2 Overview Introduction Metabolism Absorption Excretion Distribution sites,CYP450, first-pass, pro-drugsIV, SubQ, IMt1/2 vs duration of actionOral, SLExcretiontransdermal, rectal, vaginal, inhalation, topicalkidneyDistributionlivermodelsenterohepatic recyclinglungs% cardiac outputTime vs. concentration graphVd
3 IntroductionPharmacokinetics: study of how body processes drugs; think reverse-factoryAbsorptionDistributionMetabolismExcretionPharmacodynamics: study of drug effects on bodyDictionary. Merriam-Webster website. Accessed September 27, 2013.Pharmacokinetics1-introduction [video]. Handwritten Tutorials website. Accessed September 27, 2013.
4 Absorption Absorption rate: time from entry to circulation Kimberly KoonAbsorptionAbsorption rate: time from entry to circulationBioavailability: percent that reaches circulationIV drug infusion rate determined by characteristics of drug compounddrugs with small volume and can be given as a bolus or push (< 3 minutes) negate absorption timeMany IV drugs require slow infusionVancomycin ‘red man syndrome’if drug given rapidly, more than1 gram/hrVarious types of administration routes and what affects absorption ratesRed mansyndromeRed man syndrome. Daily EM website. Accessed September 27, 2013.
5 Absorption Subcutaneous small volume bolusslow absorption rateinfusions possibleIntramuscular rate varies according to drug propertiesabsorption rate variableno infusionsInsulin pumpServices. St Vincent’s Hospital Sydney website.Accessed September 29, 2013.
6 Absorption Oral absorption rate has wide variation Kimberly KoonAbsorptionOral absorption rate has wide variationdrug dissolution timepresence or absence of foodtransport time across intestinepassiveactiveCalcium (>800mg and quinolones) iron zincgrapefruitGoole 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: /j.ijpharm Accessed September 27, 2013.
7 Absorption Sublingual – rapid Kimberly KoonAbsorptionSublingual – rapidTransdermal/topical – slow, systemic or localRectal – unpredictable rateInhalation – rapid absorption, local or systemicOther: eye, ear, nose, vaginal – most drugs stay localDelayed release delivery systemsextended-release capsules and tabletsDepot subcutaneous and IM injectionsSL – good blood supplyA first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website.Accessed September 27, 2013.
8 DistributionTime 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 IVmolecules less than 10,000 grams/mole diffuse freely through capillaries
9 Distribution two compartment model: compartment 2 compartment 1 central circulatory systemrapidly perfused tissues and organscardiac musclebrainlungslivercompartment 2peripheral circulatory sys.deep organs and tissuesskeletal muscleadipose tissueskinTwo CompartmentModelA first course in pharmacokinetics and biopjharmaceutics websiteanesthesiologist book
10 Distributionthree compartment model: drugs dependent on active transportV1 circulation and rapidly perfused tissuesV2 slowly perfused tissuesV3 third much slower equilibrium compartmentWoerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things
11 DistributionExample of 3 compartment distribution model for transdermal drug deliverysystem (patch) linked by 2 sets of rate constants.Patch Compartment 2 Compartment 1 Compartment 3x space coordinate-L outer edge of matrixt timec(x,t) drug concentrationm(t) drug massp diffusivityk12, k21, k23, k32 microconstantske elimination rate constantc0 initial drug concentration in matrixGopferich A, et al. Int J Pharm
12 % Cardiac Output* (L/h) % Body Weight (body volume, L)** DistributionRate of Distribution and Volume of Physiological CompartmentsCompartment% Cardiac Output* (L/h)% Body Weight (body volume, L)**Lung100 (335)0.8 (0.6)Venous blood5.57 (3.9)Arterial blood2.43 (1.7)Other rapidly perfused tissue (brain)38 (127)83 (58.1)Kidney19 (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
13 Distribution Circulation Times From where to where Time (seconds) Arm vein to lung5-8Arm vein to left ventricle6-8Arm vein to tongue12-15Arm vein to brain13-20Foot vein to tongue37-47Right heart ventricle to ear (at level of brain stem)8Arm to foot21-35Woerlee 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 drugin tissues at consistent concentrationdoes not reflect actual plasma or blood volumeAbsorption of Fluorescent Chemotherapy Drug byMurine Tumor CellsImage from: Thurber GM, Yang KS, Reiner T, et al.Single-cell and subcellular pharmacokineticimaging allows insight into drug action in vivo. Nat Commun. 2013;4:1504.doi: /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; Accessed October 2, 2013.
15 MetabolismMetabolism starts as soon as drug reaches enzymes capable of metabolizing.liverkidneyno metabolismproteolytic catabolismlarge protein biotechdrugs
16 Metabolism CYP450 – cytochrome P450 enzyme system liver and intestines most common sitesP450 enzymes can be inhibited (slowed), induced (sped up)drugs often compete for same enzyme subgroup
17 Metabolism First-pass metabolism Prodrugs occurs before drug reaches circulationdrugs with larger oral vs IV dosepropranololmorphineProdrugsenhanced bioavailabilityavoids first-passmetabolism
18 Metabolism Half-life: t1/2 Not to be confused with duration of action describes rate drug disappears from plasmahelpful with dosing parametersexponential declineExample: drug with 11 minute t1/21st 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 actionWoerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things
19 Metabolism Drug effect does not necessarily relate to t1/2 drugs that bind irreversiblyomeprazolet1/ minutesbinds irreversibly and inactivates proton pumps on gastric parietal cellsbody must build new proton pumps before effects of omeprazole completely gone14 days average time to build a proton pumpdrugs with atypical metabolismbevacizumab binds endothelial cellsmetabolism thought to be proteolysis at endothelial cellt1/2 20 days
20 Excretion Most common routes Enterohepatic recycling kidney liver diffusionactive transportliverthrough bile duct into fecesEnterohepatic recyclingdrug excreted into fecesmetabolized in intestine and reabsorbedoral contraceptives
22 ExcretionKidneysome drugs pass through by diffusion (passive transport)some drugs pass by active transport into kidney tubulemany renally excreted drugs require dose adjustments based on renal functioncreatinine clearance (CrCl) or glomerular filtration rate (GFR) used to evaluate renal functiondeclines naturally with agehelpful online calculator:
23 Excretion Hemodialysis Lungs small molecules water soluble drugs drugs with low protein bindingLungsexcretion of gasesanesthesiaalcoholHemodialysis Schematic_procedure_info_details.asp?TPid=8&Type=1#.Ukxyuoasim4
24 Putting It All Together Pharmacokinetic parameters describing a typical plasma concentration time profile afteran oral administration.Cmax maximum concentrationtmax time to maximum concentrationDuration 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 drugFigure 1. International Journal of Impotence Research website.Accessed September 27, 2013.
25 Phase 1 Clinical TrialsPhase 1 trials determine pharmacokinetics in humansusing animal data extrapolate to humansLD50: dose required to kill 50% of the non-human populationno-observed-adverse-effect level (NOAEL) for animalshuman equivalent dose (HED) of NOAEL is calculated using body surface area (BSA)dose escalation studiesmax tolerated dose (MTD)time to max toleratedother factors determined:frequencyroutefood/drug interactionshealthy volunteers if risk:benefit acceptableIvy SP, Siu LL, Garrett-Mayer E, Rubinstein L. ClinCancer Res. 2010Wood LF, Foote M eds. Targeted Regulatory WritingTechniques. Basel, Switzerland:Birkhauser Verlag; 2009.
26 Phase 1 Clinical Trials Traditional phase 1 trial design dose escalated until 33% patients exhibit pre-determined toxicity parameterdose 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 scheduleMolecularly targeted agents (MTAs) and non-cancer agents ie biotechoften do not have DLTsstart safe dose according to animal dataescalate until toxicity or molecular-targeted effects seenthis dose is called max administered dose and sets RP2DIvy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res. 2010
27 Resources For more information on pharmacokinetics: Hand Written Tutorials:Biopharmaceutics and PharmacokineticsDavid W.A. Bourne, B.Pharm., Ph.D. of the University of ColoradoFree online textbookWoerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things