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Pharmacokinetics WebQuest

Pharmacokinetics WebQuest. http:// www.speedlighter.ca/2011/12/25/why-i-shoot-stills/courtney-craig-photo-by-michael-willems /. Kimberly Koon, Pharm. D. BW733 October 1, 2013. Overview. Introduction Absorption IV, SubQ , IM Oral, SL transdermal, rectal, vaginal, inhalation, topical

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Pharmacokinetics WebQuest

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  1. Pharmacokinetics WebQuest http://www.speedlighter.ca/2011/12/25/why-i-shoot-stills/courtney-craig-photo-by-michael-willems/ Kimberly Koon, Pharm. D. BW733 October 1, 2013

  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 • t1/2vs duration of action • Excretion • kidney • liver • enterohepatic recycling • lungs • Time vs. concentration graph

  3. Introduction • Pharmacokinetics: study of how body processesdrugs; thinkreverse-factory • Absorption • Distribution • Metabolism • Excretion • Pharmacodynamics: study of drug effects on body Dictionary. Merriam-Webster website. http://www.merriam-webster.com/dictionary/pharmacokinetics. Accessed September 27, 2013. Pharmacokinetics1-introduction [video]. Handwritten Tutorials website. http://www.handwrittentutorials.com/videos.php?is=79. Accessed September 27, 2013.

  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. http://www.dailyem.wordpress.com/2013/08/06/red-man-syndrome/. Accessed September 27, 2013.

  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. http://www.stvincents.com.au/index.php?option=com_content&task=view&id=751&Itemid=798. Accessed September 29, 2013.

  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):17-31. doi:10.1016/j.ijpharm.2010.04.0419. Accessed September 27, 2013.

  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. http://www.boomer.org/c/pl/index.html. Accessed September 27, 2013.

  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

  9. Distribution • 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 Two Compartment Model A first course in pharmacokinetics and biopjharmaceutics website anesthesiologist book

  10. Distribution • three compartment model: drugs dependent on active transport • V1 circulation and rapidly perfused tissues • V2 slowly perfused tissues • V3 third much slower equilibrium compartment Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

  11. Distribution Example of 3 compartment distribution model for transdermal drug delivery system (patch) linked by 2 sets of rate constants. Patch Compartment 2 Compartment 1 Compartment 3 x space coordinate -L outer edge of matrix t time c(x,t) drug concentration m(t) drug mass p diffusivity k12, k21, k23, k32microconstants ke elimination rate constant c0 initial drug concentration in matrix Gopferich A, et al. Int J Pharm. 1991.

  12. Distribution 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 http://2012.igem.org/Team:Slovenia/ModelingPK

  13. Distribution CirculationTimes Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

  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 Absorption of Fluorescent Chemotherapy Drug by Murine Tumor Cells 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:10.1038/ncomms2506. 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; 2011. http://www.accessmedicine.com/content.aspx?aID=16658120. Accessed October 2, 2013.

  15. Metabolism Metabolism starts as soon as drug reaches enzymes capable of metabolizing. • liver • kidney • no metabolism • proteolytic catabolism • large protein biotech drugs http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf https://elcaminogmi.dnadirect.com/grc/patient-site/psychiatric-drug-response/what-affects-psychiatric-drug-response.html

  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 http://www.boomer.org/c/p4/c07/c0702.html http://www.thebody.com/content/art875.html

  17. Metabolism • First-pass metabolism • occurs before drug reaches circulation • drugs with larger oral vsIV dose • propranolol • morphine • Prodrugs • enhanced bioavailability • avoids first-pass • metabolism http://epharmacology.hubpages.com/hub/Pharmacological-Effects-Prodrugs-Definition-Examples-and-Sources-of-Drug-Information

  18. Metabolism • Half-life: t1/2 • describes rate drug disappears from plasma • helpful with dosing parameters • exponential decline • Example: drug with 11 minute t1/2 • 1st 11 minutes concentration drops to 50% • 2nd 11 minutes concentration drops to 25% • 3rd 11 minutes concentration drops to 12.5% • 4th 11 minutes concentration drops to 6.25% • Not to be confused with duration of action Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

  19. Metabolism Drug effect does not necessarily relate to t1/2 • drugs that bind irreversibly • omeprazole • t1/2 30-60 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 • t1/2 20 days http://www.prilosecotc.com/LocaleData/enUS/Assets/Documents/Monograph.pdf http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf

  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 http://www.boomer.org/c/p4/c16/c1604.html

  21. Excretion • Enterohepatic recycling http://www.boomer.org/c/p4/c16/c1604.html

  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: www.globalrph.com http://www.boomer.org/c/p4/c16/c1604.html

  23. Excretion • Hemodialysis • small molecules • water soluble drugs • drugs with low protein binding • Lungs • excretion of gases • anesthesia • alcohol Hemodialysis Schematic http://www.medbroadcast.com/test_and _procedure_info_details.asp?TPid=8&Type =1#.Ukxyuoasim4 http://www.boomer.org/c/p4/c16/c1604.html

  24. Putting It All Together Pharmacokinetic parameters describing a typical plasma concentration time profile after an oral administration. • Cmax maximum concentration • tmax 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. www.nature.com/ijir/journal/v19/n3/fig_tab/3901522f1.html. Accessed September 27, 2013.

  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 Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res. 2010 Wood LF, Foote M eds. Targeted Regulatory Writing Techniques. Basel, Switzerland:BirkhauserVerlag; 2009.

  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. 2010

  27. Resources • For more information on pharmacokinetics: • Hand Written Tutorials: http://www.handwrittentutorials.com/ • Biopharmaceutics and Pharmacokinetics • David W.A. Bourne, B.Pharm., Ph.D. of the University of Colorado • Free online textbook http://www.boomer.org/c/p4/#topics • Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

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