  • Sylvie Job
  • Orianne Videau
  • Céline Narjoz
  • Marie-Anne Loriot
  • Philippe Beaune
  • Laurent Becquemont
  • France Mentré
  • Christian Funck-Brentano
  • Loubna Alavoine
  • Philippe Arnaud
  • Marcel Delaforge
  • Henri Bénech
Original Paper

Abstract

This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine–CYP1A2, repaglinide–CYP2C8, tolbutamide–CYP2C9, omeprazole–CYP2C19, dextromethorphan–CYP2D6, midazolam–CYP3A, acetaminophen–UGT1A1, 6&9 and 2B15, digoxin–P-gp, rosuvastatin–OATP1B1&3 and memantine–active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC–MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.

Keywords

CIME Probes Phase I Pharmacokinetics Safety 

Supplementary material

13318_2014_239_MOESM1_ESM.docx (544 kb)
Supplementary material 1 (DOCX 544 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Natacha Lenuzza
    • 1
  • Xavier Duval
    • 2
    • 3
  • Grégory Nicolas
    • 4
  • Etienne Thévenot
    • 1
  • Sylvie Job
    • 1
  • Orianne Videau
    • 4
  • Céline Narjoz
    • 5
    • 6
  • Marie-Anne Loriot
    • 5
    • 6
  • Philippe Beaune
    • 5
    • 6
  • Laurent Becquemont
    • 7
  • France Mentré
    • 3
  • Christian Funck-Brentano
    • 8
    • 9
  • Loubna Alavoine
    • 2
  • Philippe Arnaud
    • 10
  • Marcel Delaforge
    • 11
  • Henri Bénech
    • 4
  1. 1.CEA, LIST, Data Analysis and Systems Intelligence LaboratoryGif-sur-YvetteFrance
  2. 2.Clinical Investigation Center (CIC-1425)CHU Bichat Claude BernardParisFrance
  3. 3.INSERM, IAME, UMR1137, University Paris-Diderot, Sorbonne Paris CitéParisFrance
  4. 4.CEA, DSV, iBiTecS, Pharmacology and Immunoanalysis UnitGif-sur-YvetteFrance
  5. 5.Department of Biochemistry, Pharmacogenetics and Molecular Oncology UnitAssistance Publique des Hôpitaux de Paris, Hôpital Européen Georges PompidouParisFrance
  6. 6.University Paris Descartes, INSERM UMRS 1147, Sorbonne Paris CitéParisFrance
  7. 7.Clinical Research Unit EA2706 Paris sud-CHU BicêtreLe Kremlin BicêtreFrance
  8. 8.Department of Pharmacology and UMR ICAN 1166, Faculty of MedicineSorbonne University, UPMC Univ Paris 06ParisFrance
  9. 9.Department of Pharmacology and CIC-1421Assistance Publique des Hôpitaux de Paris, Pitié-Salpêtrière HospitalParisFrance
  10. 10.PharmacyCHU Bichat Claude BernardParisFrance
  11. 11.CEA, DSV, iBiTecS, UMR 8221, Bioenergetics, Structural Biology and Mechanisms UnitGif-sur-YvetteFrance

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