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).

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).

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.

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.

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, ...

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, ...

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, ...

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.

Learning objectives: Approaches to predict human pharmacokinetics.

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

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 / T_max / C_max / 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.

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 / T_max / C_max / 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.

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 / T_max / C_max / 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 (T_1/2,z, C_max, T_max, Cl, V_d) 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.

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.

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).

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.

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.

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…).

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

Key concepts: general concepts of PK-PD modelling.

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.

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.

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

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