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

Overview Introduction Metabolism Absorption Excretion Distribution sites, CYP450, first-pass, pro-drugs IV, SubQ, IM t1/2 vs duration of action Oral, SL Excretion transdermal, rectal, vaginal, inhalation, topical kidney Distribution liver models enterohepatic recycling lungs % cardiac output Time vs. concentration graph Vd

Introduction Pharmacokinetics: study of how body processes drugs; think reverse-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.

Absorption Absorption rate: time from entry to circulation Kimberly Koon 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 Various types of administration routes and what affects absorption rates Red man syndrome Red man syndrome. Daily EM website. http://www.dailyem.wordpress.com/2013/08/06/red-man-syndrome/. Accessed September 27, 2013.

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.

Absorption Oral absorption rate has wide variation Kimberly Koon Absorption Oral absorption rate has wide variation drug dissolution time presence or absence of food transport time across intestine passive active Calcium (>800mg and quinolones) iron zinc grapefruit 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.

Absorption Sublingual – rapid Kimberly Koon 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 SL – good blood supply A first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website. http://www.boomer.org/c/pl/index.html. Accessed September 27, 2013.

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

Distribution two compartment model: compartment 2 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

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

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, k32 microconstants ke elimination rate constant c0 initial drug concentration in matrix Gopferich A, et al. Int J Pharm. 1991.

% Cardiac Output* (L/h) % Body Weight (body volume, L)** Distribution Rate of Distribution and Volume of Physiological Compartments Compartment % Cardiac Output* (L/h) % Body Weight (body volume, L)** Lung 100 (335) 0.8 (0.6) Venous blood 5.57 (3.9) Arterial blood 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) *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

Distribution Circulation Times From where to where Time (seconds) Arm vein to lung 5-8 Arm vein to left ventricle 6-8 Arm vein to tongue 12-15 Arm vein to brain 13-20 Foot vein to tongue 37-47 Right heart ventricle to ear (at level of brain stem) 8 Arm to foot 21-35 Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

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.

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

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

Metabolism First-pass metabolism Prodrugs occurs before drug reaches circulation drugs with larger oral vs IV 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

Metabolism Half-life: t1/2 Not to be confused with duration of action 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

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

Excretion Most common routes Enterohepatic recycling kidney liver 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

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

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

Excretion Hemodialysis Lungs 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

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.

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:Birkhauser Verlag; 2009.

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

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