Organ Transplant- Heemer

What is the class for each of the following?

• cyclosporine

• tacrolimus

• sirolimus

• calcineurin inhibitor

• calcineurin inhibitor

• mTOR inhibitor

What is the MOA for each of the following?

• cyclosporine

• tacrolimus

• sirolimus

• complex interacts with calcineurin to inhibit its catalytic activity that’s involved with expression of genes related to production of cytokines

  • tacrolimus—> binds to FKPB-12

  • cyclosporine—> binds to cyclophyllin

• sirolimus: Binds to FKPB-12, complex binds to mTOR and inhibits IL-2 from binding and prevents T-cell proliferation and progression

What is the indication for each of the following?

• cyclosporine

• tacrolimus

• sirolimus

• cyclosporine- prevent GVHD in HSCT, prevent graft rejection in solid organ transplant, tx of psoriasis, RA

• tacrolimus- prevent allograft rejection in liver, kidney, heart, Crohn’s Disease, atopic dermatitis, dental—> lesions

• sirolimus- tx of GVHD in HSCT, prevent graft rejection in solid organ transplant

What is the dosage forms for each of the following?

• cyclosporine

• tacrolimus

• sirolimus

• cyclosporine- capsules, oral solution, IV injection

• tacrolimus- capsules, IV injection

• sirolimus- tablets, oral solution

For cyclosporine oral solution, what 2 formulations are available?

What is the ratio if you wanted to switch between the 2?

Which formulation has a higher bioavailability?

• microemulsion and regular formulation

• 1:1 ratio from regular to microemulsion

• microemulsion formulation—> higher bioavailability

What are the ADRs of cyclosporine?

• HTN!!!!

• nephrotoxicity

• hyperlipidemia

• tremor

• hirsutism

• gingival hyperplasia

What are the ADRs of tacrolimus?

• neurotoxicity

• nephrotoxicity

• hepatotoxicity

• HTN

• hyperkalemia

• hypomagnesemia

• glucose intolerance

• pruritis

• alopecia

• leukocytosis

What are the ADRs of sirolimus?

• myelosuppression

• hyperlipidemia

• delayed wound healing

• peripheral edema

• mouth ulcers

• elevated LFTs

• HTN

• skin: rash, acne

• GI: d

• arthralgia

For Cyclosporine, Tacrolimus, and Sirolimus they ALL have the same drug interactions. What are they metabolizers and substrates of?

• ALL—> CYP3A4 METABOLIZERS

• ALL—> P-gp substrates

For Cyclosporine, Tacrolimus, and Sirolimus they ALL have the same drug interactions. These interactions are put into 2 categories. What drugs are in the “known to be nephrotoxic” category?

• aminoglycoside

• abx

• vancomycin

• cotrimoxaole

• amphortericin B

• NSAIDs

For Cyclosporine, Tacrolimus, and Sirolimus they ALL have the same drug interactions. These interactions are put into 2 categories. What drugs are in the “inhibit metabolism” category?

• CCBs (verapamil, diltiazem, nicardipine)

• azole antifungals (fluconazole, itraconazole)

• macrolide abx (erythromycin, clarithromycin)

• antivirals (indinavir, nelfinavir, ritonavir)

• steroids (methylprednisolone, oral contraceptives, androgens)

• psychotropic agents (fluvoxamine, nefazodone)

• grapefruit juice

For Cyclosporine, Tacrolimus, and Sirolimus they ALL have the same drug interactions. These interactions are put into 2 categories. What drugs are in the “induce metabolism” category?

• other abx (naficillin, rifampin, rifabutin)

• anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone)

• barbiturates

• aminoglutethimide

• troglitazone

• octreotide

• ticlopidine

Sirolimus can be administered with Calcineurin Inhibitors, however with what calcineurin inhibitor do we have to carefully watch drug levels? whY?

• MUST WATCH: sirolimus + cyclosporine

• why? cyclosporine MAY inhibit sirolimus metabolism

Since cyclosporine may inhibit sirolimus metabolism, how can we solve this problem?

administer sirolimus 4 hrs after cyclosporine

What is the bioavailability of each of the following?

• cyclosporine

• tacrolimus

• sirolimus

• cyclosporine: ~30%

• tacrolimus: ~25%

• sirolimus: PO solution—> 14%, Tablet—> 17%

For cyclosporine 2 types of assays can be used to measure conc of drug in the blood. What are those 2 assays?

• HPLC + monoclonal immunoassay

• polyclonal immunoassay

For each type of assay for cyclosporine, what is the goal therapeutic range in the blood and plasma?

• HPLC + monoclonal immunoassay

  • blood: 100-400 ng/ml

  • plasma: 50-150 ng/ml

• polyclonal immunoassay

  • blood: 200-800ng/ml

  • plasma: 50-150 ng/ml

Why is the concentration of cyclosporine higher in the blood vs. plasma?

cyclosporine is mainly bound to RBCs

For Tacrolimus and sirolimus, there isn’t one specific assay utilized. What are the therapeutic ranges for each drug?

• tacrolimus

  • blood: 5-20 ng/ml

  • plasma: 0.5-2 ng/ml

• sirolimus

  • 5-15 ng/ml

(DISCLAIMER: sometimes sirolimus-specific chromatograph assay is used for sirolimus)

For sirolimus, a concentration <5 and >15 are each associated with what?

<5= acute rejection

>15= ADRs

Answer the following about the administration of CYCLOSPORINE:

• IV- concentration, dilution, infusion rate

• Oral- high fat meal does what to absorption?

• Oral solution- how is it prepared? mixed with what?

• IV: 50mg/ml concentration and before admin, dilute with 20-100ml NS or D5W, infused over 2-6 hrs

• oral: high fat meals= increase absorption

• oral solution: prepared with olive oil and alcohol and mixed in milk/orange juice

Answer the following about the administration of TACROLIMUS:

• IV- concentration, dilution, infusion rate

• Oral- dose for kidney and liver transplant, high fat meal doses what to bioavailability?

• IV: 5mg/ml concentration, diluted with NS or 5% to a concentration between 0.004-0.02 mg/L, continuous infusion

• oral:

  • kidney transplant: 0.2 mg/kg/day

  • liver transplant: 0.1-0.15 mg/kg/day (decrease 25/50%)

  • high fat meal= DECREASEs bioavailability

Answer the following about the administration of SIROLIMUS:

• oral solution- concentration, dilution, mixed with what

• oral- high fat meal does what to bioavailability? administer when?

• oral solution: 1mg/ml concentration diluted in at least 60ml of water/orange juice, stir, drink

• oral: high fat meal= increase bioavailability by 34%, administer at consistent times

Cyclosporine, Tacrolimus, and Sirolimus should not be taken with what?

grapefruit juice!!!

Which immunosuppressant should be delayed in kidney transplant? Why?

tacrolimus—> bc of nephrotoxicity

PRACTICE PROBLEM:

A 45 YO male kidney transplant pt. is receiving 300mg/day of cyclosporine IV. He is now 3 days post-op and is stable. His cyclosporine at steady state is 200ng/ml. What oral dose should he receive?

PRACTICE:

If I took grapefruit juice with Tacrolimus, which of the following would you expect to happen?

a. increase bioavailability of tacrolimus

b. decrease bioavailability of tacrolimus

c. no effect

a