# 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 resources for finding pharmacogenomic information about marketed drugs.
- Define the terms: pharmacogenetics, polymorphism, phenotype, allele, homozygous, heterozygous, haplotype, nonsynonomous and synonomous coding, non-coding, intronic polymorphisms.
- Describe at least two ways in which genetic polymorphism in drug pharmacokinetics (PK) can be demonstrated, at least two examples of such polymorphism, and in what circumstances PK phenotyping might be of therapeutic value.
- Describe the mechanism by which thiopurine methyltransferase affects toxicity of 6-mercaptopurine.
- Discuss why CYP2D6 genotyping for tamoxifen efficacy is not routinely done.
- Describe the mechanism by which UGT1A1 polymorphisms affect response to irinotecan.
- Describe how a promoter region variant in UGT1A1 can affect the pharmacokinetics of irinotecan.
- Describe how genetic variants in OATP1B1 affect toxicity to statins.

### Lecture B1 – Pharmacokinetics and Pharmacodynamics Modeling - Davide Verotta

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.