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Bioavailability & Absorption

Bioavailability & Absorption. Objectives  Factors affecting Bioavailability  The calculation of Bioavailability (F)  Absolute vs. Relative Bioavailability  The effect of ka on [ ]-time profiles  What happens if the dose does not begin to be absorbed immediately?

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Bioavailability & Absorption

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  1. Bioavailability & Absorption Objectives  Factors affecting Bioavailability The calculation of Bioavailability (F) Absolute vs. Relative Bioavailability The effect of ka on [ ]-time profiles What happens if the dose does not begin to be absorbed immediately? What is the difference between an SR and an EC product?

  2. Bioavailability & Absorption 400 mg of moxifloxacin is administered orally to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) Time Plasma Conc (hr) (mg/L) 0.0 0.00 0.25 0.88 0.5 1.40 1 1.86 1.5 1.98 2 1.99 4 1.77 8 1.34 12 1.02 24 0.44 Parameter Estimates ka = 2.365 hr-1 K = 0.06899 hr-1 T½ = 10.04 hr AUCI =33.0 mg*hr/L V/F = 175.69 when F=1 But does F=1 in this patient? CPS says F = 0.9 …?

  3. Definitions: Bioavailability: relative amount of an administered dose which reaches the general circulation and the rate at which this occurs. Relative to either and IV dose (Absolute bioavailability) or to another formulation of unknown F (Relative bioavailability).

  4. Definitions: Bioequivalence: The term applied to generic formulations of the same active ingredient and dose are said to be bioequivalent when the profiles of drug or metabolite(s) or both are similar. (considers both rate & extent)

  5. Definitions: Bioequivalence: Similar pharmacokinetic profiles of drug or metabolite(s) or both The degree of similarity between profiles is established statistically using Cmax and AUC as endpoints. Bioequivalence implies that with similar profiles, two bioequivalent drug products can be expected to have the same systemic effect (both therapeutic and adverse)

  6. Conducting a Bioavailability Study Test and Reference given in a minimum number of subjects (12) generally young males Controlled Conditions on separate occassions Assumption: Products shown to be bioequivalent in young males are assumed to be bioequivalent in the population that will use them, regardless of age, sex, and ethnic background.

  7. Conducting a Bioavailability Study Test and Reference in a 2-way cross-over design in a minimum number of subjects (12) under controlled conditions Sample to capture CMAX and 80% of AUC (~4 half-lives 90% and generally > 80% in all) Measure drug concentration with a specific and sensitive method Estimate AUC and CMAX

  8. Parameters for Estimating Bioavailability Estimating Rate Measures of Rate: Maximum concentration [Cmax], absorption rate constant [ka] Is Cmax a good measure of absorption rate? Cmax No ! …. Cmax is not a pure measure of rate … if we double the dose, Cmax will change (ka might not) But it is easy to estimate and in a profile there is no argument about the highest measured concentration. Answer: Tmax

  9. Parameters for Estimating Bioavailability Measures of Extent: Area Under the Curve [AUC] Estimating Extent Is AUC a good measure of the extent of absorption? AUC Answer: Yes ! …. Even based on trapezoidal rule AUC is a good measure of extent

  10. Calculating Bioavailability Then calculate the Relative ratio of AUC Test / reference Mean Data based on 23 subjects Data from Yacobi, J Clin Pharmacol 2000; 40: 826-35 Test Reference AUC0-∞ 27.0 ± 5.9 26.3 ± 5.3 (ng x hr / mL) Relative Ratio: 102.66 Questions: What does 27.0 ± 5.9mean? What does 102.66mean?

  11. Factors Affecting Bioavailability • Physiologic factors • pH Stomach ~ 1 and intestine ~ 6 • Surface area of the of the intestine – microvilli • Presence of carrier proteins for absorption & exsorption (Pgp) • Enzymes; endogenous and bacterial • GI blood flow • Gastric Emptying & intestinal transit (Pgp or MDR1) • Physicochemical Properties of the Drug • pKa • Water & lipid solubility • Molecular size • Stability in GI environment (pH) • Specificity for carrier proteins and enzymes (Pgp or MDR1)

  12. Factors Affecting Bioavailability • Physiologic factors • pH Stomach ~ 1 and intestine ~ 6 • Surface area of the of the intestine – microvilli • Presence of carrier proteins for absorption & exsorption (Pgp) • Enzymes; endogenous and bacterial • GI blood flow • Gastric Emptying & intestinal transit (Pgp or MDR1) • Physicochemical Properties of the Drug • pKa • Water & lipid solubility • Molecular size • Stability in GI environment (pH) • Specificity for carrier proteins and enzymes (Pgp or MDR1) Factors which change the environment. FOOD Affects pH, Blood flow Gastric emptying Interactions with enzymes DRUGS Affect Blood flow Gastric emptying Interactions with enzymes

  13. Factors Affecting Bioavailability Food can affect both rate (ka) and extent (AUC) of absorption. No general statement of the effect of food can be made. Effect depends on the drug and the nature of the meal. Food can increase / decrease or have no effect on either rate (ka) or extent (AUC).

  14. Factors Affecting Bioavailability DRUGS, & Alternative Medicines can affect both rate (ka) & extent (AUC) of absorption No general statement of the effect of drugs can be made. Effect depends on the two drugs involved in the interaction and the mechanism of interaction…if known! inhibition of MDR1, change in pH, GI transit, blood flow…

  15. Calculating Bioavailability 400 mg of moxifloxacin is administered orally to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) Time Plasma Conc (hr) (mg/L) 0.0 0.00 0.25 0.88 0.5 1.40 1 1.86 1.5 1.98 2 1.99 4 1.77 8 1.34 12 1.02 24 0.44 Parameter Estimates ka = 2.365 hr-1 K = 0.06899 hr-1 T½ = 10.04 hr AUCI =33.0 mg*hr/L V/F = 175.69 when F=1 But does F=1 in this patient? CPS says F = 0.9 …?

  16. Calculating Bioavailability To estimate absolute bioavailability in Mr BB, 400 mg of moxifloxacin is administered as an IV bolus. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) • Questions to Solve • What model best describes profile? • Calculate AUC, K, T½, V & Cl • Calculate F for Mr BB Time Plasma Conc (hr) (mg/L) 0 22.32 61.76 121.16 240.5 360.22 48BLOQ

  17. Graph Patient Data Using semi-log paper, or Excel graph the data following IV bolus administration of 400 mg of moxifloxacin 10 6 3 1 0.6 0.4 0.2 0.1 Time Plasma Conc (hr) (mg/L) 0 22.32 61.76 121.16 240.5 360.22 48BLOQ 0 4 8 10 14 18 22 24

  18. Graph Patient Data What model best describes this profile? Terminal elimination phase is log-linear… 1 Compartment Model with first order elimination (K)

  19. Calculating Bioavailability To estimate absolute bioavailability in Mr BB, 400 mg of moxifloxacin is administered as an IV bolus. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) • Questions to Solve • What model best describes profile? • Calculate AUC, K, T½, V & Cl • Calculate F for Mr BB Time Plasma Conc (hr) (mg/L) 0 22.32 61.76 121.16 240.5 360.22 48BLOQ You should solve this problem on your own. This will not be covered in Class. Use the associated Excel File to check your answers

  20. 1-Compartment IV Dosing AUC 38.38 mg*hr/L K 0.0694 hr-1 T½ 9.98 hr Cl 10.42L/hr

  21. Calculating Bioavailability To estimate absolute bioavailability in Mr BB, 400 mg of moxifloxacin is administered as an IV bolus. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) Time Plasma Conc (hr) (mg/L) 0 22.32 61.76 121.16 240.5 360.22 48BLOQ Parameter Estimates K = 0.0694 hr-1 T½ = 9.98 hr AUCI =38.38 mg*hr/L V = 150.12 L

  22. Calculating Bioavailability To estimate absolute bioavailability in Mr BB, 400 mg of moxifloxacin is administered as an IV bolus. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) • Questions to Solve • What model best describes profile? • Calculate AUC, K, T½, V & Cl • Calculate F for Mr BB • In order to calculate the absolute • bioavailability for moxifloxacin in this patient • we will need to give Mr. BB an IV dose (data • on left) and compare it to the oral data. Time Plasma Conc (hr) (mg/L) 0 22.32 61.76 121.16 240.5 360.22 48BLOQ

  23. Calculating Bioavailability Why are we comparing AUC’s? What happens to AUC if we change the dose? If I give the same patient the same dose of a drug (400 mg) will the AUC always be the same? … if NOT when NOT? Change volume Change half-life Change clearance

  24. Calculating Bioavailability AUCORAL = 33.000 mg*hr/L – from previous Slide Pak AUCIV = 38.386 mg*hr/L – Just calculated F = ?

  25. Calculating Bioavailability Oral Data IV Data L F = AUCORAL / AUC IV = 33.00 / 38.39 = 85.97% F = 85.97% CPS: F = 90% Is it wrong?

  26. Bioavailability (F) & Other parameters Oral Data IV Data L Inspect other data: Should Clearance and Volume change as a result of a change in the route of administration? Clearance is calculated as Dose / AUC. Is the Dose really 400 mg if F is 85.97%?

  27. Bioavailability (F) & Other parameters Oral Data IV Data L Ratio of Clearance (Cl IV and ClORAL) Cl IV= 10.42 L/hr and ClORAL = 12.12 L/hr Ratio = 10.42 / 12.12 = 0.8597 (Same ratio as ratio of AUC (F)) How should Clearance following and oral dose be calculated?

  28. Bioavailability (F) & Other parameters Oral Data IV Data L Clearance following an Oral Dose (ClORAL) Cl ORAL= (F x Dose)/AUC = 0.8597 x 400 mg / 33.00 mg * hr/L = 10.421 L/hr

  29. Bioavailability (F) & Other parameters Oral Data IV Data L Clearance following an Oral Dose (ClORAL) Clearance is constant. It should not change when route changes. If clearance is calculated to be different than ClIV, it is because F is not known or F is different than expected. When F is not known, F is commonly assumed to be 1 (or left out of the equation) and then Clearance is best described as Apparent Oral Clearance.

  30. Bioavailability (F) & Other parameters Oral Data IV Data L Inspect other data: Should Volume change as a result of a change in the route of administration? Clearance is calculated from K x V and Dose / AUC. Is the Volume really 175.69 L if F is 85.97%?

  31. Bioavailability (F) & Other parameters Oral Data IV Data L Ratio of Volumes (V IV and VORAL) VIV= 150.12 L and VORAL = 175.69 L Ratio = 150.12 / 175.69 = 0.8597 (Same ratio as ratio of AUC (F) and ratio of clearances) How should Volume be calculated following and oral dose?

  32. Bioavailability (F) & Other parameters Oral Data IV Data L Volumes following an Oral Dose (V IV and VORAL) Since Cl = K x V and Cl = F x Dose / AUC then: K x V = F x Dose / AUC and VORAL = F x Dose / K x AUC = ((0.8597)(400)) / ((0.0694)(175.69)) = 150.159 L

  33. Bioavailability (F) & Other parameters Oral Data IV Data L Volume following an Oral Dose (VORAL) Volume should remain constant. It should not change when route changes. If the volume following and oral dose is different than the volume following an IV dose, it is because F is not known or F is different than expected. When F is not known, F is commonly assumed to be 1 and then Volume is best described as Apparent Oral Volume of Distribution.

  34. Bioavailability (F) & Other parameters Oral Data IV Data L Clearance (FDose/AUC) L/hr 10.42 Volume (F= 85.97) L 150.1 Apparent

  35. Absorption Rate - ka Objectives  Factors affecting Bioavailability The calculation of Bioavailability (F) Absolute vs. Relative Bioavailability The effect of ka on [ ]-time profiles What happens if the dose does not begin to be absorbed immediately? What is the difference between an SR and an EC product?   

  36. Absorption Rate - ka 400 mg of moxifloxacin is administered orally to Mr BB, a 68 yr old male who weighs 75 kg. Blood samples were drawn following the dose and the plasma concentration determined. It is known that about 20% of a moxifloxacin dose is excreted in the urine unchanged. A further 20% is excreted unchanged in the bile and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide) Time Plasma Conc (hr) (mg/L) 0.0 0.00 0.25 0.88 0.5 1.40 1 1.86 1.5 1.98 2 1.99 4 1.77 8 1.34 12 1.02 24 0.44 Parameter Estimates ka = 2.365 hr-1 K = 0.06899 hr-1 T½ = 10.04 hr AUCI =33.0 mg*hr/L V/F = 175.69 when F=1 ka? 2.365 hr-1 ? What would happened to ka if we administered Moxi with food ? or increased the dose?

  37. Absorption Rate - ka ka is the absorption rate constant. It has units of hr-1. Values of ka can <theoretically> range from 0 to , but in reality the ka would never be less than 0.001 hr-1 or greater than 30 hr-1. What is the difference between a value of 0.5 hr-1 vs. 2.3 hr-1?

  38. Absorption Rate - ka What is the difference between a value of 0.5 hr-1 vs. 2.3 hr-1? A larger ka value indicates faster absorption. Here both drugs have a 2 hour half-life (parallel terminal phase) Which profile is produced with a ka of 2.3 hr-1?

  39. Absorption Rate - ka What is the difference between a value of 0.5 hr-1 vs. 2.3 hr-1? Here both drugs have a 2 hour half-life. Which profile is produced with a ka of 2.3 hr-1? Dose 1 has a ka of 2.3 hr-1 and a Tmax of ~1 hr. Dose 2 has a ka of 0.5 hr-1 and a Tmax of ~2.4 hr.

  40. Absorption Rate - ka A ka value of 100 hr-1 is so fast that it resembles IV bolus injection. ka appears to determine Tmax…? ka= 100 Tmax = 0.05 hr ka= 2.3 Tmax = 0.98 hr ka= 0.5 Tmax = 2.39 hr … any other factors?? Dose 1 has a ka of 2.3 hr-1 and a Tmax of ~1 hr. Dose 2 has a ka of 0.5 hr-1 and a Tmax of ~2.4 hr. Dose 3 has a ka of 100 hr-1 and a Tmax of ~0.05 hr (3 minutes).

  41. Absorption Rate - ka K or Half-life also determines Tmax following the first dose. Formula: ln [ ka/k] TMAX = --------------- ka - k Dose 1 has a ka of 1 hr-1 and a T-half 1 hr and T max of 1.2 hr. Dose 2 has a ka of 1 hr-1 and a T-half of 2hr and T max of 1.6 hr. Dose 3 has a ka of 1 hr-1 and a T-half of 10 hr and T max of 2.9 hr.

  42. Absorption Rate - ka Absorption from many formulations is usually first order … But does absorption occur at other rates????

  43. Absorption Rate - ka Some modified release or sustained release formulations display zero-order absorption. A zero-order absorption rate concentration-time profile will appear different. The peak will be abrupt, not smooth and rounded. These profiles are shown with the same half-life (4 hr) but a different volume so that the profiles are separated.

  44. Absorption Rate - ka A zero – order rate is Constant Each hour the same amount of drug (mg) is absorbed (or released) from the formulation. The entire dose of a 400 mg tablet that is absorbed at the zero-order rate of 200 mg/hr will all be absorbed in 2 hours. The peak will occur at 2 hours, regardless of the elimination rate Zero-Order Rate 200 mg/hr Tmax = 2 hours

  45. Absorption Rate - ka A first order rate is a constant percentage (not amount) per unit of time. A drug with ka = 0.693 hr-1, will peak at about 2.6 hours when the T½ = 4 hours. Zero-Order Rate 200 mg/hr Tmax = 2 hours • But when does • absorption for this • formulation stop? • (i) At the Tmax – 2.6 hrs • (ii) Prior to the peak • (iii) ~ 1 hr after the peak • Technically – never • It depends

  46. Absorption Rate - ka A first order rate Such as 0.693 hr-1, will peak at about 2.6 hours when the T½ = 4 hours. Zero-Order Rate 200 mg/hr Tmax = 2 hours If we deal with ka as we would K, since ka = 0.693, then T½ka = 1 hour. This means that following a 400 mg dose, rates/hr =: 6.25 mg/hr 25 mg/hr 100 mg/hr Time Amount 1 200 2 100 3 50 4 25 5 12.5 6 6.25 Peak

  47. Absorption Rate - ka A first order rate Such as 0.693 hr-1, will peak at about 2.6 hours when the T½ = 4 hours. Zero-Order Rate 200 mg/hr Tmax = 2 hours • But when does • absorption for this • formulation stop? • (i) At the Tmax – 2.6 hrs • (ii) Prior to the peak • (iii) ~ 1 hr after the peak • Technically – never • It depends

  48. Absorption Rate - ka K and ka are independent processes Factors which affect K Drug Patient Other drugs … Factors with affect ka Drug Patient Formulation Physiologic factors Food, GI environment Enzymes

  49. Absorption Rate - ka K and ka are independent processes Factors which affect K Drug Patient Other drugs … Factors with affect ka Drug Patient Formulation Physiologic factors Food, Water GI environment Enzymes

  50. Factors Affecting Bioavailability • Physiologic factors • pH Stomach ~ 1 and intestine ~ 6 • Surface area of the of the intestine – microvilli • Presence of carrier proteins for absorption & exsorption (Pgp) • Enzymes; endogenous and bacterial • GI blood flow • Gastric Emptying & intestinal transit (Pgp or MDR1) • Physicochemical Properties of the Drug • pKa • Water & lipid solubility • Molecular size • Stability in GI environment (pH) • Specificity for carrier proteins and enzymes (Pgp or MDR1)

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