Gastrointestinal System PK Concepts for Absorption 2, AY2024/25 PDF

PR2152 Gastrointestinal System IC 05 PK concepts for Absorption 2 AY2024/25 Sem 1 Chng Hui Ting, PhD E-mail: [email protected] 1 RECAP 2  Take...

PR2152 Gastrointestinal System IC 05 PK concepts for Absorption 2 AY2024/25 Sem 1 Chng Hui Ting, PhD E-mail: [email protected] 1 RECAP 2  Take this medicine with or after food Take this medicine before food Why? 3 Icon made by Freepik from www.flaticon.com Overview of Absorption lectures Part 1 Part 2 1) What factors affect the absorption of 1) What factors affect the absorption of solid drugs in solution administered orally, IM dosage forms in GI tract? and SC? 2) When looking at an EV dose profile, is the 2) What type of kinetics does drug terminal slope always elimination rate- absorption follow? How does drug constant? concentration change over time after a 3) How do we determine absolute vs relative single EV dose (disposition viewed from bioavailability? blood/plasma sample)? 4) How would changing amount absorbed, 3) What PK parameters can I derive from absorption kinetics and disposition the PK profile of a drug following Single kinetics alter PK parameters & EV profile? EV dose? 4 Absorption Part 2 LEARNING OUTCOMES At the end of this part, students should be able to: Anticipate the role of gastric emptying and intestinal transit in the systemic absorption of a drug given orally with particular reference to the physicochemical properties of the drug and its dosage form Distinguish between dissolution- and permeability-rate limitations in systemic absorption after oral administration Distinguish between disposition- and absorption-rate limited drug elimination Recognize flip-flop of two rate constants, ka and k, for absorption rate-limited drug elimination Calculate the absolute and relative bioavailability of a drug given plasma concentration data Discuss and explain observed changes in the absorption-related PK parameters and profiles of drugs 5 Gastric emptying and intestinal transit Rate-limited GI absorption (permeability vs dissolution rate-limits absorption) Rate & extent Factors affecting GI motility WHAT FACTORS AFFECT THE ABSORPTION OF SOLID DOSAGE FORMS IN GI TRACT? 6  Small non-disintegrating pellets List some key observations/ conclusions that can Diameters between 0.3 – 1.8 mm be made based on this experiment: Large single non-disintegrating units ___________________________________ Tablets with diameters Capsules (25 mm x 9mm) ___________________________________ between 8 mm – 12 mm ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Extra notes to link with concepts in GI physiology In this study, the “transit time” is tracking the time for the tablet or pellet to move through the respective section of the GIT (stomach or small intestine). In general, presence of food stimulates GI tract to increase motility for digestion and absorption. When food is present in the stomach, gastroileal reflexes is activated which also increases motility in the intestines for digestion and absorption. As food gets churned and turned into more liquid chyme, the chyme is squeezed/emptied from stomach into duodenum. Presence of food in duodenum is now an “inhibitory” response, telling stomach to slow down gastric emptying. If drug is taken with food, then the “presentation of drug from stomach to intestine, which is the main site of absorption”, will decrease compared with taking food on empty stomach because tablet/capsules stay within stomach (churned with food into chyle), and a lot is dependent on “chance” of it being squeezed to enter duodenum. 7 Gastric emptying and intestinal transit ①Gastric emptying rate Controls the rate at which the drug is presented to the major site of absorption (upper small intestine)  controls the onset along with the rate of absorption ②Intestinal motility Determines the residence time of the dosage form in the small intestine Changes in motility could alter drug bioavailability (i.e. extent of absorption) depending on whether dissolution or permeability is the rate-limiting step 8  Which is more Rate-limited GI absorption common? Dissolution >> Absorption Dissolution Absorption Dissolution > k, Absorption rate-limited elimination: k >> ka (flip-flop), Distinguishing between disposition- vs absorption-rate limited elimination Clinical implications of flip-flop kinetics WHEN LOOKING AT AN EV DOSE PROFILE, IS THE TERMINAL SLOPE ALWAYS ELIMINATION RATE- CONSTANT? 17  IV vs EV exposure time profiles of the same drug What do you see in these graph? What do you think is going on? IV IV ln C ln C EV EV Time Time Drug A Drug B 18 RECAP Big idea (3) k, (4) t1/2, (5) ka and (6) t1/2,a For most cases, ka>>k 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 First-order elimination rate constant, 𝑪𝑪 = (𝑒𝑒 −𝒌𝒌 (𝑡𝑡−𝑡𝑡𝑙𝑙𝑙𝑙𝑙𝑙 ) ) If we retrieve the C1 and C2 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) ln 𝐶𝐶1 − ln 𝐶𝐶2 values from a graph drawn on 𝑘𝑘 = a semi-log graph paper, must Usually, slope = -k 𝑡𝑡2 − 𝑡𝑡1 remember to ln the values Elimination half-life, ln 2 𝑡𝑡1 = 2 𝑘𝑘 First-order absorption rate constant, 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 𝑪𝑪 − 𝑪𝑪 = (𝑒𝑒 −𝒌𝒌𝒂𝒂 (𝑡𝑡−𝑡𝑡𝑙𝑙𝑙𝑙𝑙𝑙 ) 𝑘𝑘𝑎𝑎 = 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) Absorption half-life, Usually, slope = -ka ln 2 𝑡𝑡1 = 2,𝑎𝑎 𝑘𝑘𝑎𝑎 𝑪𝑪: plasma concentration along extrapolated line C: observed plasma concentration Note: Will practise feathering/peeling method to 𝑪𝑪 − 𝑪𝑪: residual draw the residual line during Practical 19 When ka >> k, disposition rate-limits decline of PDC Usually, absorption proceeds at much faster rate than elimination  Usually, slope = -k disposition rate-limits elimination of drug After some time, 𝑒𝑒 −𝑘𝑘𝑎𝑎 𝑡𝑡  0 faster than 𝑒𝑒 −𝑘𝑘 𝑡𝑡 Terminal slope reflects elimination rate Usually, slope = -ka Example t1/2,a = 30 min, ka = 1.39 h-1 t1/2 = 2 hr, k = 0.347 h-1 Absorption should complete within 5 t1/2,a 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 i.e. 150 min 𝐶𝐶 = (𝑒𝑒 −𝑘𝑘 𝑡𝑡 − 𝑒𝑒 −𝑘𝑘𝑎𝑎 𝑡𝑡 ) 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) 20 When k >> ka (flip-flop), absorption rate-limits decline in PDC k >> ka  When rate of absorption is much slower than rate of elimination e.g. In flip-flop kinetics, extended-release formulation or depot Terminal slope = -ka injection, terminal slope is NOT elimination rate constant  “flip-flop” kinetics Terminal slope = ka In flip-flop kinetics, Slope of residual line = -k How to distinguish between disposition- vs absorption-rate limited elimination? 21 Distinguishing between disposition- vs absorption-rate limited elimination Big idea: Regardless of route of administration, CL and V for a drug is constant  t1/2 and hence k, should be the same What’s the clinical implications of flip- flop kinetics? Compare EV profile with IV bolus profile where only elimination process is happening (no absorption)  slope of IV bolus profile is k If slope differs between EV and IV  flip-flop Can also trial different dosage forms (e.g. immediate-release vs extended-release) and see if terminal half-life changes 22 Clinical implications of flip-flop kinetics 1)Accurate determination of k vs ka 2)When absorption-rate limits disposition, prolonged half-life  require less frequent dosing Can be due to: Permeability rate-limitations Dissolution rate-limitations Formulation e.g. extended-release 23  Example: Which is disposition- vs absorption-rate limited elimination? □ Tablet dissolved in 500 mL water, empty stomach I.M. - aqueous solution ○ Tablet dissolved in 20 mL water, empty stomach P-I.M. - procaine penicillin in oil Tablet dissolved in 20 mL water, standardized high carb meal AP-I.M. - penicillin in oil with aluminum monostearate 6 volunteers took 2 x 130 mg theophylline tablet 1 individual, 3 different occasions, IM Penicillin G (3 mg/kg) Disposition- or absorption-rate limited elimination for: Disposition- or absorption-rate limited elimination for: □ _________________________ I.M. _________________________ ○ _________________________ P-I.M. _________________________ _________________________ AP-I.M. _________________________ Rate of absorption: _____ > _____ > _____ Rate of absorption: _____ > _____ > _____ 24 Absolute vs relative F Study design HOW DO WE DETERMINE ABSOLUTE VS RELATIVE BIOAVAILABILITY? 25 RECAP from PR1153 Oral systemic bioavailability, F What is the overall oral systemic bioavailability, F of the drug in this figure? ③FH: fraction that reaches liver BUT Escapes extraction within the liver 𝑭𝑭 = 𝑭𝑭𝑭𝑭 𝑭𝑭𝑮𝑮 𝑭𝑭𝑯𝑯 𝟗𝟗 𝟕𝟕 𝟓𝟓 𝑭𝑭 = = ______ 𝟏𝟏𝟏𝟏 𝟗𝟗 𝟕𝟕 CYP450 CYP450 CYP450 CYP450 Big idea The oral systemic bioavailability is the fraction of an oral administered drug that reaches systemic circulation 26 Absolute vs relative bioavailability Absolute bioavailability Relative bioavailability Fraction of an administered dose of a Systemic availability of a drug as drug which actually reaches the compared between different dosage systemic circulation (i.e. systemic forms, different routes of administration availability) after EV administration (not IV), or different conditions (e.g. compared with IV administration effect of food or different diets) From plasma data, From plasma data, and assuming CL is constant, 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 = 𝐶𝐶𝐿𝐿 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ For IV administration, F=1 𝐹𝐹𝐴𝐴 ( 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 )𝐴𝐴 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝐹𝐹 = = Assuming CL is constant, 𝐹𝐹𝐵𝐵 (𝐴𝐴𝐴𝐴𝐴𝐴0−∞ ) 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐵𝐵 ( 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 )𝐸𝐸𝐸𝐸 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐹𝐹 = 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ ( ) 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐼𝐼𝑉𝑉 27 Study design of bioavailability studies Typically, crossover design – Same subject given different administration (e.g. routes/formulations) at different times (allow for wash-out) – Subject is own control i.e. keep PK parameters e.g. CL, V constant (assumption: no changes in between time period) Two treatment, two period, two sequence crossover design Treatment A Treatment A Evaluation of outcomes Evaluation of outcomes Washout period Randomization Treatment B Treatment B 28 Changing amount absorbed – changing F or dose Changing absorption kinetics – changing ka Changing disposition kinetics – changing CL or V Integration of kinetic & physiological concepts HOW WOULD CHANGING AMOUNT ABSORBED, ABSORPTION KINETICS AND DISPOSITION KINETICS ALTER PK PARAMETERS & EV PROFILE? 29 STUDENT Overview (a) Changing (b) Changing (c) Changing amount absorbed absorption kinetics disposition kinetics F ↓ or Dose ↓ ka ↓ CL ↓ V↓ Cmax tmax 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ Half-life (terminal) ↑: increase, ↓: decrease, : no change 30 STUDENT (a) Changing amount absorbed (a) Changing amount absorbed F ↓ or Dose ↓ Cmax tmax 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ Half-life (terminal) ↑: increase, ↓: decrease, : no change ↓ ↓ 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 𝐶𝐶𝑚𝑚𝑚𝑚𝑚𝑚 = (𝑒𝑒 −𝑘𝑘 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 − 𝑒𝑒 −𝑘𝑘𝑎𝑎 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 ) 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 = 𝐶𝐶𝐿𝐿 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) 𝑘𝑘𝑎𝑎 ln ln 2 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 = 𝑘𝑘 𝑡𝑡1 = 𝑘𝑘𝑎𝑎 − 𝑘𝑘 2 𝑘𝑘 31 STUDENT No flip-flop kinetics i.e. (b) Changing absorption kinetics absorption is not rate limiting elimination (b) Changing INPUT A B absorption kinetics Dose (mg) 400 400 ka ↓ CL (L/hr) 20 20 V (L) 50 50 Cmax ka (hr-1) 0.8 0.5 tmax F 1 1 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ OUTPUT A B C max (mg/L) 4.00 3.28 Half-life t max (hr) 1.7 2.2 (terminal) k (hr-1) 0.4 0.4 ↑: increase, ↓: decrease, : no change t 1/2 (hr) 1.7 1.7 AUC (mg*hr/L) 20.0 20.0 ↓ ? 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 What is the k in this 𝐶𝐶𝑚𝑚𝑚𝑚𝑚𝑚 = (𝑒𝑒 −𝑘𝑘 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 − 𝑒𝑒 −𝑘𝑘𝑎𝑎 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 ) simulation? 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) 𝑘𝑘𝑎𝑎 ln 2 ? ln 𝑘𝑘 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 = 𝐶𝐶𝐿𝐿 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ 𝑡𝑡1 = 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 = 2 𝑘𝑘 𝑘𝑘𝑎𝑎 − 𝑘𝑘 32 STUDENT (b) Changing absorption kinetics (b) Changing Rationalizing __in Cmax and __ in tmax when ka ↓: absorption kinetics Before tmax, as time progresses; ka ↓ Aa decrease slower (compared to scenario with higher ka) Cmax  rate of absorption (ka x Aa) decreases slower tmax A increases slower 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞  rate of elimination (k x A) increases slower Half-life Therefore, longer time needed for rate of absorption = (terminal) rate of elimination  increased tmax ↑: increase, ↓: decrease, : no change At tmax, with smaller ka, since drug is absorbed slower, the Aa A is also smaller Since A = C x V and V is unchanged, Cmax is smaller ka Drug in body, A k 33 STUDENT Flip-flop kinetics! (b) Changing absorption kinetics ka < k Absorption rate-limits (b) Changing elimination absorption kinetics INPUT A B ka ↓ Dose (mg) 400 400 Cmax CL (L/hr) 20 20 V (L) 50 50 tmax ka (hr-1) 0.1 0.5 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ F 1 1 Half-life OUTPUT A B (terminal) C max (mg/L) 1.26 3.28 t max (hr) 4.6 2.2 ↑: increase, ↓: decrease, : no change k (hr-1) 0.4 0.4 t 1/2 (hr) 6.9 1.7 AUC (mg*hr/L) 20.0 20.0 Terminal half-life increased (this is not the elimination half-life though) 34 STUDENT (c) Changing disposition kinetics (c) Changing Rationalizing __ in Cmax and __ in tmax when CL ↓: disposition kinetics Before tmax, as time progresses; CL ↓  rate of elimination (k x A) increases slower Cmax Longer time needed for rate of absorption = rate of tmax elimination  increased tmax At larger tmax, less drug remains at absorption site (Aa↓) 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ But more drug in body (↑A) Half-life Since A = C x V and V is unchanged, Cmax is larger (terminal) ↑: increase, ↓: decrease, : no change ↓ 𝐶𝐶𝐶𝐶 ↓ ↓ 𝑘𝑘 = 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 = 𝐶𝐶𝐿𝐿 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ 𝑉𝑉 𝑘𝑘𝑎𝑎 ? ln 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 = 𝑘𝑘 ↓ ln 2 𝑡𝑡1 = 𝑘𝑘𝑎𝑎 − 𝑘𝑘 2 ↓ 𝑘𝑘 ? 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 𝐶𝐶𝑚𝑚𝑚𝑚𝑚𝑚 = (𝑒𝑒 −𝑘𝑘 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 − 𝑒𝑒 −𝑘𝑘𝑎𝑎 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 ) 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) 35 STUDENT (c) Changing disposition kinetics (c) Changing Rationalizing ___ in Cmax and ___ in tmax when V ↓: disposition kinetics Before tmax, as time progresses; V↓  rate of elimination (k x A) increases faster Shorter time needed for rate of absorption = rate of elimination Cmax  decreased tmax tmax At shorter tmax, more drug remains at absorption site (Aa ↑) lesser drug in body (A↓) 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ In this scenario, we can’t use A = C x V to explain Cmax since V ↓, Half-life and A also ↓ (net effect depends on the extent of decrease) (terminal) At tmax, ka x↑Aa = k x A ↑ ↑: increase, ↓: decrease, : no change At tmax, ka x Aa = CL x C 𝐶𝐶𝐶𝐶 Volume of distribution halved ↑ 𝑘𝑘 = 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 = 𝐶𝐶𝐿𝐿 𝐴𝐴𝐴𝐴𝐴𝐴0−∞ ↓ 𝑉𝑉 𝑘𝑘𝑎𝑎 ? ln 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 = 𝑘𝑘 ↑ ln 2 Control 𝑡𝑡1 = 𝑘𝑘𝑎𝑎 − 𝑘𝑘 2 ↑ 𝑘𝑘 ? 𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑘𝑘𝑎𝑎 𝐶𝐶𝑚𝑚𝑚𝑚𝑚𝑚 = (𝑒𝑒 −𝑘𝑘 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 − 𝑒𝑒 −𝑘𝑘𝑎𝑎 𝑡𝑡𝑚𝑚𝑚𝑚𝑚𝑚 ) 𝑉𝑉 (𝑘𝑘𝑎𝑎 − 𝑘𝑘) 36 ANSWER Overview (a) Changing (b) Changing (c) Changing amount absorbed absorption kinetics disposition kinetics F ↓ or Dose ↓ ka ↓ CL ↓ V↓ Cmax ↓ ↓ ↑ ↑ tmax ↑ ↑ ↓ 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ ↓ ↑ Half-life (terminal) ↑ (𝒕𝒕𝟏𝟏 𝟐𝟐,𝒂𝒂) ↑ ↓ ↑: increase, ↓: decrease, : no change tmax depends on ka or k (CL or V) 𝐀𝐀𝐀𝐀𝐀𝐀𝟎𝟎−∞ is dependent on changes in amount absorbed and CL Elimination t1/2 depends on CL or V; terminal t1/2 may be impacted in flip-flop condition i.e. absorption-rate limited elimination Cmax is impacted when any of the primary PK parameters & dose is altered 37 Integration of kinetics and physiological concepts Various factors can affect the rate and/or extent of absorption In reality, the same factor can affect both rate and extent of absorption in GI e.g. gastric motility 38 Example: Inhibition of first-pass metabolism of simvastatin by grapefruit juice ↑F due to enzyme inhibition  ↑AUC, ↑Cmax (↑ in extent of absorption) If only extent of absorption is increase, based on earlier concepts, tmax should ↑ t proposed to be due to slowing of max gastric emptying by grapefruit juice 39 Integration of kinetics and physiological concepts ↑ tmax and ↓ Cmax ↑ tmax and ↑ Cmax Big idea: Final profile and changes in PK parameter is drug and context specific Can predict if only 1 parameter is affected but in actuality, often a complex interaction of various factors Look at the profile  use fundamental concepts to postulate reasons that may cause the observed profile https://www.sciencedirect.com/science/article/pii/S0928098719301411 40 Follow Prof Eric Chan on LinkedIn for bite-sized dose of basic PK concepts https://www.linkedin.com/posts/ericchanphd_keylearningpoints-pharmacokinetics-concepts-activity- 7075259678384934912-1Mrx?utm_source=share&utm_medium=member_desktop https://www.linkedin.com/posts/ericchanphd_pharmacokinetics-concepts-season2-activity- 7151130399992102912-im6o?utm_source=share&utm_medium=member_desktop https://www.linkedin.com/posts/ericchanphd_pharmacokinetics-concepts-season2-activity- 7189224715826225152-1HyF?utm_source=share&utm_medium=member_desktop 41 Absorption Part 2 sub-topic summary 1) What factors affect the absorption of 3) How do we determine absolute vs relative solid dosage forms in GI tract? bioavailability? – Gastric emptying and intestinal transit – Absolute vs relative F – Rate-limited GI absorption (permeability vs – Study design dissolution rate-limits absorption) – Factors affecting GI motility 4) How would changing amount absorbed, 2) When looking at an EV dose profile, is the absorption kinetics and disposition terminal slope always elimination rate- kinetics alter PK parameters & EV profile? constant? – Changing amount absorbed – changing F or – Disposition rate-limited elimination: when dose ka >> k, – Changing absorption kinetics – changing ka – Absorption rate-limited elimination: k >> ka – Changing disposition kinetics – changing CL (flip-flop), or V – Distinguishing between disposition- vs – Integration of kinetic & physiological absorption-rate limited elimination concepts – Clinical implications of flip-flop kinetics Post-absorption lectures, watch 2 x eL videos on: eL01: Introduction to DDI eL02: DDI impacting absorption of drugs 42