CSA and Tacrolimus

Question 1

Main pharmacological target for immunosuppressants:

Answer 1

Cytokines; IL-2 especially.

Question 2

Cyclosporine and Tacrolimus drug-class and MOA

Answer 2

Calcineurin-Inhibitors

MOA: Block calcineurin, which leads to decreased transcription of inflammatory cytokine genes.

Question 3

Place in therapy for Calcineurin-Inhibitors

Answer 3

Maintenance phase immunosuppression, after transplant for example.
Tacrolimus used 90% of the time
Cyclosporin used if neurotoxicity is a problem
- Seizure patients for example.
- Tough to give them AEDs.

Question 4

Consequences of supratherapeutic concentrations

Answer 4

Infections

Malignancies

Question 5

Adverse effects seen within therapeutic range

Answer 5

Nephrotoxicity*
Hypertension*
Diabetes
Neurotoxicities

Question 6

Consequences of subtherapeutic concentrations

Answer 6

Breakthrough rejections

Question 7

Main PK points of Cyclosporine, Tacrolimus, and Sirolimus

Answer 7

Highly variable

Metabolized via 3A4

PGP substrates/inhibitors

Question 8

How do we monitor levels of CSA/Tac in the US?

Answer 8

Troughs @ 12 hours

Question 9

CSA absorption dependent on:

Answer 9

Bile

Question 10

To measure CSA levels you have to collect:

Answer 10

Whole blood concentrations.

Question 11

CSA dosing

Answer 11

Initial: 5mg/kg/day in 2 divided doses

Late: 3-5mg/kg/day in 2 divided doses

Question 12

CSA/Tac SE’s

Answer 12

Hypertension* (CSA >)
Nephrotoxicity*
Headache (Tac >) (Hx migraine)
Hyperglycemia (Tac >)
Hyperlipidemia (CSA >)
Tense skin
Hyperkalemia
Hirsutism* (CSA >)
Gingival Hyperplasia* (CSA >)

Question 13

3A4 Inhibitors to remember:

Answer 13

Macrolides (Azithro safe)
Azoles
- Use echinochandin if invasive
- Use nystatin if local
CCBs (Nifedipine safe)

Question 14

3A4 Inducers to remember:

Answer 14

Anti-TB
AEDs (levetiracetam safe)
St. John’s wart

Question 15

CSA/Tac pharmacodynamic DDI’s: Nephrotoxicity

Answer 15

AmphoB
NSAIDs
Aminoglycosides
Tacrolimus
Acyclovir - crystallization

Question 16

CSA/Tac pharmacodynamic DDI’s: Gingival Hyperplasia

Answer 16

Nifedipine

Phenytoin

Question 17

CSA/Tac pharmacodynamic DDI’s: Hirsutism

Answer 17

Phenytoin
Prednisone (high dose)

Question 18

CSA/Tac pharmacodynamic DDI’s: Rhabdo/Myositis

Answer 18

Statins

Colchicine

Question 19

Ethnicities that require higher doses of CSA:

Answer 19

AA
Hispanic
Children

Question 20

Tacrolimus absorption

Answer 20

Highly variable
- average: 29%

Not bile dependent

Be consistent in terms of meals

Question 21

Tacrolimus Distribution

Answer 21

Partitions into erythrocytes

Present in placenta, fetal circulation, and breast milk.

Question 22

Renal excretion of Tacrolimus

Answer 22

< 1%

Dialysis doesn’t matter.

Question 23

Tacrolimus dosing

Answer 23

Around 0.1mg/kg/day in two divided doses.

May start higher in AA’s

Question 24

Tacrolimus trough goals

Answer 24

Troughs:

10 +/- 5ng/mL whole blood

• High end early on
• Low end later on

0.5-1.5ng/mL plasma

Question 25

Sirolimus place in therapy

Answer 25

We hardly ever use this.
Through it in if rejection.
Synergistic with CSA in terms of efficacy AND toxicity.

Question 26

Sirolimus MOA

Answer 26

Binds FKBP-12 to inhibit IL-2 stimulated T-cell proliferation.

Question 27

Sirolumus PK

Answer 27

Low oral F
Extensive blood:plasma partitioning
t1/2 = 60hrs
3A4 Metab.

Question 28

Sirolumus SE’s

Answer 28

Dose-dependent thrombocytopenia

Hyperlipidemia

Question 29

Pharmaceutical equivalents

Answer 29

Same shit.

Question 30

Therapeutic equivalents

Answer 30

Same efficacy and SE profile

Question 31

Bioequivalence

Answer 31

They are interchangeable

- Generic is AB-rated

Question 32

Sirolimus major drug interactions

Answer 32

3A4

Question 33

Goal trough CSA

Answer 33

200 +/- 50 mcg/mL initially

150 +/- 50 mcg/mL later

Question 34

CSA and Tac during dialysis

Answer 34

Doesn’t matter.

Question 35

If patient needs to be on something for HTN as well, what should it be?

Answer 35

Nifedipine

Question 36

What to do about the hyperkalemia

Answer 36

Avoid any additional drug that can cause it if possible.

Remember; 1 + 1 = 5

Question 37

What to do if they have DM or hyperglycemia comes up during treatment and poor renal function?

Answer 37

No metformin!

Use insulin: NPH - to match the steroids they are most likely on. Give around 11am-noon to match PK.

Question 38

What if HLD?

Answer 38

Low dose pravastatin only