Elective Topics

Elective-session topics and objectives

Lecture A1 - Multicompartment Kinetics - Svein Øie


The ratio of concentrations in the central (sampleable) vs. peripheral compartments diminishes with time after dosing.

As the apparent volume (V) = [amount in both cpts] ⁄ [conc in the central cpt]:
V initially (V1) < V at steady state (Vss) < V during the terminal phase (Vβ).

  1. Explain why a simple one-compartment model, as a description of drug distribution in the body, often does not suffice.
  2. Compare exponential, compartmental, and noncompartmental methods of representing pharmacokinetic data when distribution kinetics is evident.
  3. When the disposition kinetics of a drug after a single intravenous dose is described by the sum of two exponential terms, ascertain which term is associated predominantly with elimination and which with distribution following a single bolus dose.
  4. Estimate the clearance and elimination half-life of a drug showing multi-exponential disposition.
  5. Define and calculate the following parameters: initial dilution space (V1); volume during the terminal phase (V); volume of distribution at steady state (Vss).
  6. Describe the impact of distribution kinetics on the interpretation of plasma concentration-time data following extravascular drug administration.
  7. Describe how distribution kinetics influences plasma tissue levels with time following:
    1. a constant-rate infusion and
    2. a fixed-dose, fixed-interval dosage regimen.
  8. When the disposition kinetics of a drug can be described by the sum of two exponential terms:
    1. Explain why the extent of the fall in the plasma concentration post infusion, associated with the first phase, depends on the duration of the infusion; and
    2. Estimate the values of clearance, small and large coefficients and exponents (and corresponding half-lives), initial dilution space (V1), and the volume of distribution at steady state (Vss) from plasma-concentration data during and after stopping a constant-rate infusion.

Lecture A2 - Pharmacogenomics in the Management of Variability - Kathleen Giacomini

dose optimization diagram

Dose optimization can be greatly enhanced by genetic insights.

  1. List three reasons why drug response may be variable among individuals.
  2. Define the terms: pharmacogenetics, polymorphism, phenotype, allele, homozygous, heterozygous, haplotype, nonsynonomous and synonomous coding, non-coding, intronic polymorphisms.
  3. Describe how reduced function genetic variants in the enzyme, thiopurine methyltransferase (TPMT), result in increased toxicity of the drug, 6-mercaptopurine.
  4. Describe how reduced function genetic variants in the enzyme, CYP2D6, may result in non-response to tamoxifen.
  5. Describe how a drug-drug interaction between two drugs that are ligands of CYP2D6 may phenocopy a reduced function genetic variant in CYP2D6.
  6. Draw a schematic of the conversion of irinotecan to SN-38 and include the elimination of SN-38 through glucuronidation. Indicate UGT1A1 in the schematic.
  7. List the common reduced function alleles of SLCO1B1 and their frequency in European, African and East Asian populations.

Lecture B1 – Pharmacokinetics and Pharmacodynamics Modeling - Rada Savic


The intensity of pharmacologic effect at a particular conc is not always the same when concs are rising as when they later fall (the hysteresis loop). Pharmacodynamic models need to cover such phenomena.

Learn about:

  1. The relationship among drug dose, pharmacokinetics (PK), and pharmacodynamics (PD).
  2. Types of Dose/PD relationships: linear vs non-linear.
  3. Drug-receptor interaction, and transduction to observed PD.
  4. Steady-state vs. non-steady-state experiments: the influence of PK on PD.
  5. Distributional effects: effect-compartment model.
  6. Effects of drug on endogenous substances: indirect-action models.
  7. How to differentiate between alternative mechanisms of drug action directly from the PK/PD observations and by means of mathematical modeling.

Lecture B2 - Macromolecule Pharmacokinetics - Sara Kenkare-Mitra


Antibody pharmacokinetics is target-mediated and dose-dependent.

Learn about and understand:

  1. The current state of monoclonal antibodies as therapeutics.
  2. The basics of structure of monoclonal antibodies and those structural attributes critical in understanding their PK.
  3. Key differences between the PK of large and small molecules.
  4. What drives PK of monoclonal antibodies, in particular the role of receptor binding.
  5. Target-specific and non-specific binding of mAbs, and their respective roles in the clearance and distribution of antibodies.
  6. The definition of linearity/non-linearity of PK in the context of antibody therapeutics.
  7. Immunogenicity to antibody therapies and its impact on PK.

Lecture C1 – Nonlinear Pharmacokinetics - Deanna Kroetz


The mathematical mechanics of drug absorption is very different when the dose is incompletely soluble in G‑I fluid, potentially leading to plasma conc‑time curves of unexpected shapes.

  1. List at least 10 sources of nonlinearities in drug absorption, distribution, and elimination.
  2. Apply the principle of superposition for the detection of nonlinear pharmacokinetics.
  3. Analyze pharmacokinetic data to determine which parameters, if any, are affected by concentration- or time-dependent mechanisms.
  4. Propose possible mechanisms for such dose- or time-dependent changes in pharmacokinetic parameters.
  5. Predict whether a drug will exhibit saturable metabolism given estimates of the Michaelis-Menten parameters, Vmax and KM, and knowledge of the therapeutic concentration range.
  6. Predict the relative importance of a capacity-limited metabolic pathway for a drug which is eliminated by parallel saturable and linear routes.
  7. Distinguish between saturable first-pass metabolism and capacity-limited systemic elimination.
  8. Estimate an individual’s Vmax and KM from steady-state blood levels for a drug eliminated almost entirely through a saturable metabolic pathway.

Lecture C2 - Application of Pharmacokinetics in Clinical Practice - Michael Winter


Clinical pharmacokinetics applied to designing, monitoring and, if necessary, adjusting drug therapy tailored for a specific individual patient — in real time.

  1. Estimate, as an index of renal-function status, the creatinine clearance for a patient given his or her gender, age, weight, and serum creatinine; list at least two factors that would be expected to influence the accuracy of the predicted creatinine clearance.
  2. Given a drug’s half-life and dosing interval, be able to indicate the number of doses required to achieve approximately 90% of steady state.
  3. List at least two problems commonly associated with peak plasma concentrations.
  4. List three reasons why, in most clinical settings, trough concentrations are more useful than peak concentrations.
  5. Given a drug half-life, indicate the earliest time at which one would be capable of calculating, from a single drug concentration, a reasonably accurate clearance for a patient.
  6. List two factors known to alter the binding of drugs to serum albumin, and indicate what effect the alteration in binding would have on the expected therapeutic range.