Clinical Pk Exam 3- Immunosuppressive Drugs

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premise of organ rejection and cytokine involved

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IL‐2 activates the immune system even further, leading to
a vicious cycle of foreign tissue destruction rejection

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4 Challenges of Immunosuppressive
Therapy

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Infection/ Malignancy
Adverse Events
finding appropriate dose to avoid:
Acute Rejection
Chronic rejection

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5 ways that immunosuppressive therapies are individualized

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patient, organ transplant,
time after transplantation, indication of transplant
and hospital specific therapy protocol

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organ transplant and renal failure

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Chronic renal failure- highest failure among non renal organ transplant recipients
-I guess organ transplant/therapy predisposes to renal issues

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immunosuppression cocktail- consists of ... (4)

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Calcineurin Inhibitor
mTOR Inhibitor
Antiproliferative Agents
corticosteroids

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Calcineurin Inhibitors (2)

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cyclosporine
tacrolimus

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mTor inhibitor

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Sirolimus

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antiproliferative agents (2)

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Azathioprine (Imuran®)
– Mycophenolate mofetil (Cellcept®)

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3 drugs that require TDM (therapeutic drug monitoring)

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cyclosporine
tacrolimus
sirolimus

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MoA of cyclosporine/sirolimus (2)

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bind to different intracellular
immunophilins (cyclophilin or FK binding protein).

The calcineurin inhibitor-immunophilin
complexes inhibit the phosphatase activity of calcineurin and thereby inhibit the nuclear factor of activated T-cells (NFAT) that control transcription of IL-2 and other cytokines

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2 organ transplants more predisposed to kidney failure

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liver
lung

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Therapeutic Drug Monitoring in Transplantation: WRYY? (5)

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• Correlation exists between concentration and therapeutic response
• Drugs have narrow therapeutic range
• Pharmacological response is not easily assessed
• Wide inter-subject range in plasma concentrations for a given dose
• Potential for drug interactions

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structure of cyclosporine

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cyclic polypeptide consisting of 11
amino acids

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how is cyclosporine made

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produced as a metabolite by the fungus species
Tolypocladium Gams

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cyclosporine used in combo with...(3)

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steroids, Azathioprine or
mycophenolate

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indications for cyclosporine (3)

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prophylaxis of organ rejection in
kidney, liver, and d ey, e , a d heart allogeneic transplants

may also be used in the treatment of chronic rejections
in patients previously treated with other
immunosuppressive agents

Also indicated in autoimmune diseases

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cyclosporine contraindication

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active ocular infections

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cyclosporine absorption

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Bioavailability: 10% to 89%
very variable so can't use same dose for everyone

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extent of cyclosporine absorption is dependent on...(6)

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–Patient characteristics
–Intra‐ and inter variability
–Ethnicity- white/AA- have diff PK with cyclosporine
–Type of transplant
–Time posttransplantation when you give drug
–Formulation

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3 formulations of cyclosporine

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Sandimmune- normal
Neoral - microemulsion
Cyclosporine‐Modified (gengraf)- bioequivalent to neoral

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only 2 bioequivalent cyclosporine formulations

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neoral
gengraf

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sandimmune- properties

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• Bile dependent for absorption
- changes on empty vs full stomach (i guess amt of bile differs)

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neoral properties (3) (compare to sandimmune)

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Decreased intra‐patient variability
• Less bile dependent absorption
• Better correlation of PD fx with trough and AUC levels

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neoral vs sandimmune AUC curve properties (3)

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Cmax is higher for neoral
Tmax is shorter
AUC is bigger

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inter/intrapatient variability in neoral vs sandimmune

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neoral- less variation

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Cyclosporine Vd range (2)

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Volume of distribution: 3 to 5 L/Kg
distribution is variable in different types of transplants

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Cyclosporine- total protein binding %
this protein binding is dependent on what?

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• Total protein binding: 90% (lipophilic)
– Temperature dependent: varies by lab used. Plasma levels are taken at 37°C (body temp) while whole blood samples are tested at room temperature

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Blood to plasma ratio of cyclosporine distribution?

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• Blood to plasma ratio 2:1

i guess this is how you convert between blood and plasma?

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sites of metabolism for cyclosporoine (2)
enzymes/proteins involved (2)

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– Intestinal wall and liver

– Substrate for P‐glycoprotein
– CYP3A to > 25 metabolites

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cyclosporine drug interaction- probable?

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Potential for significant drug interaction due to CYP3A and pgp involvement in metabolism

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excretion route of CsA (2)

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• < 6% excreted unchanged in urine
• Extensively excreted in bile (this is why some formulations are sensitive to bile (enterohepatic recirculation))

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half life of CsA (2)

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5 to 18 hours (median 8 hours) and
varies with the type of transplants

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starting dose of CsA depends on what? (3)

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Type of transplant
• Patient’s condition
• Concurrent medications

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titrate CsA based on what parameters (2)

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Titrate based on 12‐hour trough levels or C2 levels (levels 2 hrs post dose)

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why do we need TDM for CsA (3)

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– Wide inter‐ and intra individual variability
– Narrow therapeutic index
– Correlation with trough level and AUC
(Controversial- sometimes not predictive but..still)

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starting dose for CsA

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5-8 mg /kg/ day divided into 2 doses

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what happens if you get sub or supra therapeutic lvls of CsA? (2)

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• Subtherapeutic: Rejection, graft loss
• Supratherapeutic: Seizure, renal failure

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CsA: survival rate vs BA

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>50% BA had best survival

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assays used for monitoring TDM of drugs: properties
which is most sensitive

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whole blood matrix
Therapeutic ranges differ from assay to assay (based on sensitivity of the assay)

HPLC Is most sensitive

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2 methods to monitor CsA levels

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– 12‐hour trough level (prior to the morning dose)
– C2 level (2 hours after the morning dose)

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target level for CsA (2)

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– Patient dependent
– General 100 to 400 ng/ml (12‐hour trough)

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goal of TDM

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Adjust dose to achieve target level

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Correlation of AUC and C0 (trough) with
Rejection in CsA

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AUC was associated with acute rejection but trough lvls was not

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4 questions to ask prior to dosing adjustment

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– Steady state level?
– Is this a trough level or a C2 level?
– Is the patient experiencing any clinical conditions that
can alter CsA PK? Drug interactions?
– Is the patient compliant?

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converting IV dose to PO of CsA

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Dose IV= 0.3 dose PO

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what to do if CsA conc is...
25 ng/mL off?
50 ng/mL off?
100 ng/mL off?

(mention when to repeat testing)

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1) no change, repeat lvls in 1 week
2) incr or decr by 25 mg per dose , repeat in 2 days
3) incr/decr by 50 mg per dose, repeat in 2 days

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changing dose- what is the threshold (max amount you can change at one time)

exception ?

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do not change dose >25% at any time unless lvl is <150 ng/mL

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CNS AE of CsA (3)

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seizure
confusion
paresthesia

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HEENT AE of CsA (2)

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Alopecia, gingival hyperplasia

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CV AE of CsA (2)

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Hypertension, hyperlipidemia

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GI AE of CsA (3)

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n/v/d
glucose intolerance
hepatotoxicity

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renal AE of CsA (4)

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nephrotoxicity
decrease Mg
Increases K
increases uric acid

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skin AE of CsA (2)

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Hirsutism, acne

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tacrolimus- type of molecule

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macrolide lactone antibiotic

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tacrolimus comparative potency (2)

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more potent than CsA (100x) in vitro
10x more potent than CsA in vivo

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usage of tacrolimus

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Used to prevent and treat acute rejection

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tacrolimus BA

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Bioavailability: 14 to 32%- pretty crap and variable

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6 reasons for BA variability in tacro

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• Intra and inter‐patient variability
• Ethnicity
• Drug interaction
• Types of transplant
• Time posttransplant
• Genetic polymorphisms in the CYP3A5 gene

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Tacrolimus bioavailability and ethnicity (2)

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only white vs AA is characterized
AA have much lower avg BA

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tacrolimus metabolism where? how many metabolites? drug interactions?

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Extensively metabolized in the liver via CYP3A4/5
(>99%)

>10 metabolites, some are active

Potential for significant drug interaction

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Vd of tacrolimus- what is special about it? give relative values

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– 1 to 1.5 L/ Kg (whole blood)
– 5 to 65 L/ Kg (plasma)- VARIABLE

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plasma protein blinding of tacro- %
which proteins (2)

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Plasma protein binding 75 to 99%
albumin
alpha1 acid glycoprotein

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blood to plasma ratio of tacro and what htis means

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– Blood to plasma ratio 15:1- means it is very highly bound to protein ,because none in plasma

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metabolism of tacro influenced by what 2 things

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– Type of transplant
– Time posttransplant (especially liver transplant)

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CL of tacro- values for blood, plasma and renal CL (idk what blood/plasma CL is)

why is CL higher...in plasma?

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total body CL- blood is 6 ml/min/kg
plasma is 30 ml/min/kg
renal CL is 6 mL/min
mostly bound to proteins so CL will be higher in plasma (less drug per volume)

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Half life (hours) of tacro

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variable- ~12 hrs avg

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tacrolimus CL in liver disease- what happens (2)

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half life goes up
CL goes down

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children and tacrolimus excretion/metabolism
also effect on dosing

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Increased clearance in children (Ontogeny) so much increase dosage (they have more CYPs i think)

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tacrolimus starting dose

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0.15-0.3 mg/kg/day in 2 divided doses

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tacro starting dose depends on...(3)

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type of transplant- renal transplant requires higher doses?

patient's condition- comorbid, etc

concurrent medications

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maintenance dose- titrate based on what?

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12 hr trough lvls

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tacrolimus- why TDM? (3)

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SAME AS CsA HERP DERP

narrow therapeutic index (supra/sub = bad)
correlation/proportionality with trough/C2 levels (PD effect correlation stronger with tacro than with CsA)
wide inter/intrapt variability

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clinical evidence for serum level monitoring importance with TDM (i.e. what happens if you don't monitor...) (4)

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low blood conc. reported to precipitate acute rejection

high blood conc. reported to cause acute renal failure

high blood conc. assoc with post transplant diabetes

wide range of doses required to maintain doses in therapeutic range (5-20 ng/mL) so we have to monitor, can't just give one dose for everyone

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when to sample 12 hr trough for tacro

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24-36 hrs prior to morning dose

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tacro target lvl

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5-15 ng/mL

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tacro target level depends on...(2)

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depends on patient characteristics
cocurrent immune suppression

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tacro- prior to adjusting dose ask...(4)

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– Steady state level?
– Is this a true trough level?
– Is the patient experiencing any clinical condition
that can alter tacrolimus PK? Drug interaction?
– Is the patient compliant?

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max dose adjustment %

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do not change dose > 50% at any time

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oral to IV dose conversion for tacro

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oral = 4x IV

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graphical relationship with tacro dose and blood levels

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linear

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AE of tacrolimus (vs CsA) (3)

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same except for...

hyperlipidemia and htn are less severe
no cosmetic AEs (gum hyperplasia, acne, hirsutism)

higher incidence of glc intolerance (related to high therapeutic lvls)

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Calcineurin Inhibitors Induced
Nephrotoxicity trend

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goes up over the years on drug

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converting from CsA to Tacro steps (6)

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1) want to wait until CsA lvls drop to ~50 ng/mL
2) you can calc this by using the half life and current blood levels to tell when to start tacro dose
3) calc the starting dose RANGE based on weight 0.15x wt and 0.3xwt
4) then base the dose on pt characteristics (race, organ failure)
5) DIVIDE dose by 2- it is BID
6) Determine your target dose (higher end of range if recent rejection)


don't have to know dosing/blood lvls apparently...

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pt characteristics that will warrant for higher dosing of tacro on start (2)

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characteristics- is she AA? will need higher dose. did she have recent organ rejection? will need higher dose