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Kimberly Koon, Pharm. D. BW733 October 1, 2013 Pharmacokinetics WebQuest 1

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Presentation on theme: "Kimberly Koon, Pharm. D. BW733 October 1, 2013 Pharmacokinetics WebQuest 1"— Presentation transcript:

1 Kimberly Koon, Pharm. D. BW733 October 1, 2013 Pharmacokinetics WebQuest 1 /

2 Overview Introduction Absorption – IV, SubQ, IM – Oral, SL – transdermal, rectal, vaginal, inhalation, topical Distribution – models – % cardiac output – Vd Metabolism – sites, – CYP450, first-pass, pro-drugs – t 1/2 vs duration of action Excretion – kidney – liver – enterohepatic recycling – lungs Time vs. concentration graph 2

3 Introduction Pharmacokinetics: study of how body processes drugs; think reverse-factory – Absorption – Distribution – Metabolism – Excretion Pharmacodynamics: study of drug effects on body 1.Dictionary. Merriam-Webster website. Accessed September 27, Pharmacokinetics1-introduction [video]. Handwritten Tutorials website. Accessed September 27,

4 Absorption Absorption rate: time from entry to circulation Bioavailability: percent that reaches circulation IV drug infusion rate determined by characteristics of drug compound drugs with small volume and can be given as a bolus or push (< 3 minutes) negate absorption time Many IV drugs require slow infusion Vancomycin ‘red man syndrome’ if drug given rapidly, more than 1 gram/hr Red man syndrome Red man syndrome. Daily EM website. Accessed September 27,

5 Absorption – Subcutaneous small volume bolus slow absorption rate infusions possible – Intramuscular rate varies according to drug properties absorption rate variable no infusions Insulin pump Services. St Vincent’s Hospital Sydney website. Accessed September 29,

6 Absorption Oral absorption rate has wide variation – drug dissolution time – presence or absence of food – transport time across intestine passive active Goole J, Lindley DJ, Roth W, et al. The effects of excipients on transporter mediated absorption. Int J Pharm 2010;393(1-2): doi: /j.ijpharm Accessed September 27,

7 Absorption Sublingual – rapid Transdermal/topical – slow, systemic or local Rectal – unpredictable rate Inhalation – rapid absorption, local or systemic Other: eye, ear, nose, vaginal – most drugs stay local Delayed release delivery systems – extended-release capsules and tablets – Depot subcutaneous and IM injections A first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website. Accessed September 27,

8 Distribution Time from circulation to target tissue: factors are rate (cardiac output), volume, diffusion model, drug properties. one compartment model (linear kinetics): drug absorbs and distributes quickly, ie bolus IV – molecules less than 10,000 grams/mole diffuse freely through capillaries 8

9 two compartment model: – compartment 1 central circulatory system rapidly perfused tissues and organs – cardiac muscle – brain – lungs – liver – compartment 2 peripheral circulatory sys. deep organs and tissues – skeletal muscle – adipose tissue – skin Distribution Two Compartment Model A first course in pharmacokinetics and biopjharmaceutics website anesthesiologist book 9

10 Distribution three compartment model: drugs dependent on active transport – V 1 circulation and rapidly perfused tissues – V 2 slowly perfused tissues – V 3 third much slower equilibrium compartment Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things

11 Distribution Example of 3 compartment distribution model for transdermal drug delivery system (patch) linked by 2 sets of rate constants. x space coordinate -L outer edge of matrix t time c(x,t) drug concentration m(t) drug mass p diffusivity k 12, k 21, k 23, k 32 microconstants k e elimination rate constant c 0 initial drug concentration in matrix PatchCompartment 2Compartment 1Compartment 3 Gopferich A, et al. Int J Pharm

12 Distribution Compartment% Cardiac Output* (L/h)% Body Weight (body volume, L)** Lung100 (335) 0.8 (0.6) Venous blood100 (335)5.57 (3.9) Arterial blood100 (335)2.43 (1.7) Other rapidly perfused tissue (brain) 38 (127) 83 (58.1) Kidney 19 (64)0.44 (0.3) Slowly perfused tissue (skin, muscle, fat, etc) 18 (60) 5.16 (3.6) 12 Rate of Distribution and Volume of Physiological Compartments *Average cardiac output 335 L/h **Average body weight = 70kg; average body density = 1 L/kg = body volume = 70L

13 Distribution From where to whereTime (seconds) Arm vein to lung5-8 Arm vein to left ventricle6-8 Arm vein to tongue12-15 Arm vein to brain13-20 Foot vein to tongue37-47 Right heart ventricle to ear (at level of brain stem) 8 Arm to foot21-35 Circulation Times 13 Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things

14 Distribution Volume of distribution (VD) – quantifies extent to which drug is present in tissues (extravascular) – hypothetical volume required to contain all drug in tissues at consistent concentration – does not reflect actual plasma or blood volume Image from: Thurber GM, Yang KS, Reiner T, et al. Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat Commun. 2013;4:1504. doi: /ncomms Buxton IL, Benet LZ. Chapter 2. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; Accessed October 2, Absorption of Fluorescent Chemotherapy Drug by Murine Tumor Cells

15 Metabolism Metabolism starts as soon as drug reaches enzymes capable of metabolizing. liver kidney no metabolism proteolytic catabolism – large protein biotech drugs https://elcaminogmi.dnadirect.com/grc/patient-site/psychiatric-drug-response/what-affects-psychiatric-drug-response.html 15

16 Metabolism CYP450 – cytochrome P450 enzyme system – liver and intestines most common sites – P450 enzymes can be inhibited (slowed), induced (sped up) – drugs often compete for same enzyme subgroup 16

17 First-pass metabolism occurs before drug reaches circulation drugs with larger oral vs IV dose – propranolol – morphine Prodrugs enhanced bioavailability avoids first-pass metabolism Metabolism 17

18 Metabolism Half-life: t 1/2 – describes rate drug disappears from plasma – helpful with dosing parameters – exponential decline Example: drug with 11 minute t 1/2 – 1 st 11 minutes concentration drops to 50% – 2 nd 11 minutes concentration drops to 25% – 3 rd 11 minutes concentration drops to 12.5% – 4 th 11 minutes concentration drops to 6.25% Not to be confused with duration of action 18 Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things

19 Metabolism Drug effect does not necessarily relate to t 1/2 drugs that bind irreversibly – omeprazole t 1/ minutes binds irreversibly and inactivates proton pumps on gastric parietal cells body must build new proton pumps before effects of omeprazole completely gone 14 days average time to build a proton pump drugs with atypical metabolism – bevacizumab binds endothelial cells metabolism thought to be proteolysis at endothelial cell t 1/2 20 days 19

20 Excretion Most common routes – kidney diffusion active transport – liver through bile duct into feces Enterohepatic recycling – drug excreted into feces – metabolized in intestine and reabsorbed oral contraceptives 20

21 Excretion Enterohepatic recycling 21

22 Excretion Kidney – some drugs pass through by diffusion (passive transport) – some drugs pass by active transport into kidney tubule – many renally excreted drugs require dose adjustments based on renal function creatinine clearance (CrCl) or glomerular filtration rate (GFR) used to evaluate renal function – declines naturally with age – helpful online calculator: 22

23 Excretion Hemodialysis – small molecules – water soluble drugs – drugs with low protein binding Lungs – excretion of gases – anesthesia – alcohol 23 _procedure_info_details.asp?TPid=8&Type =1#.Ukxyuoasim4 Hemodialysis Schematic

24 C max maximum concentration t max time to maximum concentration Duration of action for this hypothetical drug: time above the minimum effective concentration (MEC) Therapeutic range: concentration above MEC but below maximum tolerated concentration (MTC) Area under curve (AUC) is a function of concentration and time that describes total body exposure to drug Figure 1. International Journal of Impotence Research website. Accessed September 27, Pharmacokinetic parameters describing a typical plasma concentration time profile after an oral administration. Putting It All Together 24

25 Phase 1 Clinical Trials Phase 1 trials determine pharmacokinetics in humans – using animal data extrapolate to humans LD50: dose required to kill 50% of the non-human population no-observed-adverse-effect level (NOAEL) for animals human equivalent dose (HED) of NOAEL is calculated using body surface area (BSA) – dose escalation studies max tolerated dose (MTD) time to max tolerated – other factors determined: frequency route food/drug interactions – healthy volunteers if risk:benefit acceptable Wood LF, Foote M eds. Targeted Regulatory Writing Techniques. Basel, Switzerland:Birkhauser Verlag; Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res

26 Phase 1 Clinical Trials Traditional phase 1 trial design dose escalated until 33% patients exhibit pre- determined toxicity parameter – dose dropped down once to pre/toxic dose and this is called maximum tolerated dose (MTD) – study continues with MTD to determine recommended phase 2 dose (RP2D) and schedule Molecularly targeted agents (MTAs) and non-cancer agents ie biotech – often do not have DLTs – start safe dose according to animal data – escalate until toxicity or molecular-targeted effects seen – this dose is called max administered dose and sets RP2D Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res

27 Resources For more information on pharmacokinetics: – Hand Written Tutorials: – Biopharmaceutics and Pharmacokinetics David W.A. Bourne, B.Pharm., Ph.D. of the University of Colorado Free online textbook – Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things


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