Pharmacokinetics and Pharmacodynamics

Cellular and Molecular Biology, Biochemistry, Organic Chemistry

The contents related to modules 1-3 leverage fundamental knowledge in Pharmacokinetics and Pharmacodynamics (PK/PD), which is applied to solving real cases, fostering analytical and critical thinking skills. Modules 4-5 advocate for the objective application of knowledge in more complex situations, encouraging the development of practical PK/PD competencies. The selected teaching methodologies (TM) combine strategies of pedagogical innovation through active learning moments, centered on the student, aiming to promote the trilogy of knowledge in its dimensions of knowing (knowledge), doing (skills), and being (competences):

 TM1 – Interactive expository teaching through suitable audiovisual means, with active moments of individual learning focused on solving PK/PD problems for knowledge application: Mentimeter Platform (Worlcloud, Q&A, Multiple Choice, Ranking tools) [Modules 1-3]

TM2 – Interactive expository teaching through audiovisual means with active group learning moments centered on the analysis and discussion of PK/PD scientific articles for knowledge application: Jigsaw Activities [Modules 1-3]

TM3 – Teaching based on technical planning and execution: practice is action-oriented with the development of skills in the analysis and resolution of practical PK/PD cases in a real context – Hands-on laboratory [Module 4]

TM4 – Problem-Based Learning (PBL): practice is action-oriented with the development of skills in the analysis and resolution of practical PK/PD cases, using online available software such as UCSF-FDA TransPortal, CYPstrate, and GLORYx [Module 5]

TM5 – Project-Based Learning: practice is action-oriented with the development of skills in the analysis and formulation of BD/BE protocols [Module 5]

TM6 – Teaching based on planning and resolution: practice is action-oriented with the development of skills in the analysis and resolution of practical PK/PD cases according to current regulatory guidelines [Module 5]

Structured knowledge of theoretical principles of pharmacokinetics and pharmacodynamics, complemented by a practical plan for the integrated resolution of problems of increasing complexity, promotes the articulation of content with related curriculum units (e.g., Pharmacology I, Pharmacology II).

By the end of the course unit, students are expected to have acquired skills to:

 C1 – Calculate pharmacokinetic parameters that enable understanding of therapeutic inequivalence issues of medications.

C2 – Predict the kinetics and extent of the ADME process of drugs based on physicochemical, biochemical, physiological, and pathological variables.

C3 – Establish and optimize dosage regimens.

C4 – Apply appropriate protocols for assessing availability and recognize the pharmacotherapeutic consequences of its modification.

C5 – Distinguish between various equivalences and master the rules for medication substitution.

C6 – Understand the biochemical determinants of molecular targets for drugs and their fundamental pharmacodynamic concepts.

C7 – Identify drug interactions of pharmacokinetic and pharmacodynamic nature.

C8 – Articulate integrate problem-solving skills, introducing methodologies of systemic and collaborative thinking in Pharmacokinetics and Pharmacodynamics.

Theoretical Matrix (T)

 Module 1. Fundamental Mathematical Concepts for Biopharmacy and Pharmacokinetics (4h T)

1.1. Exponents and logarithms

1.2. Calculation of the area under the curve (AUC): concepts of differential and integral calculus applied to the evaluation of incorporation and disposition phenomena

1.3. Calculation of the mean residence time (MRT) in the organism, mean dissolution time (MDT), and mean absorption time (MAT)

1.4. Mathematical expressions and graphical representations of reaction rates: zero and first-order reaction kinetics

1.5. Equations for describing linear, nonlinear, and compartmental pharmacokinetic models

1.6. Units used to express drug concentrations

Module 2. L.A.D.M.E. Series (20h T)

2.1. Biopharmaceutical Classification System (BCS): solubility/permeability and BCS classes I, II, III, and IV

2.2. Forms of rapid, prolonged, and/or controlled release

2.3. Dissolution calculation: Noyes-Whitney equation

2.4. Absorption

2.4.1. Sites of drug absorption

2.4.2. Mechanisms of transmembrane passage

2.4.3. Membrane transporters of drugs: ABC and SLC

2.4.3. First-pass and pre-systemic degradation of the active ingredient

2.4.4. Factors influencing absorption

2.5. Distribution

2.5.1. Distribution in the vascular space

2.5.1.1. Plasma protein binding

2.5.1.2. Free and bound fraction

2.5.1.3. Factors conditioning binding to plasma proteins

2.5.2. Tissue distribution

2.5.2.1. Aspects of distribution velocity: effects of blood flow

2.5.2.2. Aspects of distribution velocity: effects of diffusion rate

2.5.2.3. Aspects of the extent of tissue distribution

2.5.3. Apparent volume of distribution

2.6. Metabolism

2.6.1. Phase 1 reactions

2.6.2. Phase 2 reactions

2.6.3. Multiplicity and isomerism of cytochrome P450

2.6.4. Drugs with high and low hepatic extraction coefficients

2.6.5. Inducers and inhibitors of metabolizing enzymes

2.6.6. Metabolism kinetics

2.6.1. Single dose: Determination of the rate-limiting step

2.6.2. Multiple doses: steady-state and accumulation effect

2.6.3. Factors susceptible to modifying the kinetic profile

2.7. Elimination

2.7.1. Elimination rate constant

2.7.2. Half-life

2.7.3. Clearance concept

2.7.4. Renal excretion

2.7.5. Biliary excretion and enterohepatic circulation

2.7.6. Other excretion pathways

2.8. Dosage: Single and multiple doses administration – loading and maintenance dose

2.9. Bioavailability

2.9.1. Absolute bioavailability

2.9.2. Relative bioavailability

2.9.3. Methods of determining bioavailability

2.9.4. Pharmacotherapeutic consequences of changes in bioavailability or bioinequivalence: single and multiple doses

2.9.5. Rules to follow in drug substitution

2.9.5.1. Pharmacological equivalence

2.9.5.2. Chemical equivalence

2.9.5.3. Pharmaceutical equivalence

2.9.5.4. Biological equivalence or bioequivalence

2.9.5.5. Clinical or therapeutic equivalence

3. Chronopharmacokinetics and special situations

4. Pharmacokinetic interactions

Module 3. Pharmacodynamics (6h T)

3.1. Molecular targets of drugs:

3.1.1. Ionotropic receptors: blockers and allosteric modulators

3.1.2. Metabotropic receptors

3.1.3. Receptors with intrinsic kinase activity or coupled to kinases

3.1.4. Nuclear receptors

3.1.5. Post-translational modifications of receptors and macromolecular complexes

3.1.6. Enzymes: inhibitors, false substrates, prodrugs, and cofactors

3.1.7. Transporters: Inhibitors and false substrates

3.1.8. Desensitization, tolerance, and resistance

3.2. Dose-response curves (total agonists, partial agonists, inverse agonists, and antagonists)

3.3. Definition of the concepts of specificity, affinity, intrinsic efficacy, and potency

3.4. Types of concentration-effect pharmacological relationships

3.4.1. Indirect effects

3.4.2. Irreversible effects

3.4.3. Reversible direct effects

3.5. Application of receptor theory and Hill equation

3.6. Pharmacodynamic interactions

Practical Matrix (P)

 Module 4. Models for evaluating the extent of absorption and current EMA guidelines (15h P)

4.1. Transporter toolkit and international guidelines for identifying substrates, inhibitors, and inducers of transporters

4.1.1. Membrane models: ATPase assay and vesicle membrane assay

4.1.2. Cellular models: cell lines overexpressing a transporter (Caco-2) or transfected with genes encoding the transporter (MDCK-MDR1, MDCK-BCRP)

4.1.2.1. Accumulation assays (Bidirectional assays and hepatocyte sandwich cultures)

4.1.2.2. Uptake assays

4.1.3. In vivo models

4.2. Practical models for studying intestinal absorption

4.2.1. In vitro models (isolated organs)

4.2.2. Ex vivo models (open perfusion)

4.2.3. In vivo models (fluorescent probes, scintigraphic methods)

Module 5. Investigation protocols for bioequivalence and current EMA guidelines (15h P)

5.1. Guidelines in BE investigation (EMA)

5.2. Establishment of a bioavailability protocol:

5.2.1. Choice of sampling

5.2.2. Dosage method: carryover effect and washout period

5.2.3. Experimental conditions – Harvest frequency, harvest duration, crossover or non-crossover trial, randomization, statistical analysis, administration rate, choice of reference form, feeding, and bioavailability study

5.3. Practical cases for problem-based learning:

5.3.1. Determination of systemic, hepatic, and intrinsic clearance

5.3.2. Determination of hepatic extraction coefficient

5.3.3. Determination of kinetic parameters associated with bioavailability

5.3.4. Comparison of PK profiles and parameters in different study situations associated with bioavailability

5.3.5. Simulated prediction of CYP substrates and inhibitors

5.3.6. Simulated prediction of Phase I and II metabolite structures

5.3.7. Assessment of the impact of pharmacogenetics/pharmacogenomics on drug PK/PD

NAO

Principal Bibliography

Terapêutica Medicamentosa e suas Bases Farmacológicas, 5a edição. Coordenado por S. Guimarães, D. Moura e P. Soares da Silva. Porto Editora, 2006.
Basic & Clinical Pharmacology, de Katzung, 10a edição, editado pela McGraw-Hill.
Goodman and Gilman’s. The Pharmacological Basis of Therapeutics, 10a edição. Editado por A. G. Gilman et al. Pergamon Press.

Secondary Bibliography

Professor notes
Scientific articles, peer-reviewed, indexed in Medline.
Applied Biopharmaceutics and Pharmacokinetics 5ª Ed., SHARGEL, L. YU ABC, Prentice Hall Connecticut. (2005)
IUPHAR/BPS Guide to Pharmacology: http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=691
 UCSF-FDA TransPortal:
http://dbts.ucsf.edu/fdatransportal