PK II: Exam 1

therapeutic drug range

used to determine the safety and effectiveness of a drug

digoxin therapeutic range

*Between 0.5-2 ng/ml or microg/L* • >2 ng/ml toxicity 1. Afib: • Upper end 1.0-2.0 ng/ml 2. CHF pts • Lower end: 0.5-0.8 ng/ml • U/L recently dec. from 1.0 ng/mL (no additional benefit, > 1.2 ng/mL considered harmful)

Quadrupole Mass Spectrometer

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digoxin metabolism

-75% digoxin is excreted unchanged -25% as metabolites -Considerable metabolism in the GI tract -Converts to 3-keto and 3-epi digoxigenin in liver followed by conjugation -Metabolites are more polar -Digoxin is a prototypical P-gp substrate

magnetic sector mass spectrometer

-A device that separates gaseous ions that have the same kinetic energy by passing them through a magnetic field perpendicular to their velocity. -Trajectories of ions w a certain mass-to-charge ratio are bent exactly enough to reach the detector. Other ions are deflected too much or too little.

tx for digoxin toxicity

-A life threatening situation -Treated by using a lyophilized powder of antigen binding fragments: digibind -Digibind is anti-digoxin antibodies raised in sheep -binding of antibody to digoxin stops it from binding to its biological target and reduces toxicity

levothyroxine therapeutic equivalence example

-AB represents various brands. -levothyroxine Mylan is AB1-4 so it can replace 4 different brands. •Synthroid is AB1/2 •Levo-T is AB1/2/3 •Levoxyl is AB1/3 •Levothroid is AB4 -levothyroxine Mylan is AB1-4 so it can replace 4 -however, levothyroxine Merck is AB2/3 -and Unithroid is AB1-3 -The Brands in this list are Synthroid /LevoT /Levoxyl / Levothroid/ Unithroid -Since levothyroxine Mylan is AB1-4 it can replace any of these Brands -However, levothyroxine Merck cannot replace levothroid AB4 -Levothroid can ONLY be replaced by levothyroxine Mylan since levothroid is an AB4 drug

uses of digoxin

-CHF -Afib -Paroxysmal Supraventricular Tachycardia (PSVT)

Vincent Van Gogh and foxglove toxicity

-physical imbalance -tinnitus (in his good ear) -Xanthopsia: a visual disturbance in which all objects appear yellow; visible in Van Gogh's paintings -vertigo & dizziness -visual disturbances -depression -suicide

thymoglobulin & ATGAM

-polyclonal antibodies (rabbit, equine) -induction therapy

balancing risk of TDM in immunosuppression

-risk of organ rejection vs. risk of opportunistic infection

MDRD advantages vs. disadvantages

Advantages -Validated equation -GFR measured by iothalamate assay -May be slightly > accurate than Cockroft-Gault -Accts for gender & certain ethnicities disadvantages: -Hasn't been tested/validated in all groups, including healthy individuals, children (<18YO), & elderly (>70YO) -Nutritional status and med use are not accounted for -Not accurate in acute renal failure -MDRD equation gives an estimate of GFR...intended for staging CKD pts (GFR <60 mL/min) -Should NOT to be used for drug dosing until further studies are conducted.

biopharmaceutics

As defined by Levy in 1961: -biopharmaceutics is "the study of the relationship b/w some of the physical and chemical properties of a drug & its dosage form & the biological effects observed following its admin in man & animals" -Biopharmaceutics is the study of the factors that influence Bioavailability -The essential goal of biopharmaceutical studies is to optimize the biological response of drug products

Vdss

IV: cl x MRT EV: Cl x MRT

generic drug review

• Abbreviated New Drug Application (ANDA) vs. NDA • Drug company must show the generic drug is "bioequivalent" to the brand-name drug • Active ingredient works in the same way • Active ingredient works in the same amount of time -comparable PK

sirolimus absorption

• Absorption -Tmax value ~1 hour (CV = 86%) • Bioavailability ~ 14% in stable renal availability transplant pts • Dose-proportionality: Cmax and AUC linear over 1-12 mg/m2 in stable renal transplant pts

mycophenolic acid metabolism

• After admin, mycophenolic mofetil is rapidly converted to mycophenolic acid by esterases (CES1, CES2) • MPA is glucuronidated by UGT1A1 and 1A9 to MPA-glucuronide and plasma conc of MPAG is several fold > conc MPA • MPAG can undergo entrohepatic re-circulation in the gut resulting in the secondary peak of MPA in the conc. time profile

noncompartmental analysis

• Also called - Model independent analysis - Compartment model free • NCA is based on algebraic equations • Compartmental analysis are based on linear and non-linear diff. equations • Compartmental analysis is old fashioned but useful for prediction and simulation why use it? -Requires fewer assumptions than compartmental analysis -Body consists of many compartments -1, 2, or 3 compartmental models are not physiologically meaningful -not always feasible to obtain frequent enough blood samples to correctly determine the number of compartments

amiodarone

• Amiodarone is an anti-arrhythmic agent • FDA approved for tx of ventricular arrhythmias • Discovered in 1961 & initially used as anti‐anginal agent • Considered a class III antiarrhythmic: K+ channel blocker • Delays repolarization thereby prolonging the refractory period during a heart beat -Lengthens cardiac AP which slows conduction -contains iodine which can cause thyroid toxicities

cyclosporine A

• An 11-amino acid cyclic peptide -still considered small molecule • Inhibits the production of interleukin IL-2 by helper T-cells • It is effective both in the prevention and in the treatment of ongoing acute rejection

maintaining an allograft

• At least 3 immuno-suppressive agents • Meds for co-morbidities -Bacterial/fungal infections -BP - Hyperlipidemia - Depression - ED

mycophenolate mofetil

• Dose: 1-1.5g BID • DI: -acyclovir, ganciclovir, probenecid, antacids, cyclosporine • ADR: N/V/D, gastritis, dyspepsia, myelo-suppression • may cause teratogenic effects in women transplant recipients • No evidence of teratogenicity in male transplant recipients fathering a child

cyclosporine AE

• HTN • Renal dysfxn • Hirsutism • Hyperkalemia • Gingival hyperplasia • Hypomagnesemia

brand vs. generic drugs

• Brand-name drug -supplied by one drug company -sold under drug company's trademarked name • Generic drug -may be supplied by more than one company -may be sold under active ingredient(s) name(s)

equations at steady state

• Constant infusion Css=dose rate/ Cl • Oral Css= [F*(Dose/tau)] /Cl • Dose change DOSEnew =(Cssnew/Cssold) * DOSEold

drugs which are candidates for TDM

• Cyclosporine and other immunosuppressive agents • Phenytoin, CBZ, phenobarbital and other anti-epileptic drugs. • Digoxin, procainamide, lidocaine and other CV drugs. • Lithium • Gentamicin, tobramycin and other AGs • Vancomycin • Drugs during toxicity • PD monitoring: anti-coagulants

sirolimus DI

• Cyclosporine, tacrolimus and sirolimus are substrate for CYP3A4 and P-gp • Many DIs exist that are very important to consider by pharmacists in dispensing, counseling or TDM inhibitors of 3A4: -macrolides -CCBs -azole antifungals -PPIs -cimetidine, grape fruit juice inducers of 3A4: -phenytoin -Phenobarb -CBZ -rifampin -dexamethasone -prednisone -octreotide -st. johns wort

amiodarone ADR

• Dose‐related: more at > doses • Occur more w longer durations of therapy • Common: bradyarrhythmia, hypotension, constipation, loss of appetite, N/V, abnormal gait, coordination problems, involuntary movement, peripheral neuropathy, fatigue or malaise • OD: Bradycardia, heart block, torsades de pointes, hypotension, & optic, respiratory, neurologic, hepatic, musculoskeletal, & endocrine toxicities

methods for assessing bioavailability

• Drug conc in blood, plasma or serum -most direct approach -conc of active drug -Tmax, Cmax and AUC -analytical methods must be sensitive, selective and specific (FDA guidance) • Urinary drug excretion -cum. amt of drug excreted in urine (Du) -rate of drug excretion in urine (dDu/dt) -the time for max urinary excretion

definition of pharmaceutical equivalent

• Drug products are pharmaceutical equivalents if they meet these 3 criteria: -contain the same active ingredient(s) -same dosage form and route of admin -identical in strength or concentration • Pharmaceutically equivalent drug products may differ in characteristics such as -shape -release mechanism -labeling (to some extent) -scoring -excipients (colors, flavors, preservatives)

amiodarone distribution

• Extensive: into adipose, hepatic, myocardial, pulmonary, kidney, thyroid, skin, ocular, splenic, and pancreatic tissue -Highly lipophilic -Can be distributed in saliva, semen, breast milk & bile -Metabolite has similar distribution -Tissue distribution = 10‐400x plasma levels • Vd = 70 L/kg

amiodarone metabolism

• Extensively metabolized by the liver: CYP3A4 & 2C8 • Major active metabolite: N‐desethyl‐amiodarone (DEA) -similar distribution -May take a few days of continuous IV to see blood levels accumulate -May eventually equal same levels of amiodarone • Minor metabolite: -Bis‐N‐desethyl‐amiodarone -Deiodinated metabolites

new immunosuppressive agents

• FTY-720 or Fingolimod (Novartis, failed in transplantation, developed for MS) • Tofacitinib (Pfizer, failed in transplantation, developed for RA) • Leflunomide (Astellas, development was d/c in transplant) • Bortezomib (FDA approved in Multiple Myeloma, off label use in transplant)

maintenance immunosuppression

• General Guidelines for Combo Immuno-suppressive Therapy: -Primary + Secondary +/- Tertiary • Primary: Calcineurin Inhibitors • Cyclosporine • Tacrolimus mTOR Inhibitor • Sirolimus • Secondary: Inhibitors of T-Cell Proliferation • Azathioprine • Mycophenolate mofetil • EC mycophenolic acid Inhibitors of Late T-Cell Fxn • Sirolimus • Tertiary: Non-specific: -Corticosteroids

FDA generic drug regulations & guidelines

• Hatch-Waxman Act, or the Patent Term Restoration Act of 1984 -Loopholes in the act prevent generic competition • President's 2003 budget increased FDA's funding to speed up generic drug reviews (more reviewers, etc.) • FDA-CDER website (guidance to the industry) -Statistical approaches to establishing bioequivalence • Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs —General Considerations • USP

cyclosporine & plasma protein binding

• Highly bound (>99%) to HDL, VLDL, blood & plasma components • Predominantly bound LDL 12% to plasma lipoproteins • Unbound fraction = 1% -cyclosporine unbound fraction is a better predictor of organ rejection than total conc.; -low unbound fraction correlated w rejection

statistical eval. of PK data

• Hypothesis -2 forms are BE if the rate & extent of absorption differ only by -20% to +25% (a 45% variance) • 90% CI • 2 one sided test at the P=0.05 level • log transformation of data -why transform? PK data (AUC & Cmax) is not distributed normally -cannot use T test in the case of abnormal distribution • Geometric mean

IV admin of amiodarone

• IV: thru central line -Loading: rapidly infuse 150mg in 100mL (1.5 mg/mL) over 10min • Infusion rate: 15 mg/min -Maintenance: 360 mg / 6H followed by 540mg /18H • Total of 900mg in 500mL spread throughout these 24H -Initial rate: 1 mg/ min for initial 360mg -Then: 0.5 mg/min for 540mg

tacrolimus absorption

• Incomplete & variable -Absolute bioavailability ~ 20% • Effect of food -rate & extent of tacrolimus absorption is greatest under fasted conditions. -presence and composition of food ↓ both the rate & extent of tacrolimus absorption when admin to 15 healthy volunteers -diarrhea = higher absorption

stages of medical immunosuppression

• Induction Therapy -monoclonal Abs injected throughout transplant surgery and for a few days after • Maintenance Therapy • Anti Rejection Therapy (Reversal of Established Rejection) -methyl-prednisolone at very high doses w long taper

PK summary: cyclosporine

• Linear PK • Bioavailability: 30% • Vd: 4-5 L/kg • Cl: 5-10 mL/min/kg • Half life: 6-12 hr • Unbound fraction: 1-2%

sirolimus metabolism and elimination

• Metabolism: Substrate for intestinal and hepatic CYP3A4 • 7 major metabolites • Elimination: -91% GI -2.2% renal • Terminal half-life ~ 62 hours -Loading dose will dec time to SS

cyclosporine metabolism

• Metabolized extensively by liver (CYP3A4 ) • Mean t1⁄2 6h • Subject to gut metabolism &/or P-gp • Eliminated mainly in bile • Elimination not affected by renal impairment • Cyclosporine is not dialyzable

tacrolimus side effects

• Nephrotoxicity • Neurotoxicity • Dizziness • New Onset Diabetes after Transplant (NODAT): unknown mechanism

purpose of bioavailability studies

• New formulation of drugs must be approved by the FDA • FDA requires that the drug product is safe and effective (clinical & PK studies) • To ensure these standards are met FDA requires bioavailability/PK study -Measure of bioavailability: AUC/dose, Cmax, Tmax -Absolute bioavailability -Relative bioavailability remember... • bioavailability = Fraction of the drug dose that reaches the systemic circulation, compared with IV injection • indicates measurement of both the rate & extent of drug absorption that reaches the general circulation from an administered dosage form • Bioequivalence=relative bioavailability • Absorption: -favoured by lipid soluble drugs 1st pass metabolism: • drugs absorbed into the portal circulation • some are extensively metabolised as they pass thru the liver (e.g. lignocaine)

cyclosporine absorption

• PO bioavailability is highly variable (~25%) • PO absorption is erratic, incomplete, and dependent on food & bile (mostly for non-emulsified formulation) Cyclosporine microemulsion (Neoral) • For the microemulsion absorption 20-50% >> conventional formulation. • Microemulsion absorption < affected by food or bile

amiodarone admin

• PO or IV • Onset may be delayed up to 2‐3mo. if admin PO w/o loading dose -May take 1‐5mo. to reach SS • That is why IV used in emergency situations or loading doses initiated

why monitor plasma drug concentrations?

• Prevent toxicity • Optimize dose/therapeutic response • Detect changes in PK -Absorption -Drug interactions • Monitor compliance

relative bioavailability

• Relative or apparent bioavailability is the avail. of a drug from a drug product (e.g. a new form) in comparison to a recognized standard (reference)

bioavailability study design

• Scientific question to be answered • nature of reference material and dosage form to be tested • availability of analytical methods • risk / benefit for testing in humans -IRB of the clinical facility

TDM assay requirements

• Sensitivity -Micro gram, nano gram, pico gram • Specificity - Lack of cross reactivity w metabolites • Linearity & conc range • Precision • Accuracy • Robustness (rapid turnaround time)

TDM and amiodarone?

• Several studies showed correlation between plasma conc. of amiodarone & N‐desethyl‐amiodarone w clinical effects • Trough, SS conc ranging from 0.8-2.8 mg/L for amiodarone & 0.3-1.3 mg/L for N‐desethyl‐amiodarone • AE have been reported at conc. of 2.6 mg/L for amiodarone & 2 mg/L for N‐desethyl amiodarone • Serious AE (i.e. pulmonary tox.) was not assx w conc. of amiodarone • Currently, routine TDM of amiodarone is NOT rec.

bioequivalence study designs

• Single-dose, 2-way crossover, fasted • Single-dose, 2-way crossover, fed • Alternatives -Single-dose, parallel, fasted -Single-dose, replicate design -Multiple-dose, 2-way crossover, fasted -Clinical endpoint study -crossover best tho

elimination rate constant

• Slope of the terminal portion of the conc time curve = lnCp1 - lnCp2 / t1 - t2 -natural log used to linearize data Estimation by linear regression: • Calculation of slope using a linear regression analysis is a preferred method. -Calculator w regression analysis -Microsoft Excel Worksheet -PK software

AUC

• Statistical moment analysis • Linear trapezoidal rule -sum of individual areas • Remaining portion of the AUC (AUCt-∞) • AUC(all) (sum of the 2) = Σ[(Cn + Cn+1) / 2] x (tn+1 - tn) AUCt-∞ = C(last) / kel

TDM and maintenance immunosuppression

• TDM is an integral part of maintenance immunosuppressive therapy • Aimed at -Optimizing dose for an individual pt -Monitor adherence -Prevent side effect d/t DIs

cyclosporine TDM

• Total trough conc of cyclosporine (Ctotal) in whole blood is routinely monitored following organ transplant to allow dose individualization -Immunoassay (non-specific) -HPLC (laborious) -LC-MS/MS • Ctotal does not correlate w clinical outcomes i.e. rejection, infection side effects • Some European Centers monitor conc at 2-hour post dose

liver metabolism in CKD

-Despite the common belief, CYP3A4 mediated drug metabolism can be affected by kidney dysfunction

CRRT

-Different from intermittent hemodialysis -Rely heavily on continuous ultrafiltration of plasma water, CRRT has the potential for the removal of large quantities of ultrafilterable drugs contained in plasma. -Ultrafiltration rate is driving force for drug removal (range 10-50 mL/min) -Hemofilters allow passage of larger MW drugs (up to 5000 Da) -Drugs w large Vd are not likely to be removed by CRRT

digoxin absorption

-Absorbed passively from upper part of SI -No significant first pass effect -PO bioavailability (F) ranges from 0.5 - 0.9 (average ~ 0.7) -Food dec. rate, but NOT extent of absorption -Bioavailability is dec. w co-admin: -Charcoal, Antacids -Cholestyramine, Kaolin-pectin, Metoclopramide

NTI

-Aka critical-dose drugs -NTI drugs are defined as those drugs where small differences in dose or blood conc may lead to dose & blood conc dependent, serious therapeutic failures or adverse drug rxns. -Serious events are those which are persistent, irreversible, slowly reversible, or life-threatening, possibly resulting in hospitalization, disability, or even death

elimination of water soluble molecules vs. non water soluble molecules

-All water soluble molecules are eliminated by the kidneys -All non water soluble molecules are eliminated in bile or metabolized to more water soluble forms that are then renally eliminated -Look for xLogP value of a compound; logP is the partition coefficient between polar and non polar environments -example: naphthalene, high logP (3.3) will prefer octanol layer, whereas glucose, low logP (-2.2) will prefer the water layer

AB is a 45-year-old male with newly diagnosed Afib. He is 70kg, 70" and his SCr is stable at 0.9 mg/dL. You are asked to calculate an IV loading dose and a maintenance dose for AB.

-B/c conc range for AF is b/w 1-2 ng/mL, use 1.5 ng/mL for calcs: LD = Vd*Cp/ F = (6.55 L/kgx70 kg)x(1.5µg/L/1) = 687.5g -Round to 675µg -Loading doses for digoxin are always admin. in divided doses so that the pt can be eval. for tox. & efficacy. -doses are usually separated by 4-6H: -50% at first followed by 2 doses of 25%. -Therefore, an initial dose of 350µg is given first, followed by 2 doses of 175µg and 150µg. -assume desired avg. SS conc of 1.5 µg/L calculate a digoxin maintenance dose (tau=1 day, F=1) -Make sure you convert the time and vol. units (i.e.: ml/min to L/hr)

C&G equation vs. MDRD

-C&G equation was developed in 1973 from 249 men w CrCl b/w 30-130 mL/min -It systematically overestimates GFR d/t tubular secretion of Cr and is not normalized for BSA Modification of Diet in Renal Disease (MDRD)* -Developed in 1999 using data from 1628 pts w chronic renal dz GFR (mL/min/1.73 m2) = 186 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African-American)

glomerular filtration rate

-CKD is a public health problem -dec. kidney fxn influences the elimination of renally eliminated drugs, therefore results in the inc. risk of ADRs -Initial dosing or dose adjustment of renally eliminated drugs is often based on the estimated GFR therefore accurate estimation of GFR is very important

Drug Dosing: Hemodialysis

-CSS peak at start of diagram; -pre dialysis: little peak where line turns green -post dialysis: trough (give replacement dose) also consider type of dialyzer: -Standard / Conventional Dialyzers -High-Flux Dialyzers (Kuf >8 mL/hr/mmHg)

package inserts & PK

-Describe "relevant" PK info obtained during drug development & (sometimes) clinical practice -Provides info about dosing and possible interactions -info is checked by independent scientists & government regulators -Published PK studies -Specific research aim to investigate a hypothesis -May involve studies in vitro, animals (i.e. rats), humans (healthy subjects and pts) -Quality & relevancy issues need to be addressed -Conducted by researchers in Pharmaceutical companies, Universities, Hospitals and research centers -Usually peer-reviewed by independent scientists

digoxin MOA

-Direct positive inotropic -Binds to & interferes w Na-K-ATPase complex --this pump uses ATP to excrete Na & bring K+ into the cell -remember, Na conc in bood is 70x > conc of K -Affects intracellular Ca++ conc: inc contractibility -Slows conduction through AV node -More effective & toxic in hypokalemia

pharmaceutical alternatives

-Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, but are diff. salts, esters, or complexes of that moiety, or are different dosage forms or strengths (e.g., tetracycline HCl, 250mg caps vs. tetracycline phosphate complex, 250mg caps; quinidine sulfate, 200mg tabs vs. quinidine sulfate, 200mg caps). -Data are generally not avail. for FDA to make the determination of tab to cap bioequivalence. -Diff. dosage forms and strengths w/in a product line by a single manufacturer are thus pharmaceutical alts, as are ER products when compared w IR or standard-release forms of the same active ingredient." -Pharmaceutical alts are drug products that can provide the same therapeutic moiety. -Diff. dosage forms, doses & even salts can be pharmaceutical alts.

therapeutic equivalence

-Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents & if they can be expected to have the same clinical effect and safety profile when admin. to pts under the conditions specified in the labeling. • contain identical amts of the same active drug ingredient in the same dosage form & route • meet compendial or other applicable standards of strength, quality, purity, and identity • they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard • they are adequately labeled • they are manufactured in compliance with Current Good Manufacturing Practice regulations --Orange Book lists therapeutic equivalencies

goal of TDM

-For a limited number of drugs where there is a better relationship b/w plasma or blood conc & response than between dose & response, the conc measurement has become a valuable surrogate index of drug exposure. -It is the goal of TDM to optimize a pt's clinical outcome by managing their med regimen w the assistance of measured drug conc"

pre-dialysis drug dosing in CKD

-For drugs that rely on the kidney for elimination from body (>30%), drug dose adjustment is generally recommended. -underlying PK model is: Cl = (S)(F)(dose/tau) / Cpss -Maintenance Dose = Cpss * CL -Thus, estimation of the drug's renal CL must be based on CrCl for renally cleared drugs

evaluation of glomerular function

-Gold standard (important) -Contrast media agents like inulin, Iohexol or iothalamate for exact determination of GFR (i.e. 10 mL iohexol iv followed by collection of blood sample at 2, 3 and 4 hours post dose) A. Serum creatinine B. CrCl -Measured (24h, inaccurate) -CLcr=(Ucr*Vol)/(Scr*time) C. Estimated creatinine clearance Cockcroft-Gault (CG) equation CLcr (mL/min) = [(140-Age) x Wt / (Scr x 72)] x 0.85 if female

digoxin & suboptimal clinical response

-Hyperkalemia -Uncorrected hyperthyroidism -Interacting drugs that delay or prevent PO absorption: i.e., Antacids, Cholestyramine, Metoclopramide

factors predisposing a pt to digoxin toxicity

-Hypokalemia -Hypomagnesemia -CAD -Cor pulmonale -Uncorrected hypothyroidism -Renal dysfunction -Interacting drugs that dec. digoxin clearance (quinidine, spironolactone, and verapamil) ---digoxin is a Pgp substrate

digoxin toxicity

-In the US: Approx 0.4% of all hospital admissions, 1.1% of outpts on digoxin, and 10-18% of nursing home pts develop toxicity. -Morbidity is usually 4.6-10% -morbidity is 50% if the digoxin level > 6 ng/ mL -Advanced age (>80YO) is an independent risk factor and is assx w inc morbidity & mortality •Narrow TI (effective vs. toxic) -Elderly -Renal impairment -Electrolyte abnormalities: High K, high Ca & low Mg -Drug interactions

hepatic dz and liver fxn assessment

-Liver is responsible for many physiological processes and metabolism of endogenous and exogenous compounds -Typically lipophilic compounds are metabolized to metabolites that are more water soluble and then excreted via bile or kidneys -Liver impairment may dec. the metabolism of some drugs

sirolimus dosing

-Loading dose: 6 mg. -Maintenance dose: rec. dose is 2 mg/d. • Trough levels: 3.0 - 18.0 ng/ml, often depends on immunosuppressive regimen. • Interactions: CYP 3A4 substrate • ADR: hyperlipidemia (mostly TG's), mouth ulcers, inhibits wound healing, elevated LFTs, thrombocytopenia, leukopenia, anemia, N/V/D

mean residence time

-MRT = AUMC / AUC -After drug admin, each drug molecule spends a different length of time in the body. -Some will be eliminated almost immediately via metabolism and some will stay in the body for a long time; i.e. deposited in tissues. -MRT describes the average time for all the drug molecules to reside in the body. why? -t1/2 hard to calc if you don't have k, also doesn't work for nonlinear PK. -MRT defines how long each drug molecule (on average) spends in the body. -drugs that partition into tissues stay longer; the % relinquished to first pass spends no time in the body

electron multiplier

-Most common MS detector; analogous to a photomultiplier tube; ions strike cathode, emitting multiple electrons; each secondary electron strikes a series of intermediate dynodes held at successively higher voltages; current gain of 107 possible.

factors affecting sirolimus PK

-No significant difference b/w Black & Non-Black pts High-fat meal -Cmax ↓ 64% -Tmax ↑ Fourfold -AUC ↑ 35% -Oral Soln & Tabs should be taken consistently w or w/o food Hepatic impairment -Cmax & Tmax unchanged -T1/2 ↑ 43% -CL/F ↓ 33%

generic substitution of NTI drugs

-Overall, pt, pharmacist, and physician have a great concerns on the use of generic NTIs • Physicians caring for epileptic pts: • 606 physicians responded to survey • 88% concerned about breakthrough seizures with formulation switch (65% had seen this occur) • 55% prescribed AED "brand only" examples of NTI's: • NTI drugs include warfarin, levothyroxine, carbamazepine, digoxin, lithium carbonate, phenytoin, immunosuppressives & theophylline. • Efforts to improve generic substitution of NTI • Narrower range proposed by FDA • 90-111% (or 95-105% ????)

types of pharmacokinetic information

-PK parameters: Dose individualization and dose regimen design -PK characteristics: Predict effect of organ dysfxn, possible DIs & dose adjustments -DIs: Avoid and manage serious adverse outcomes -disposition in special pop: Dose individualization to avoid serious adverse outcomes

summary: PK properties of digoxin

-PO absorption: 60-75% -Protein binding: 25% (fu=0.75) -Vd 6 (3-9) L/kg -t1/2 36H (26-46) -Route of elimination: renal -Onset of action (min) IV: 5-30 Oral: 30-90 -Maximal effect (hr) IV: 2-4 Oral: 3-6 -Therapeutic levels 0.5 - 2 ng/mL

child pugh classification

-Point system that assesses the severity of chronic liver dz -Assx w survival or development of complications -Helps determine strength of tx needed and the necessity for a liver transplant -Determines the need for dose adjustment for hepatically cleared meds

digoxin elimination

-Predominantly by renal route -Renal dz substantially influence digoxin PK --Vd, Cl -dec. cl in geriatrics -Verapamil & other CCBs dec. renal & non-renal cl

TDM sampling digoxin

-Proper timing of serum sampling is critical. -Serum samples should be drawn just prior to (trough level) daily dose -AND no sooner than 6H after admin of the drug.

digoxin dosing in mod-severe HF

-Pts w NYHA grade III-IV HF have dec. CO that causes dec. liver blood flow & dec. hepatic clearance. -B/c digoxin clearance is dependent upon both renal and non-renal clearances, therefore: -Cl total (NYHA III-IV) = (0.33 ml/kg/min)(weight in kg) + (0.9)(Clcr as ml/min)

absolute bioavailability (F)

-Systemic availability of a drug after EV admin (e.g. PO, PR, transdermal, inh.) in comparison to IV admin. • For plasma/blood data • For urinary excretion data • [Du](inf) is the total amt of drug excreted in urine

digoxin dosing in renal failure

-T1/2 = 120H -Vd = 4.5 L/kg -CrCl is in ml/min -equation above is corrected for weight -Use IBW if >30% overweight -aka LBW (Lean Body Weight) is estimated by: -IBW (males) = 50 Kg + (2.3 Kg for every inch > 5 feet) -IBW (females) = 45.5 Kg + (2.3 Kg for every inch > 5 feet) Rules for use of IBW vs. TBW (Total Body Weight): -If TBW<IBW, use TBW (e.g. underweight or small adults) -If low muscle mass, w Scr < 1.0 (e.g. frail elderly, AIDS, cancer, spinal cord inj), use Scr of 1.0 -If TBW is > 30% over IBW, use IBW --Also the Salazar & Corcoran equation for obese pts

digoxin dosing in "normal" adults

-T1/2 = 36H (24-48H) -Vd=7 L/kg (5-9 L/kg) -models 2 comp PK -Usual dose: 250 microg/day (150-500) -Aim for average therapeutic conc for dz state (CHF vs. AF)

clin pharm: 5 rights

-The Right drug -The Right patient -The Right dose -the right route -The Right time

induction therapy

-Use of potent immunosuppressive agents in the critical early post transplant period. -usually biological agents -dec incidence of acute rejection in the immediate post-transplant period

digoxin loading dose

-Use only when urgent digitalization is required -Loading doses are often admin in divided doses, so that the pt can be evaluated for toxicity & efficacy prior to receiving the total loading dose

types of continuous renal replacement therapy (CRRT)

-Used for renal replacement therapy when a pt can not tolerate 4h long hemodialysis process -There are 3 primary CRRT categories: 1. Cont. arterio-venous hemofiltration (CAVH) -Cont. veno-venous hemofiltration (CVVH) 2. Cont. arterio-venous hemodialysis (CAVHD) -Cont. veno-venous hemodialysis (CVVHD) 3. Cont. arterio-venous hemodiafiltration (CAVHDF) -Cont. veno-venous hemodiafiltration (CVVHDF)

digoxin distribution

-Very large Vd (7-8 L/kg); pump it targets is well distributed throughout the body / skeletal musculature -Not distributed into adipose tissue • Ideal body weight -Distribution into organs reach in Na-K-ATPase (including skeletal muscles) -protein binding: 20-25% to serum albumin -Conc. myocardial tissue can be 20-155x >> plasma -Quinidine dec. Vd by displacing digoxin from its binding sites & inc. its toxicity

clinical s&sx of digoxin toxicity

-Visual disturbances (color halos) -N/V/D -Confusion & depression -Loss of appetite -Unusual tiredness or weakness -HA -drowsiness -Fainting

Belatacept (Nulojix, BMS)

-a selective T-cell co-stimulation blocker -Used instead of calcineurin inhibitors cyclosporine and tacrolimus for transplant

mass spectrometry

-a technique that separates particles according to their mass -Mass spec = gold standard expensive, & needs someone w the ability to properly read results

tacrolimus

-aka prograf -Macrolide (no Ab activity) of fungal origin (Streptomyces Tsukubaenis) • More potent calcineurin inhibitor than cyclosporine (lower doses) -MOA: Calcineurin inhibitor

sirolimus mechanism of action

-aka rapamycin • Macrolide antibiotics • Discovered is Island of Rapa Nui (Easter Island)

AUMC

-area under the first statistical moment curve • 1st statistical moment is a mathematical procedure that tries to recognize the effect of time on a factor, -i.e. plasma conc * time vs. time is a first statistical moment curve. • No apparent physiological meaning • Useful for calculation of secondary parameters such as: -Mean residence time -Vdss

basiliximab

-chimeric monoclonal; -25% murine & 75% human protein. -induction therapy -Selective IL-2 Receptor Antagonist

why measure blood levels of drugs?

-concentration at SOA is hard to measure (invasive) -pharmacologic effect is also hard to measure and leaves room for ADRs to occur -if there is a surrogate marker (i.e., LDL and statins), this would be preferable

what is the easiest transplant surgery?

-cornea is the easiest transplant -limited vasculature means no systemic immunosuppression needed

NTI

-defined as those drugs where small differences in dose or blood conc. may lead to dose and blood conc. dependent, serious therapeutic failures / ADRs. -Serious events are those which are persistent, irreversible, slowly reversible, or life-threatening, possibly resulting in hospitalization, disability, or even death.

digoxin distribution in renal dysfunction

-distribution of digoxin in pts w renal dysfxn is dec. -b/c of dec. digoxin binding to tissues in renal failure -Tissue binding dec. -Vd dec. -Vd (normal) = 468L -Vd (CrCl = 15mL/ min) = 327L

heart allograft rejection

-donated heart comes from brain dead donor -HLA matching useful, but typically not possible -risk of coronary artery damage, perhaps mediated by host antibodies ISHLT classification for heart allograft rejection: Grade 0: none Grade 1a, 1b: mild Grade 3a, 3b rejection: mod Grade 4 rejection: severe -lymphocytes infiltrate interstitial space of b/w myocytes in rejection process

ELISA

-enzyme-linked immunosorbent assay

AB is a 45-year-old male with newly diagnosed Afib. He is 70kg, 70" and his SCr is stable at 0.9 mg/dL. first calculate AB's kidney function, determine if IBW should be used, and estimate digoxin clearance. also calculate Vd.

-first, estimate CrCl using Cockcroft- Gault equation. -Since AB is not obese, TBW may be used. CrCl = 103 mL/min -Next estimate digoxin clearance. Since AB does not have HF, non-renal clearance will be 40 mL/min Cl = 1.303 (Clcr)+ Clnr = 1.303 (103 mL/min) + 40 mL/min = 174 mL/min -Vd = 458.5 ; to convert to weight adjusted Volume: 458.5L/70kg = 6.55 L/kg -Calculation of Vd can be done using population methods because the pt has adequate kidney fxn

Tolypocladium inflatum Gams

-fungus isolated from soil sample in Norway —from there, isolated several molecules called "cyclosporines" —originally thought to be an antibiotic, later discovered it didn't have use for this purpose, idea shelved for several years. -tested for immunosuppressive activity in the 70s, & found to be effective

allograft rejection

-immunologically mediated rejection of grafted tissues or organs from a genetically nonidentical donor. -mainly d/t recognition of nonself MHC molecules on graft. -APCs move to lymphoid organs d/t host-graft adaptation. -effector T cells come to inflamed sites: CD8, CD4 -APCs trigger T cells in secondary lymphoid organs -helper T cells help B cells to make allo-antibodies

digoxin hemodynamic effects

-inc Cardiac output -inc LV ejection fraction -inc Exercise tolerance -inc Natriuresis (excessive loss of Na in urine) -dec Neuro-hormonal activation

daclizumab

-induction therapy -humanized monoclonal (mouse, human) -90% human protein -Selective IL-2 Receptor Antagonist

mycophenolic acid

-inhibits T cell proliferation • Use: Maintenance therapy prevention of acute rejection.

salazar corcoran

-measuring the renal function for obese individuals -Men: CrCl = [(137-Age) x [(0.285 x IBW)+(12.1 x Ht2)]]/(51 x Scr) -Women: CrCl = [(146-Age) x [(0.287 x IBW)+(9.74 x Ht2)]]/(60 x Scr)

why monitor digoxin serum levels?

-monitor pt compliance. -investigate deterioration after an initial good response. -In pts w marked alteration in renal fxn. -When digoxin toxicity is suspected. -To evaluate the need for cont'd therapy. -When there is a suspected DI.

precision vs. accuracy

-precision: the degree of refinement with which something is done / measured -accuracy: closeness between the determined value and true value

variability in drug response

-renal dz -hepatic dz -DI -pregnancy, -obesity -age -environmental factors -genetics -other diseases

foxgloves

-source of digitalis lanata glycosides, digoxin -cardiotonic steroid -among most frequently prescribed drugs in the US, 23 million scripts annually

basic enzymatic reaction

-substrate to product (glucose-6-phosphate ---> gluconate) or -cofactor to product (NAD--->NADH)

chromatogram

-technique for TDM -Retention time and peak high/area are the two most important characteristics of a chromatogram

sieving coefficient

-useful tool to predict the likelihood of a drug to cross the hemofilter membrane is Sieving Coefficient (SC). -This term is defined as the ratio of drug conc. in the ultrafiltrate to the prefilter plasma water conc. of the drug. -more drug in ultra filtrate = more removal of drug -SC: Cuf / Cp -If close to 1.0, the drug has relatively free passage across the filter. -example: Erythromycin SC=0.37 vs. Gentamicin SC=0.81; gent more likely crosses hemofilter b/c its SC is closer to 1

Orange book

1. "A" Drug products -no known or suspected bioequivalence problems. -designated AA, AN, AO, AP, or AT, depending on the dosage form -Actual or potential bioequivalence problems have been resolved w adequate in vivo &/or in vitro evidence supporting bioequivalence. --These are designated AB. 2. "B" Drug products -NOT considered to be therapeutically equivalent to other pharmaceutically equivalent products, -i.e., drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. -Often the problem is with specific dosage forms rather than w the active ingredients. -These are designated BC, BD, BE, BN, BP, BR, BS, BT, BX, or B*

digoxin monitoring parameters

1. Digoxin serum level -Obtain level w/in 24H of digitalization, QW until stable, & at SS. 2. BUN & SCr -Measure QOD, or QD in unstable renal fxn. 3. Weigh pt QD: determine response to therapy and water weight retention 4. Measure & monitor urine output QD 5. Monitor apical pulse QD

evolution of cyclosporine

1. Sandimmune®: Cyclosporine oral solution 2. Neoral®: Cyclosporine microemulsion 3. Gengraf®: Cyclosporine modified -Branded generic, bioequivalent to Neoral® -Sandimmune is NOT bioequivalent to Neoral. it is 47% less bioavailable.

digoxin dosing and thyroid dz

1. hyperthyroidism -Pts w hyper-thyroidism may not respond well to tx w digoxin but can develop toxicity if the dosage is inc. 2. hypothyroidism: -Pts w hypo-thyroidism are more sensitive to the effects of digoxin and it can be very difficult to find the correct dosage

terminal t1/2

= 0.693 / k

OKT3

A moAb (mouse) that targets mature T cells. -induction therapy

trapezoidal rule

Advantages: Simple -can calculate by hand, Excel or a simple calculator Disadvantages: • Assumes straight line between data points • If curve is steep, error may be large • Under or over-estimate depends on whether curve is ascending of descending -Verticals dropped from each point. Points joined by straight lines. -Divides the area into a series of 6 trapezoids. -Total area of the trapezoids gives a good approximation of the AUC up to the last blood sample. area of each trapezoid: -Mean height = (C1 + C2)/2 -Width = t2-t1 -Area = (C1+C2)/2 x(t2-t1) area of the tail: -true AUC0-∞ should include the 'tail' area beyond the last actual measured conc. Calculate as: -Tail = (Final measured conc) / Kel

factors affecting drug removal by hemodialysis

Drug Physicochemical Properties Molecular Weight: -Small molecules (<500 Da) are more easily removed. Water Solubility: -Water insoluble molecules will tend to remain in the blood compartment rather than diffusing into the aqueous dialysate. Protein-binding: -Only free drugs can cross the dialysis membrane

drugs considered NTI

Drugs considered NTI Cyclosporine Digoxin Flecainide Lithium Phenytoin Sirolimus Carbamazepine Warfarin

digoxin dosage forms

Formulation 1. Tabs: -Strengths: 0.125, 0.25 mcg -F: 0.7 (0.5-0.9) 2. Elixir: -Strengths: 0.05 mcg/mL (children) -F: 0.8 (0.75-0.85) 3. Gelatin caps: -Strengths: 0.05, 0.1, 0.2 mcg -F: 0.95 (0.9-1.0) 4. IV: -Strengths: 0.25, 0.1 mcg/mL -F: 1.0

NYHA grades of HF

Grade I: No limitation of physical activity Grade II: Slight limitation Grade III: Marked limitation Grade IV: Inability in carrying out physical activity without discomfort

interpretation of TDM

Interpretation • Just relating a measured drug concentration to a published range is meaningless • A conc must be interpreted in the light of followings: -Clinical response -Demographic & clinical status of the pt -Dosage regimen used -PK characteristics of drug

heart failure

LVF: pulmonary congestion, dyspnoea RVF: venous pressure, peripheral edema, hepatic congestion Biventricular HF: Congestive, both coexist drug therapy: -Digoxin -Diuretics -ACE-i -Blockers -ARBs

digoxin dose adjustment

Linear PK: LD = Vd*Cp/F Css = [F (Maintenance Dose/ )] / Cl Dose change: DOSEnew =(Cssnew/ Cssold) x DOSEold DIV=DosePOxF Cssnew = Cssold x (Dose rounded/ DOSEcomputed)

kinetic homogeneity

The predictable relationship b/w plasma drug conc. & conc. at receptor site

cyclosporine dosing regimen

Transplantation -Starting dose 7-15 mg/kg/day bid -Dose change based on the Css trough (before dose) as defined by local transplant protocols -Chronic maintenance dose (2-6 mg/kg/d) Autoimmune diseases - 2-5 mg/kg/day bid - usually no monitoring required

PK properties in hemodialysis

Vd -Drugs w large Vd are generally not avail. for removal by dialysis. -Route of drug elimination -Inherent metabolic clearance Maybe altered in pts w renal failure: -Conc-dependent PK -May alter the magnitude of various routes of elimination.

drug action and disposition

basic concepts: PK: what the body does to the drug PD: what the drug does to the body

purpose of BE

bioequivalence: • Indicates that a drug in 2 dosage forms reaches the general circulation at the same relative rate and the same relative extent; i.e., the plasma level profiles obtained are similar (super-imposable) purpose: • To confirm therapeutic equivalence (TE) • Therapeutically equivalent products can be substituted for each other w/o any adjustment in dose or other additional therapeutic monitoring. • The most efficient method of confirming TE is to assure that the forms perform in an equivalent manner.

myfortic vs. cellcept

myfortic: • 720mg bid (2 x 360mg tablets) • Mycophenolate sodium -salt of sodium = inc absorption • Active moiety: mycophenolate • DR, EC • Release in SI cellcept: • 1000mg bid (2 x 500mg tablets) • Mofetil ester -prodrug • Active moiety: mycophenolate • IR • Release in stomach

bioavailability

• Bioavailability: the rate & extent to which the active ingredient or active moiety is absorbed from a drug product and becomes avail. at SOA. • For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes avail. at the site of action." • Absorption: extent to which intact drug is absorbed from the gut lumen into the portal circulation. • 1st pass clearance: extent to which a drug is removed by the liver during 1st pass in the portal blood thru the liver to systemic circulation • Bioavailability: is the fraction of drug reaches the systemic circulation as an intact drug -Expressed as: Bioavailability = fraction absorbed * fraction escaping first pass Cl -Example: 50% absorbed, 60% 1st pass metabolism F=0.5*(1-0.6)

Enzyme Multiplied Immunoassay Technique (EMIT)

• Developed by Syva Corp. (Palo Alto, CA) in '70s, now owned by Behring Diagnostics • Offered an alternative to RIA or HPLC for measuring therapeutic drugs • Sparked the widespread use of TDM • Adaptable to virtually any chemistry analyzer • Has both quantitative (TDM) and qualitative (DAU) applications -in image: picture on left leads to signal, whereas image on right would cause no signal

PO absorption of amiodarone

• Incomplete and slow absorption from GI tract • Absolute bioavailability ~ 50% (widely variable) -May be attributable to variable first pass metabolism in the liver and GI tract -Inter‐pt differences in CYP3A4 activity • Food inc. rate & extent of absorption! -Dec. Tmax (normally 3‐7H) -reaches peak conc. quicker -Inc. Cmax by ~3.8x and AUC by ~2.3x -Must be consistent w meals (i.e. always take w food or w/o food) • Depending on indication, initial dose may range from 600‐1600mg x 1‐3W • Lowered to 600‐800mg x 1 month • Then followed by lowest possible maintenance

measures of bioavailability in clinical practices

• Parent drug • Major metabolite • Pharmacodynamic marker -Pharmacodynamic (PD) effect -max PD effect (Emax) -time for max PD effect -area under PD effect vs time -onset time for PD effect • In vitro studies -drug dissolution

sirolimus distribution

• Partitioning into RBC; Mean B/P ratio = 36 • Plasma protein is high • SS volume ~ 1.6 L/kg in stable renal of distribution transplant patients

amiodarone elimination

• Prolonged d/t extensive distribution into adipose tissue • Primarily biliary, negligible renal excretion • Biphasic: -Distribution t1/2 17H -Terminal: slower, average t1/2 becomes ~55d (range of 26‐107d) -Elderly have slower clearance -No publications on effect of hepatic impairment on amiodarone elimination but lower elimination can be assumed

patents

• Protects the investment of the drug company that developed the drug (the manufacturer) • Gives the drug company the sole right to sell the drug while the patent is in effect • When the patents on a brand-name drug near expiration, drug companies that want to manufacture a generic can apply to the FDA to sell a generic version of the drug.

tacrolimus protein binding

• Protein binding: unbound fraction <1% • Vd = 17 L/kg; it crosses placenta and gets into mother's milk -nonteratogenic • eliminated in bile; t1⁄2 = 4-40h, typ ~ 12 hrs • Tacrolimus is not removed by dialysis

tacrolimus pharmacogenomics

• Tacrolimus is metabolized in the GI tract and liver by CYP3A4 & 3A5 • CYP3A5 is highly polymorphic; present mainly in GI tract - *1 active - *3 inactive • Abundant degree of clinical research suggest a role for CYP3A5*1 polymorphism in tacrolimus disposition (especially in people of African origin) -d/t *3 expression, japanese and caucasians need less drug (genetically based inference) than an African American might

accessible pool

• The difference between non-compartmental and compartmental models is how the non-accessible portion of the system is described. characteristics: • Kinetically homogeneous • Instantaneous & well-mixed single accessible pool: -direct input into plasma w/ plasma samples 2 accessible pools: -PO dosing or plasma and urine samples

PK summary: tacrolimus

• Therapeutic conc: 5-20 ng/ml • F: 25% (4-93%) • Vd: ~17L/kg • Cl: 0.04-0.083 L/kg/hr • Half life: 8-12 hrs, (4-41 hrs) • Fu (fraction unbound): 1%

summary PK: sirolimus

• Therapeutic concentration: 5-15 ng/ml • F: -PO soln: 14% -Tablet: 18% • Vd: 12 L/kg • Cl: 0.139-0.221 L/kg/hr • Half life: 62 hours • Free fraction: 2-8% • ASSAY METHODS: HPLC, CEDIA immunoassay

estimation of clearance by non compartmental analysis

• Total clearance -IV: Cl = dose/AUC -EV: Cl = SFD/AUC

how do you perform TDM?

• Type of specimen - Serum or plasma - Whole blood • Time of sample - Peak (Cmax) vs Trough (Cmin), Peak & Trough - Steady state

transplantation surgery

• Unique method for treatment for a number of end stage diseases • Success depends on immuno-suppression • 1955: 1st successful kidney transplant w long term survival b/w 2 identical twins (Brigham & Women's Hospital, Boston) • 1978, introduction of cyclosporine, J.F. Borel, Sandoz Inc (Novartis).

cyclosporine distribution

• Widely distributes in body • Accumulates in liver, kidney, adipose tissue etc. • Vd = 4-6L/kg • Bound to RBCs, leucocytes & plasma proteins

PK parameters pertaining to bioavailability

• extent of bioavailability (AUC) • the rate of absorption is usually also important for the onset of drug action (Tmax) • the peak plasma conc (Cmax) is also an important parameter -for keeping drug conc w/in therapeutic window

bioavailability study population

• well-controlled (food, alcohol and drug intake) • healthy volunteers (PE & lab tests, 18YO , informed consent) • sample size calculation (80% power) • cross over (Latin square, 2 period, 2 sequence) • washout period (at least 5 t1/2)

quantification methods of drug concentration

•Chromatographic techniques -HPLC -LC/MS or LC/MS/MS • Immunological techniques - RIA (Radio-ImmunoAssay) - ELISA (Enzyme Linked ImmunoSorbent Assay - FPIA (Fluorescence Polarization ImmunoAssay) - EMIT (Enzyme-Multiplied Immunoassay Technique) - CEDIA (Cloned Enzyme Donor Immunoassay)