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UZ Leuven, Campus Gasthuisberg, UZ Gent

Human Pharmacology course: Pharmacokinetics, pharmacodynamics and biomarkers in early clinical development

Healixia/EUFEMED Certificate Course in Human Pharmacology - Module 4

  1. Day 1, Wednesday, January 15

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    • Introduction of Faculty and participants & Setting the scene by Jan de Hoon

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    • Pharmacokinetics: drug absorption (1) by Jan de Hoon

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      Learning objectives: How do drugs get into the body? How do drugs get across biological membranes? Physicochemical properties of a drug affecting / limiting drug absorption. Factors influencing passage of drugs across membranes.

      Key concepts: the pharmaceutical phase / paracellular versus transcellular transport / passive diffusion (Fick’s law) / carrier mediated transport (Michaelis-Menten law) / pinocytosis / transcytosis / influence of pH, efflux mechanisms, metabolism, food, disease / the biopharmaceutical classification system (BCF).

  4. -

    • Lunch break

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    • Pharmacokinetics: drug absorption (2) by Jan de Hoon

      More information

      Learning objectives: How do drugs get into the body? How do drugs get across biological membranes? Physicochemical properties of a drug affecting / limiting drug absorption. Factors influencing passage of drugs across membranes.

      Key concepts: the pharmaceutical phase / paracellular versus transcellular transport / passive diffusion (Fick’s law) / carrier mediated transport (Michaelis-Menten law) / pinocytosis / transcytosis / influence of pH, efflux mechanisms, metabolism, food, disease / the biopharmaceutical classification system (BCF).

  6. -

    • Coffee break

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    • Pharmacokinetics: drug distribution by Jan de Hoon

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      Learning objectives: Physicochemical properties of a drug affecting / limiting distribution and measuring distribution in humans.

      Key concepts: distribution volume / perfusion dependent distribution versus diffusion dependent distribution / protein binding / displacement interactions / influence of disease / blood-brain barrier.

  8. -

    • Coffee break

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    • Predicting drug absorption and distribution: preclinical models by Pieter Annaert

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      Learning objectives: understand / know preclinical models for predicting drug absorption / distribution as used in the Investigator’s Brochure.

      Key concepts: overview of preclinical (in vitro and in vivo) models for predicting drug absorption / distribution in humans.

  10. Day 2, Thursday, January 16

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    • Pharmacokinetics: drug elimination by biotransformation (1) by Isabel Spriet

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      Learning objectives: To provide an understanding/knowledge of drug elimination by biotransformation.

      Key concepts: different elimination pathways / phase 1 versus phase 2 reactions / metabolic clearance / activation versus inactivation by biotransformation / prodrugs / factors influencing biotransformation: induction, inhibition, drug-drug interactions, disease, genetic polymorphisms, ...

  12. -

    • Coffee break

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    • Pharmacokinetics: drug elimination by biotransformation (2) by Isabel Spriet

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      Learning objectives: To provide an understanding/knowledge of drug elimination by biotransformation.

      Key concepts: different elimination pathways / phase 1 versus phase 2 reactions / metabolic clearance / activation versus inactivation by biotransformation / prodrugs / factors influencing biotransformation: induction, inhibition, drug-drug interactions, disease, genetic polymorphisms, ...

  14. -

    • Lunch break

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    • Pharmacokinetics: drug elimination by excretion by Isabel Spriet

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      Learning objectives: To provide an understanding/knowledge of drug elimination by excretion.

      Key concepts: renal excretion/clearance / biliary excretion/clearance / entero-hepatic recirculation / entero-buccal recirculation / factors influencing clearance by excretion: drug-drug interactions, disease, ...

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    • Predicting drug elimination / clearance in humans by Pieter Annaert

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      Learning objectives: Understand / know preclinical models for predicting drug clearance as used in the Investigator’s Brochure.

      Key concepts: overview of preclinical (in vitro and in vivo) models for predicting drug elimination in humans.

  17. -

    • Coffee break

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    • Predicting pharmacokinetics in humans: IVIVE and PBPK by Pieter Annaert

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      Learning objectives: Approaches to predict human pharmacokinetics.

      Key concepts: IVIVE and PBPK modelling (pharmacokinetic physiology based modelling).

  19. Day 3, Friday, January 17

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    • Pharmacokinetics: PK analysis after single and repeated dosing (1) by Jan de Hoon

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      Learning objectives: How to perform a quantitative analysis of PK data after single and repeated dosing.

      Key concepts: elimination constant / (terminal) elimination half-life / distribution volume / Tmax / Cmax / area under the curve (AUC) / clearance / steady-state concentration / accumulation ratio / bioavailability / bio-equivalence / compartment models / non-compartimental analysis / therapeutic window / therapeutic drug monitoring (TDM) / loading dose.

  21. -

    • Coffee break

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    • Pharmacokinetics: PK analysis after single and repeated dosing (2) by Jan de Hoon

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      Learning objectives: How to perform a quantitative analysis of PK data after single and repeated dosing.

      Key concepts: elimination constant / (terminal) elimination half-life / distribution volume / Tmax / Cmax / area under the curve (AUC) / clearance / steady-state concentration / accumulation ratio / bioavailability / bio-equivalence / compartment models / non-compartimental analysis / therapeutic window / therapeutic drug monitoring (TDM) / loading dose.

  23. -

    • Lunch break

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    • Pharmacokinetics: PK analysis after single and repeated dosing (3) by Erik Mannaert

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      Learning objectives: How to perform a quantitative analysis of PK data after single and repeated dosing.

      Key concepts: elimination constant / (terminal) elimination half-life / distribution volume / Tmax / Cmax / area under the curve (AUC) / clearance / steady-state concentration / accumulation ratio / bioavailability / bio-equivalence / compartment models / non-compartimental analysis / therapeutic window / therapeutic drug monitoring (TDM) / loading dose.

      Assignments:

      1. SAD FIH trial: Provide PK data of a SAD FIH trial as well as the protocol and the IB of the compound. To do:
        1. Summarize the essentials of the preclinical PK data.
        2. Given the preclinical PK data in rodents and non-rodents, calculate the MRSD in humans.
        3. Given the human PK data, calculate the PK parameters (T1/2,z, Cmax, Tmax, Cl, Vd) based on a non-compartimental approach.
        4. What about the next proposed dose step?
      2. MAD FIH trial: based on the SAD PK data, propose a dosing scheme for the MAD.
      3. Summarize the essential PD data based on the IB.

  25. -

    • Coffee break

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    • Pharmacokinetics: capita selecta by Erik Mannaert

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      Learning objectives: Know about the existence of drugs with a special/exceptional pharmacokinetic behavior.

      Key concepts: Linear versus non-linear PK / time dependent PK / stereoselective PK / flip-flop PK / population PK.

  27. -

    • Coffee break

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    • Pharmacokinetics: sources of variability by Karel Allegaert

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      Learning objectives: Be aware of the large number of sources causing variability in PK.

      Key concepts: PK variability due to drug formulation, demographics (e.g. age, gender, body composition,…), interactions (drug-drug, drug-food, drug-…), co-morbidity (e.g. renal, liver, heart disease).

  29. Day 4, Wednesday, April 2

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    • Pharmacodynamics at molecular and organ level (1) by An Vermeulen

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      Learning objectives: A qualitative and quantitative understanding of the interactions between drugs and their target / organs.

      Key concepts: drug-targets and drug-target interactions / receptor binding curves / affinity versus dissociation constant / concentration-effect curves / potency and efficacy / agonism versus antagonism (full, partial, invers) / allosteric modulation / Hill equation and Hill coefficient.

  31. -

    • Coffee break

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    • Pharmacodynamics at molecular and organ level (2) by An Vermeulen

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      Learning objectives: A qualitative and quantitative understanding of the interactions between drugs and their target / organs.

      Key concepts: drug-targets and drug-target interactions / receptor binding curves / affinity versus dissociation constant / concentration-effect curves / potency and efficacy / agonism versus antagonism (full, partial, invers) / allosteric modulation / Hill equation and Hill coefficient.

  33. -

    • Lunch break

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    • Pharmacodynamics at subject / population level by An Vermeulen

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      Learning objectives: Understand the response to drugs at an individual or population level as well as variability in PD response.

      Key concepts: dose-response relationship / therapeutic index / benefit/risk ratio / time dependent PD (tolerance, tachyphylaxis and rebound/withdrawal) / hysteresis (clockwise – anti-clockwise) / sources of PD variability (formulations, dosing, drug adherence, demographics, co-morbidity…).

  35. -

    • Coffee break

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    • Assignment 1: group discussion by Jan de Hoon and Erik Mannaert

  37. Day 5, Thursday, April 3

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    • MID3: model informed drug discovery & development by Erwin Dreesen

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      Learning objectives: To provide the principles of PK-PD modelling.

      Key concepts: general concepts of PK-PD modelling.

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    • Assignment 2: group discussion by An Vermeulen

  40. -

    • Coffee break

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    • Biomarkers by Sylvie Rottey

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      Learning objectives: To provide the principles of the use of biomarkers in early clinical drug development.

      Key concepts: what is a biomarker? / different kinds of biomarkers / biomarkers in phase 1 trials.

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    • Lunch break

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    • PK and PD in special populations by Pieter De Cock

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      Learning objectives: Be knowledgeable about the differences in PK and/or PD in special populations.

      Key concepts: PK and PD in pregnancy, neonates, children and elderly.

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    • Differences between small molecules and biologicals by Stephan Glund

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      Learning objectives: Be knowledgeable about the differences in PK/PD behaviour between small molecules and biologicals.

      Key concepts: overview of PK differences between small molecules and biologicals.

  45. -

    • Coffee break

  46. -

    • Final test (mandatory)

  47. -

    • Closing remarks and adjourn

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Schedule of Human Pharmacology course: Pharmacokinetics, pharmacodynamics and biomarkers in early clinical development