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Pharmacokinetic Aspects of Multiple Dose Studies

  • Steven G. WoolfreyEmail author
  • James Gilmour Morrison
Living reference work entry

Abstract

The development of a new chemical entity (NCE) in man is highly regulated and normally starts with a single ascending dose study (SAD) followed by a multiple ascending dose study (MAD), both in young healthy volunteers using the route and dose regime proposed in the final product. The aim of a MAD study is to establish the safety, maximum tolerated dose, and pharmacokinetics of the NCE on repeated dosing, usually to steady state. This chapter describes the pharmacokinetic aspects of MAD studies and some of the design modifications that can be included in the study design. The MAD may be one of the few opportunities for assessing the pharmacokinetics of the compound in detail following multiple dosing, albeit not usually in patients. Previous data from the SAD should be used to optimize the design of the MAD including blood sampling regime, lower limit of sensitivity for the bioanalytical assay, and pharmacokinetic analysis. In addition to the pharmacokinetics and safety, the design should consider the need to characterize drug-related material in urine, carry out a preliminary assessment of the metabolic route, and characterize the potential for CYP3A4 induction. Suggestions are also provided for an approach when the impact of prandial status is unknown and more frequent dosing other than once daily is required.

References and Further Reading

  1. Diczfalusy U, Kanebratt KP, Bredberg E, Andersson TB, Böttiger Y, Bertilsson L (2009) 4β-hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin. Br J Clin Pharmacol 67(1):38–43CrossRefPubMedPubMedCentralGoogle Scholar
  2. Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y (2013) Investigation of CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol 72:1223–1234CrossRefPubMedPubMedCentralGoogle Scholar
  3. Dutreix C, Lorenzo S, Wang Y (2014) Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin. Eur J Clin Pharmacol 70(8):915–920CrossRefPubMedPubMedCentralGoogle Scholar
  4. FDA (2016) Guidance for industry: safety testing of drug metabolites, revision 1Google Scholar
  5. Galteau MM, Sharmsa F (2003) Urinary 6β-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol 59(10):713–733CrossRefPubMedGoogle Scholar
  6. Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J (1995) Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Inf J 29:1039–1048CrossRefGoogle Scholar
  7. ICH (2005) Gender considerations in the conduct of clinical trialsGoogle Scholar
  8. ICH M3 (R2) (2008) Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticalsGoogle Scholar
  9. ICH-E3 (1995) Structure and content of clinical study reportsGoogle Scholar
  10. ICH-E8 (1997) General considerations for clinical trialsGoogle Scholar
  11. Lui KA, Mager NA (2016) Women’s involvement in clinical trials: historical perspective and future implications. Pharm Pract (Granada) 14(1):708. 1–9CrossRefGoogle Scholar
  12. Rowland M, Tozer TN (2011) Clinical pharmacokinetics and pharmacodynamics: concept and applications, 4th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  13. Xiao W, Shen G, Zhuang X, Ran X, Zhu M, Li H (2016) Characterization of human metabolism and disposition of levo-tetrahydropalmatine: qualitative and quantitative determination of oxidative and conjugated metabolites. J Pharm Biomed Anal 128:371–381CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Independent Pharmaceutical Consultant – Clinical Pharmacology and PharmacokineticsNewcastle Upon TyneUK
  2. 2.GW PharmaceuticalsCambridgeUK

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