Bioavailability & Bioequivalence: Pharmacokinetic Principles

1. Bioavailability & Bioequivalence:Pharmacokinetic Principles Sandip K. Roy, Ph.D. Exploratory Clinical Development – PK Novartis Pharmaceutical Corporation

2. Pharmacokinetics “what the body does to the drug” Absorption Distribution Metabolism Elimination Pharmacodynamics “what the drug does to the body” wanted effects - efficacy unwanted effects - toxicity disposition

3. Pharmacodynamics Pharmacokinetics Dose regimen Exposure Response Site of action

4. Pharmacokinetics is either directly or indirectly associated with just about every part of pharmaceutical business: • Research and the selection of a promising molecule • Dosage formulation development • Dose regimen • Toxicology and safety assessment • Dosing recommendations for age groups & sub-populations (renal/hepatic/race/DDI) • Effect of meals and dosing • Marketing claims and promotion • Generic substitution • Manufacturing changes

5. General Outline • Basic Pharmacokinetic Concepts • Bioavailability • Definition • How absorption affects bioavailability? • Food Effect • How drug metabolism affects bioavailability? • How transporters affect bioavailability? • Bioequivalence • Definition • Bio-IND • Waivers of In Vivo Study Requirements • Biopharmaceutics Classification System (BCS)

7. Drug Product Distribution to Tissue and Receptor sites Drug in Blood Metabolism Excretion Basic Concepts • Easy to understand using intravenous route • No absorption phase • Simple to follow • Concepts clear with less assumptions • Need some math background • algebra, log scale, Simple linear Equations etc • complex math (differential equations, statistical concepts etc) for Modeling, Population PK, PK-PD etc.

8. Blood withdrawal IV administration, contd., • Following dose administration, we need to follow its drug’s disposition to understand its PK characteristics. • This is achieved by analyzing the changes of the drug and/or its metabolite(s) in blood, plasma, urine etc. • A simple approach is to generate Drug Concentration-Time profile Sampling at Pre-determined Time intervals Conc. vs time profiles Dosing Bio-analytics

9. Concentration versus Time Profiles Broadly the concentration – time profiles can be viewed as two different ways One-Compartment Model Assumes body as one compartment Dose 1 k Two-Compartment Model Central compartment (drug entry and elimination) Tissue compartment (drug distributes) Dose 1 2 k

10. The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment. This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues.

11. The distribution phase for aminoglycosides is only 15-30 minutes, therefore, we can use a one-compartment model with a high degree of accuracy

12. Drugs which exhibit a slow equilibration with peripheral tissues, are best described with a two compartment model

13. Vancomycin is the classic example, it's distribution phase is 1 to 2 hours. Therefore, the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model.

14. Volume of Distribution • The concentration in plasma is achieved after distribution is complete is a function of dose and extent of distribution of drug into tissues • This extent of distribution can be determined by relating the concentration obtained with a known amount of drug in the body • Concentration is related to the amount by a constant, VOLUME (V) Amount (mg) = C (mg/L) * V (L) OR V = Amount / C V is known as Apparent Volume of distribution. Plasma volume ~ 3 L; Extracellular water ~16 L; Total body water ~ 42 L

15. Volume of Distribution • Case -1 • At Time zero, the drug amount in the body is the dose (500 mg) • Calculated drug concentration at Time zero is 50 mg/L • Then, the V = 10 L • Case -2 • Dose = 500 mg • Calculated Concentration at time Zero is 5 mg/L • Then, V = 100 L • Examples: Ibuprofen: V is 10 L; Diovan 17 L; Digoxin: ~500L; Chloroquin: 15000 L

16. Area Under the Concentration – Time Curve (AUC) • A quantitative measure for exposure from dosing time to time ‘t’ • An important parameter in PK • AUC(t) and AUC(inf) • Determined by trapezoidal method • AUC(inf) = AUC(t) + Ct/k Units: Conc*t (mg/L * h) • Proportional to Dose (linear PK) • Accuracy of the estimate depends on frequency of sampling Concentration (Units/ml) Time (hr) Area Under the Curve (AUC)

17. How is drug excreted/eliminated? • The Kidneys • This is the main excretory organ for drugs • The Nephron: Glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting tubule • Drug enters the lumen of the nephron by filtration and secretion • Filtration occurs in the glomerulus; secretion is primarily restricted to the proximal tubules • Reabsorption occurs all along the nephron; Active reabsorption usually occurs in the proximal tubule • Appearance of drug in the urine is the net result of filtration, secretion, and reabsorption

18. Drug metabolism/biotransformation • This mainly occurs in the liver, via liver enzymes. • But it can also occur in the blood plasma or at various other places (stomach, intestines, lungs, skin, or kidneys) directly by various enzymes at those locations • In any case, these metabolites are then excreted/eliminated (more easily than would the parent molecule have been) metabolites are often smaller in size, ionized • Some drugs are excreted/eliminated in unmetabolized form, as the original drug molecule (e.g. Lithium)

19. Other Routes of Excretion/Elimination • In bile (which then empties into gut, excreted in feces) [can excrete from 5 to 95% of drug dose, esp. antibiotics] • In sweat, saliva, tears, exhaled breath, milk, hair, nails [as heart rate increases --- pulmonary circulation --- which then increases amounts of breath exhaled --- more drug eliminated]

20. Concept of “Half Life” • ½ life = how much time it takes for blood levels of drug to decrease to half of what it was at equilibrium • There are really two kinds of ½ life… • “distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs • “elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated • It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug

21. Concept of “Half Life”

23. Elimination

24. “Rule of Five” 5x the elimination ½ life = time at which the drug is “completely” (97%) eliminated from the body 1x ½ life - 50% of the original drug removed 2x ½ life - 75% 3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875%

25. Clearance “Of the concepts in pharmacokinetics, clearance has the greatest potential for clinical applications. It is also the most useful parameter for the evaluation of an elimination mechanism.” Rowland & Tozer

26. Clearance • Quantifies Elimination • Is the volume of body fluid cleared per time unit (L/h, mL/min) • Is Usually Constant

27. Clearance Proportionality factor relating rate of drug elimination to plasma drug concentration

28. Clearance Rate of elimination is proportional to the amount (A) of drug present

29. Dependence of Half-life on Clearance and Volume

30. Why is Clearance Important? Clearance is the one parameter that determines the maintenance dose rate required to achieve a desired plasma conc. Dosing rate = clearance X desired plasma conc.

31. For a given dose rate, the blood drug concentration is inversely proportional to clearance

32. Multiple Dose Administration • Minimum and maximum conc should be within therapeutic window – depends on dose, frequency and t1/2 • Depending on dosing frequency and t1/2, accumulation occurs • Degree of accumulation is important for safety assessment purposes Concentration Time (hr)

33. Bioavailability and Its Assessment Bioavailability: The rate and extent to which the parent compound reaches the general circulation. Absolute Bioavailability • requires I.V. administration • Ratio of the oral:intravenous AUC values normalized for dose • Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral) Relative Bioavailability • no I.V. reference • comparison AUC values (ratio) of different dosage forms / formulations • Frel = (AUC a / AUC b) * (Dose b /Dose a)

34. 20 mg administered as an i.v. bolus (Diovan) 80 mg given as a solution and a capsule (Diovan)

35. F=0.6 F=0.4* F=0.2* AUC *dose - adjusted

36. Anatomical Considerations Gut Lumen Portal Vein Liver Gut Wall Systemic Circulation Metabolism Metabolism Release + Dissolution Permeation Elimination Absorption Bioavailability

37. How Absorption affects Bioavailability?

38. Drug Product Distribution to Tissue and Receptor sites Drug in Blood Metabolism Excretion Absorption Absorption • Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement. • Drugs are frequently administered extravascularly • oral, sublingual • intramuscular, • topical, patches, inhalation • Absorption is a prerequisite for a drug to exert it’s pharmacologic effect (other than local effect) • Several possible sites contribute to the loss

39. Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose Rate of drug accumulation at any time: dDBODY/dt= dDABS/dt - dDELIM/dt Absorption Phase: dDABS/dt > dDELIM/dt At time of peak drug conc.: dDABS/dt = dDELIM/dt Post-absorption Phase: dDABS/dt < dDELIM/dt

40. Physiological Considerations • Surface area • small intestine = 200 m2 • stomach = 1 m2 • Permeability • intestinal membrane>stomach • Blood flow (for perfusion rate-limited absorption) • small intestine = 1000 mL/min through intestinal capillaries • stomach = 150 mL/min • Gastric emptying and pH • GI transit • Rate of gastric emptying is a controlling step for rapid absorption

41. Physico-Chemical Factors • Partition Theory • Ionization, pH-pKa Relationship • Polymorphism • Particle Size • Complexation

42. Absorption Involves Movement Through Membranes Influx Efflux • Passive diffusion • Active transport • Rate of diffusion = P *(C1-C2) where P is permeability coefficient • Lipophilicity (partition between oil and water) • Hydrophilicity (paracellular movement depends on size, shape and charge) Transcellular Paracellular

43. Passive diffusion Passive Diffusion of Molecules

44. Comparison of the Rates of Drug Absorption A = Passive diffusion B = Active transport/ carrier mediated system

45. Naproxen Piroxicam Propanolol Ketoprofen L-leucine Phenylalanine Percent Absorbed (%) Benserazide D-glucose L-Dopa Antipyrine Metoprolol Terbutaline Furosemide Atenolol Enalaprilate Human Permeability (104, cm/sec) Percent Dose Absorbed vs. Human Permeability • Very low concentration • No saturation effects • Already in solution • No dissolution effects

46. Effect of Blood Flow on Absorption • High resistance to drug movement • movement insensitive to changes in perfusion • If the membrane offers no resistance • movement is dependent on blood flow

47. pH – pKa Ionization Weak acid pka - pH = log [(un-ionized)/(ionized)] Weak base pka - pH = log [(ionized)/(un-ionized)] Examples: • Aspirin, pka : 3.5, at pH = 1, mostly unionized • Phenytoin, pka : 8.3, unionized in stomach • Diazepam, pka : 3.3, mostly ionized in stomach • Procainamide, pka : 9.5, mostly ionized in stomach

48. Gastrointestinal pH and Transit Time in the Fasted State

49. Assessment of Drug Absorption • Absorption is measured as Rate of Absorption, ka. and Extent (AUC) • For Rate - Need to fit the data and it is model dependent • A surrogate is Cmax/AUC • Example: Lescol capsule (IR) : 0.37 hr-1 Lescol XL: 0.19 hr-1 • Usually (also) measured as Cmax and Tmax Cmax Tmax Lescol IR 438 0.5-1 h Lescol XL 101 1.5-4 h

50. 0.5/hr 0.2/hr Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve