Elective Topics

Elective-session topics and objectives (subject to change for 2024)

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.

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Lecture A2 - 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 B1 – Nonlinear Pharmacokinetics 

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, V_max and K_M, 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 V_max and K_M from steady-state blood levels for a drug eliminated almost entirely through a saturable metabolic pathway.

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Lecture B2 - Pharmacogenomics in the Management of Variability - Kathleen Giacomini

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.