Week 2 – Pharmaceutics and Pharmacokinetics

1. Week 2 – Pharmaceutics and Pharmacokinetics Pn. KhadijahHanimbt Abdul Rahman School of Bioprocess Engineering

2. Drug Development • All pharmaceuticals undergo extensive research and development prior to approval by the U.S. Food and Drug Administration (FDA). • The physicochemical characteristics of the active pharmaceutical ingredient (API, or drug substance), the dosage form or the drug, and the route of administration are critical determinants of the in-vivo performance, safety and efficacy of the drug product. • The properties of the drug and its dosage form are carefully engineered and tested to produce a stable drug product that upon administration provides the desired therapeutic response in the patient.

3. For drugs absorption, distribution and therapeutic effect we need to consider first drug substance and dosage form. • The dosage forms are oral, intravenous, subcutaneous, transdermal, etc., route of administration. • Next, the drug is released from the dosage form in a predictable and characterizable manner

4. Then, some fraction of the drug is absorbed from the site of administration into either the surrounding tissue, into the body (as with oral dosage forms), or both. • Finally, the drug reaches the site of action. • If the drug concentration at the site of action exceeds the minimum effective concentration (MEQ), a pharmacologic response results.

5. Pharmaceutical scientists have evaluated the relative drug availability to the body, in-vivo after giving a drug product to an animal or human. • Then pharmacologic, clinical, or possible toxic responses are compared. • The bioavailability is the measure of systemic availability of a drug

6. Biopharmaceutics is the science that examines this interrelationship of the physi­cochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption.

7. Biopharmaceuticsinvolves • The stability of the drug within the drug product, • the release of the drug from the drug product • the rate of dissolution/release of the drug at the absorption site • And the systemic absorption of the drug.

8. Scheme demonstrating the dynamic relationship between the drug, the drug product and the pharmacologic effect.

9. Biopharmaceuticsstudies use both in-vitro and in-vivo methods. • In-vitro methods are procedures employing test apparatus and equipment without involving laboratory animals or humans. • In-vivo methods are more complex studies involving human subjects or laboratory animals.

10. Pharmacokinetics • After a drug is released from its dosage form, the drug is absorbed into the surrounding tissue, the body, or both. • The distribution through and elimination of the drug in the body varies for each patient but can be characterized using mathematical models and statistics. • Pharmacokinetics is the science of the kinetics of drug absorption, distribution, and elimination (ie, excretion and metabolism).

11. Pharmacodynamics • Pharmacodynamicsrefers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response, including biochemical and physiologic effects that influence the interaction of drug with the receptor.

12. Measurement of Drug Concentration • Drug conc. –important element in determining pharmacokinetics. Drug concentrations are measured in biologic samples, such as milk, saliva, plasma, and urine. • Invasive methods include sampling blood, spinal fluid, synovial fluid, tissue biopsy, or any biologic material that requires parenteral or surgical intervention in the patient. • Noninvasive ve methods include sampling of urine, saliva, feces, expired air, or any biologic mate­rial that can be obtained without parenteral or surgical intervention.

13. Drug Concentrations in Blood, Plasma, or Serum • Whole blood contains cellular elements including red blood cells, white blood cells, platelets, and various other proteins, such as albumin and globulins. • Serum or plasma is most commonly used for drug measurement. • To obtain serum, whole blood is allowed to clot and the serum is collected from the supernatant after centrifugation. • Plasma is obtained from the supernatant of centrifuged whole blood to which an anticoagulant, such as heparin, has been added.

14. Plasma Level—Time Curve MEC (minimum effective concentration) – reflects the min. conc. O`fdrugs needed at the receptors- to produce desired pharmacologic effect. MTC (minimum toxic concentration)- represents the drug concentration needed to just barely produce a toxic effect. Onsite time- time required for the drug to reach the MEC Intensity- proportional to the no. of drug receptors occupied- higher plasma drug conc., produce greater pharmacologic response. Duration- difference between onsite time and the time for drug to decline back to MEC

15. Other methods for measurement of drug concentrations • in tissues • in urine and feces • In saliva

16. Significance of measuring plasma drug concentrations • To evaluate the intensity of pharmacologic/toxic effect of a drug • Individual variations- Monitoring the conc. of drugs in blood/plasma ascertains that calculated dose delivers the plasma level required for therapeutic effect. • Allows for the adjustment of the drug dosage in order to individualized and optimize therapeutic drug regimens.

17. Pharmacokinetic Models -Mathematical models- to simulate the rate processes of drug absorption, distribution and elimination - describing and predicting drug conc. in the body as a func. of time. -Pharmacokinetic models are used to: • Predict plasma, tissue, and urine drug levels with any dosage regimen • Calculate the optimum dosage regimen for each patient individually • Estimate the possible accumulation of drugs and/or metabolites • Correlate drug concentrations with pharmacologic or toxicologic activity • Evaluate differences in the rate or extent of availability between formulations (bioequivalence) • Describe how changes in physiology or disease affect the absorption, distribu­tion, or elimination of the drug • Explain drug interactions

18. Pharmacokinetic Models • 3 types of pharmacokinetic models • Empirical model • practical, but not useful in describing the actual process of drug absorption, distribution eliminated in the body. • Physiological model • Have limitations. Need to obtain actual tissue and monitors blood flow to the liver in vivo. • Compartmentally based model - Very simple and useful tool in pharmacokinetics.

19. One compartment model • Assume a drug is given by intravenous injection and that the drug dissolves (distributes) rapidly in the body fluids. • One pharmacokinetic model that can describe this situation is a tank containing a volume of fluid that is rapidly equilibrated with the drug.

20. The concentration of the drug in the tank is governed by two parameters: • the fluid volume of the tank that will dilute the drug, and • the elimination rate of drug per unit of time.

21. fluid-filled tank model called the • one-compartment open model • If drug concentrations in the tank are determined at various time intervals following administration of a known dose, then the volume of fluid in the tank or compartment (VD, volume of distribution) and the rate of drug elimination can be estimated.

22. Compartment Models • A compartment: considered as tissues that have similar blood flow and drug affinity. • The drug is considered to be distributed evenly • Drug conc. represents an average conc. and each drug molecule has equal probability of leaving a compartment • Rate constants- represent the overall rate processes of drug entry and exit from compartment

23. Multi-compartment model: Mammillary model • Mammillary model- most common compartment model in pharmacokinetics. • Strongly connected system- can estimate the amount of drug in any compartment of the system after drug is introduced. • Central compartment- represent plasma and highly perfused tissues (i.e. liver and kidney) that rapidly equilibrate with drug. • IV dose- drug enters directly into central compartment. Elimination occurs from central compartment- organ involved are highly perfused tissues (liver/kidneys)

24. drug can move between the central or plasma compartment to and from the tissue compartment. • Although the tissue compartment does not represent a specific tissue, the mass balance accounts for the drug present in all the tissues. • In this model, the total amount of drug in the body is simply the sum of drug present in the central compartment plus the drug present in the tissue compartment.

25. The pharmacokinetic rate constants are represented by the letter k. • Compartment 1 represents the plasma or central compartment, • and compartment 2 represents the tissue compartment.

26. The drawing of models has three functions. • The model enables the pharmacokineticist to write differential equations to describe drug concentration changes in each compartment, • gives a visual representation of the rate processes, • And shows how many pharmacokinetic constants are nec­essary to describe the process adequately.

27. Model 1: • Two parameters are needed to describe • the volume of the compartment • and the elimination rate constant, k.

29. Model 4, • the pharmacokinetic parameters consist of the volumes of compartments 1 and 2 • and the rate constants—ka, k, k12, and k21 • total of six parameters.

30. Problem The pharmacokinetic model presented in the Figure represents a drug that is eliminated by renal excretion, biliary excretion, and drug metabolism. The metabolite distribution is described by a one-compartment open model. The following questions pertain • How many parameters are needed to describe the model if the drug is injected intravenously (i.e., the rate of drug absorption may be neglected)? • What would be the overall elimination rate constant for elimination of drug from compartment 1? • Write an expression describing the rate of change of drug concentration in compartment 1 (dC1ldt).

31. Pharmacokinetic model for a drug eliminated by renal and biliary excretion and drug metabolism. • km= rate constant for metabolism of drug: • ku= rate constant for urinary excretion of metabolites: • kb= rate constant for biliary excretion of drug, and • ke= rate constant for urinary drug excretion.