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PKPD II > exam 4 > Flashcards

exam 4 Flashcards

1
Q

top selling drugs are what kind of drugs

A

protein drugs.

top selling drug: humira

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2
Q

what is the most prevelent antibody isotype in man

A

IgG

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3
Q

polyclonal vs monoclonal

A

monoclonal: ab produced from 1 b cell lineage
polyclonal: multiple clel lineage. usedc from animals

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4
Q

four main applications of antibodies

A
  1. immunotoxicotherapy: complete neutralization of toxin/xenobiotic
    ex: digibind
  2. elimination of cells:opsonize cells for destruction
    ex: anti-CD4 IgG, rituximab (cancer),
  3. alter of cell function/ cell signaling
    ex: abciximab (anti-CD41-prevents PLT aggregation
  4. drug delivery: increasing the efficienc y of drug delivery to desired sites
    ex: gemtuzumab ozogamicin: deliver toxin to tumor cells
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5
Q

geenral antibody PK

A
  1. good absoprion following SQ or IM
  2. bioexponential disposation
  3. long half life (~20 days)m and low rates of cl )~10mL/h)
  4. small V (3-9L)
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6
Q

elimination mechanisms for peptides and proteins

fluid phase endocytosis

A

considered to be non specific

proteins broken down to amino acids

degredation producsts are not likely to be toxic (basiclaly dot have toxic metabolites to worry about like in small molecules)

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7
Q

elimination mechanisms for peptides and proteins

renal filtration/ phagocytosis and proteolysis

A

size specific mechanism

phagocytosis may be a primary mechanism for >400kDa

renal filtration and subsequent prteolysis when MW<50 kda

*some of the proteins are renally filtered, but a lot of the proteins are filtered back up into cells and then metabolized. can see this by saturation the reuptake pathways. more prevelant in smaller proteins

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8
Q

elimination mechanisms for peptides and proteins

receptor mediated endocytosis and catabolism

A

interaction with component of protien and receptors tat recognize it
ex: high tpa cl due to recognition of mannose by mannose recpetors

ex: ** FcRn. protects IgG from elimnation, and reson why igG has low levels of elimination

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9
Q

note on FcRn

A

only IgG, not any other antibodies
the brambell recptor

transient saturable gi absoprtion in nepnates

saturable

PH DEPENDENT BINDING: at ph of 6, binds, at ph of 7.4, released

verly long t 1/2

concentraiton -dependent elmination:
so basically saturation causes increased elmin. of IgG because it protects igG form elmination, so high conc concsaturated mechanisms will increase its elmin

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10
Q

elimination mechanisms for peptides and proteins

target mediated disposition

a. dose dependency
b. treatment dependency

A

DOSE DPEENDENCY
binding of drug to its pharmaco;pgoc target influencing PK

nonlinear pk: Vss decreases with increasing dose
CL: decreases with increasing dose
CL decreases with dose when recpetor binding leads to drug elmination (basically when cl mediated w. interaciton w. receptor, cl will decrease w. increase in dose)

basically as dose is increased, cl mechanisms of binding to receptor become saturdated, and CL decreases

TREATMENT DEPENDENCY

ab is destroying cells that have the target, and target is mediated elmination of ab. so at first dose, we have a lot more cells that hasve the target, but subsequent doses dont have as many targets, therefor decreased cL

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11
Q

elimination mechanisms for peptides and proteins

anti drug antibodies

A

protein drugs often lead to production of anti drug antibodies

for mAb: risk for ADA appears to be greatest for rodent>chimeric> humanized> fully humen

SQ>IM>IV

when ADA is present, rapid cl of drug occurs

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12
Q

the more specific the pathway, more like to be ____

A

saturable

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13
Q

elimination processes that are liekly to be dose independent

A

Fluid phase endocytosis
phagocytosis
renal filtration
catabolism

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14
Q

elimination processes more likely to be dose dependent

A

drug spefici and compoonent specific

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15
Q

so basically 2 main non liner elimination mechanisms we tlaked about

A

targeted mediated disposition:
with increase indose, decrease in CL

FcRn saturation: increase in dose, increase in clearance

however, mAb are dosed so loww that these nonlinearities probably wont occur. but… still the most important type of nonlinearity for an mAb woul dbe used by satuation from TMD

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16
Q

distribution of AB

A

diffusion across plasma mebranes largely driven by convection. PRIMARY mechanism of distribution
fluid movement from blood space into intrastitial space

assumptions for small molecules drug in regards to elimination and distribution are invalid for protein drugs

conc of protein in tissue «< conc protein in plasma

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17
Q

does variability i fc gamma explain terindividual variability in mAb PK?

fc gamma receptors

A

present on macrophages. opsonizes b cells when interacted with, cause phagocytosis
ex: rituximab:

variation in receptors:
pts with 158V demonstrate superior responses

pt withs phenylalanine, have lower affinity binding for drugs like rituximab, have lower survival

definately affects PD: not so much PK

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18
Q

does anti drug AB contribute to the interindividual variability in mab PK?

Antidrug AB against ADAlimumab (AA)

A

pts produce AB for adalimumab when treated chronically

effect: in individuals with high conc of AAA, low conc of drug

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19
Q

does DDI contribute to the interindividual variability in mAb PK

a. FcRn
b: ADA
c: convection

A

FcRn: saturation of FcRn accounts for 50% of therepeutic benefit of IVIG

Ada: methotrexate decreases development of anti drug antibodies of infliximab

convection: ab Bevacizumab: ANTI VEGF mAb:prevents neovascurization, decreasing growth of tumor. prevent.
however vessels are less, leaky so further admin of other drugs to treat cancer may not get to tumor and wont work as effectively. this is a DDI with anti VEGf mAb and other mAb?

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20
Q

does disease contribute to the interindividual variability in mAb PK

A

nephropathy: greater elimination of protein in the urine, including therepeutic proteins

Urinary albumin excretion (UAE): as uae increases, AB elimination increased in urine

other diseases that affect this. SLE, RA, PLE

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21
Q

inter-individual variability

genetics:

disease:

route dependency:

A

difference in variability btw ppl

genetics: differeny genotype of c2d6 affect nortriptyline concentrations
disease: cirrhosis greatly increases t 1/2 of chlordiaxepoxide, which inturn decreases clearance

route dependent: theophylline
propanolol given orally is low extraction, if given IV it is a high extraction drug

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22
Q

within subject variability

A

aka occasion. unexplained cl varibaility for example

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23
Q

sources of pd variability

A

gened for receptor, genes affecting drug response, age, concurrent drugs and diseases, environmental factors,
pd variability exists, but must look at pk varibialitt first

ex: albuterol conc in 2 pts were same, but response was different due to mutations (homozygotes vs heterozygotes)

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24
Q

implimation of target concentratio strategy

A
  1. estimste likely values of pk parameters
  2. using appropriate pk model, estimae plasma conc expected at time of sampling
  3. compare the observed and expected concentrations
  4. if observed and expected conc are judged to be different, then pk parameters are revised
  5. a recommendation is made o the dose level and or dosing interval
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25
Q

implimation of target concentratio strategy

A
  1. estimste likely values of pk parameters
  2. using appropriate pk model, estimae plasma conc expected at time of sampling
  3. compare the observed and expected concentrations
  4. if observed and expected conc are judged to be different, then pk parameters are revised
  5. a recommendation is made o the dose level and or dosing interval
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26
Q

target -specific covalent inhibitoin things to consider

A

continum of reversibility (irreversible model)

turnover of E, I, and comples (PKPD)

relative concentrations of E and I (TMDD)

Genetic polymorphisms

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27
Q

warfarin pk parameters

A

maintenanse dose: 1.5-12 mg/day

F: >90%

tmax: 1-2 hrs

V: 0.08–0.12

protein binding%: >99%

plasma conc: 1.5–8 umol/L

terminal elimatoin 1/t2:
S-WAY: 24-33 h
R-WAR: 35-58

plasma CL:
s-WAR: 0.10-1.0
R-WAR: 0.07-0.35

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28
Q

targeted mediated drug

A

binding of drug target influenec pk of drug

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29
Q

pk characteristics of target mediated drug disposition

A

nonlinear vd and cl

steep distributive phase for low doses

long terminl eliminatino

dose proportional (liner) on multiple dosing

time lab to css with low dose IV infusion

30
Q

warfarin tissue concentration

A

dependent on concentration: tissue binding can become saturable (non linear)

at low doses, it takes longer to get to css because at high doses, you have saturable tissue binding, getting to css faster

31
Q

TMD

effect of multiple dosing on linearity

A

for low doses, experience non linear kinetics, however for higher doses, target becomes saturated, and then effects exhibit linear kinetics

32
Q

warfarin metabolism

A

low extraction drug

s warfarin almost exclusively CYP2C9

R-warfarin: metabolized by CYP1A1, 1A2, 2C19, 3A4, catechol-O-methyltransferase and ketoreductases

33
Q

warfarin PD

A

indirect pD response:

while peak conc. happen immediately, peak response time doesnt happen until days later

34
Q

clnincal considerations for warfarin

A

inexpensive

slowonset of action and narrow Therapeutic wondow

factors that influence resonse

  • age
  • genetic polymorphisms
  • body weight
  • sex
  • DDI
  • disease conditions
  • adherance
  • dietary intake of vitamin K

traditional methods of TDM have limited value

INR must be measured (target 2-3)

35
Q

do pharmacogenetics have a riole in the dosing of warfarin

A

trials adress the process of INITIATION og anticoag therapy, not intermediate or longterm anticoagulation.

pharmacogenetic testing has no or marginal effect on usefulness in dosing, especially given the cost.

better to focus on INR, PT ADHERANCE, COMMUNICATION, ETC.

36
Q

goals of population modeling

A

estimate pkpd and intersubject variability

determine influence of pt characteristics in explaining varibaility

adress regulatory concerns

provide scientific basis fo rindividualized therapy

37
Q

covariates of warfarin studies

A

pk: age and polymorphisms in cyp 2c9
pd: polymorphisms in VKORC1(warfarin target)

38
Q

bayseian methods for warfarin mointoring

A

provide improved individualization of warfarin pharmacotherapy

39
Q

are traditional methods of drug minotrin g(drug concentrations) useful in monitoring warfarin ?

A

no! we moinitor using INR

40
Q

genetic polymorphisms of what influence pk pd variability of wafarin

A

cyp2c9 and VKORC1

41
Q

is target mediated drug dosing common for small molecules?

A

no. less common

42
Q

what to think about if inr is out of range

A

consider adherance

change in diet

DDI

43
Q

what happens if inr is below target range (<0.5) and below

A

if all other considerations adressed and havent changed,such as new meds, adherance, or others. you could maintain the dose and follow up in 1-2 weeks

44
Q

what happens if inr is consistantly low

A

consider increasing dose by 7-10%

45
Q

DDI of warfarin

A

amiodarone: inhibits 2C9 (also 1a2, and 3a4)

Septra,BActrim(specifically sulfemethoxazole): inhibits 2C9 competitively

ciprofloxacin: increases effect

fluconazole

erythromycin

Rafampin: decreases INR through induction

46
Q

food interactions of warfarin

A

green leafy vegetables contain high amount of vitamin k

ex: broccali

spinach

47
Q

dabigatran is an anticoagulant that inhibits which clotting factor

A

thrombin (clotting factor II)

48
Q

what components do you need for bayseian adaptive feedback

A

prior popilation-based pkpd model
feedback INR assessments
dosing information and patient characteristics
computer program

49
Q

what regulates release of erythropoeitien in the kidney

A

oxygen pressure

50
Q

regu;ation of EPO

A

EPO-> increases rbc -> more hgb, more o2,

o2 goes down, kidney produced EPO

51
Q

EPO and its receptor

A

EPO synthesized by renal glomerular in response to tissue hypoxia

EPOR: upon binding, epo dimerizes and activates JAK2 tyrosine kinase:
effects: increases proliferation, stimaulates maturation, and inhibits apoptosis

52
Q

recombinant EPO indication

A 
CRF
cancer
aids
prematurity
autologous transfusion
53
Q

EPO adverse effects

A

HTN
iron deficiency
pure red cell aplasia (rare)
increased survivial of cancer cells (large doses)

54
Q

erythropoesis stimulating agents

protein based EPO therapied

A

epoetin
darbepoetin
CERA

55
Q

pk model for EPO

A

linear and non linear clearance

endogenous EPO: circadian rhythm

peripheral distribution

continuous first order absorption form SC site

satural F vs. dose relationship

56
Q

epo absoprtion

A

dual absorption: slow via lymp. system
fast via transport to extrcellular ocmpartment

exhibits flip flop kinetics (so absorption t1/2) is 24-79 hr

bioavailability is dose dependent, increases with dose

57
Q

EPO distiburiton

A

similar to plasma volume

58
Q

EPO elimination

A

EPOR mediated endocytosis (TMD)

IV t1/2: 8 hrs

59
Q

EPO clearance differ in liver disease and renal disease patients?

A

liver: no difference
renal: small differance, not statistically significant

60
Q

PD markers of EPO response

A

RBC
Hct
hgb: most important
ret= percentage of rbc containing residual rna0

61
Q

which is more effective: sc or iv admin for EPO

A

SC. keeps EPO above minimum effective concentration for a longer period of time

62
Q

what is cancer

A

cell proliferation, metastasis

63
Q

malignant cancers

A

Solid tumors

  • carcinoma: epithelial cells (lung,, colom, breast)
  • sarcomas : connective tissue (bone, muscle

hematological
lymphoma: tumors of the lymph system(hodgkin)
leukemias (tumor of blood forming elements (myeloid or lymphoid)

64
Q

treatment of cancers (main

A

chemo

2.targeted therapy: newer type of cancer treatment that uses drugs or other substances to more precisely identify

immunotherapy

65
Q

objectives of chemotherapy

A

neoadjuvant therapy: before procedure to shrink cncer

adjuvant: destory left over cells after procedure

maintenance : low doses to prolong remission

first line: best probability of treating cancer

second line: given if not responded or reoccured

palliative: symptom management

66
Q

classification of chemo agents

A

cell sycle specific phase most active during a specific phase, but could also be active in another.

non specific have greater activity in one phase than the other, but not as much as the phase specific ones

67
Q

pk of anticancer drugs

A

narrow ti

wider interpt variability

68
Q

PK variability of anti cancer agents: DDI

A

because they take a lot of other drugs

especially pts could be used Complementary and alternative medicaine (CAM)

69
Q

pd interactoin of anti cancer agents

A

folic acid enhances the effectr of 5-FU by inhibiting thymidylate, which is moa of 5 -fu

PD DDI btw platinum agent (cisplatin or carboplatin) and paclitaxel. increases exposure

70
Q

dose individulation method

A

BSA based majority of the time

carboplatin: dose adjusted based on pt GFR

71
Q

a priori dose adjustment

propensity for toxicity

A

platelet count determines dose given. higher plt, highr dose

72
Q

limited sampling method

A

purpose: limit frequency of blood sampking
limitation: need to be used for same drug regimen (agent, dose, administration, and duration of infusion as orinigannl study when LSM was established

PKPD II (4 decks)

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