# Elective Topics

## Elective-session topics and objectives

### Lecture A1 - Multicompartment Kinetics - Svein Øie

- Explain why a simple one-compartment model, as a description of drug distribution in the body, often does not suffice.
- Compare exponential, compartmental, and noncompartmental methods of representing pharmacokinetic data when distribution kinetics is evident.
- 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.
- Estimate the clearance and elimination half-life of a drug showing multi-exponential disposition.
- Define and calculate the following parameters: initial dilution space (V
_{1}); volume during the terminal phase (V); volume of distribution at steady state (V_{ss}). - Describe the impact of distribution kinetics on the interpretation of plasma concentration-time data following extravascular drug administration.
- Describe how distribution kinetics influences plasma tissue levels with time following:
- a constant-rate infusion and
- a fixed-dose, fixed-interval dosage regimen.

- When the disposition kinetics of a drug can be described by the sum of two exponential terms:
- 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
- Estimate the values of clearance, small and large coefficients and exponents (and corresponding half-lives), initial dilution space (V
_{1}), and the volume of distribution at steady state (V_{ss}) from plasma-concentration data during and after stopping a constant-rate infusion.

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

- List three reasons why drug response may be variable among individuals.
- Define the terms: pharmacogenetics, polymorphism, phenotype, allele, homozygous, heterozygous, haplotype, nonsynonomous and synonomous coding, non-coding, intronic polymorphisms.
- Describe how reduced function genetic variants in the enzyme, thiopurine methyltransferase (TPMT), result in increased toxicity of the drug, 6-mercaptopurine.
- Describe how reduced function genetic variants in the enzyme, CYP2D6, may result in non-response to tamoxifen.
- Describe how a drug-drug interaction between two drugs that are ligands of CYP2D6 may phenocopy a reduced function genetic variant in CYP2D6.
- 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.
- 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

Learn about:

- The relationship among drug dose, pharmacokinetics (PK), and pharmacodynamics (PD).
- Types of Dose/PD relationships: linear vs non-linear.
- Drug-receptor interaction, and transduction to observed PD.
- Steady-state vs. non-steady-state experiments: the influence of PK on PD.
- Distributional effects: effect-compartment model.
- Effects of drug on endogenous substances: indirect-action models.
- 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

Learn about and understand:

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

### Lecture C1 – Nonlinear Pharmacokinetics - Deanna Kroetz

- List at least 10 sources of nonlinearities in drug absorption, distribution, and elimination.
- Apply the principle of superposition for the detection of nonlinear pharmacokinetics.
- Analyze pharmacokinetic data to determine which parameters, if any, are affected by concentration- or time-dependent mechanisms.
- Propose possible mechanisms for such dose- or time-dependent changes in pharmacokinetic parameters.
- 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. - Predict the relative importance of a capacity-limited metabolic pathway for a drug which is eliminated by parallel saturable and linear routes.
- Distinguish between saturable first-pass metabolism and capacity-limited systemic elimination.
- 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.

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

- 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.
- 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.
- List at least two problems commonly associated with peak plasma concentrations.
- List three reasons why, in most clinical settings, trough concentrations are more useful than peak concentrations.
- 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.
- 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.