PHRM 542 Solid Organ Transplant Maintenance Therapeutics

What are the goals of maintenance immunosuppression?

Prevent acute and chronic rejection

Optimize patient and graft survival

What is a typical maintenance immunosuppression regimen?

Prednisone, tacrolimus, and mycophenolate mofetil

What is the oral starting dose of tacrolimus?

0.1 mg/kg/day to 0.2 mg/kg/day in TWO divided doses

What is the goal tacrolimus trough concentration for high risk patients?

8-12 ng/mL for first 3 months

What is the goal tacrolimus concentration for low risk patients?

7-12 ng/mL for first 3 months

What is the goal tacrolimus concentration for patients with no rejection?

5-8 ng/mL for stable grafts

How often should tacrolimus trough levels be monitored?

Starting 3 days post-op, twice a week for the first three weeks

Tacrolimus IR twice daily capsule

Prograf

How can tacrolimus IR capsules be administered for NPO patients?

Can be opened and administered SL for NPO instead of using IV

Describe equivalent doses of tacrolimus IR if switching between oral and SL (and vice versa)

Oral to SL = give 50% of the dose

SL to oral = double the dose

Tacrolimus ER once daily

Astragraf XL

Envarsus XR

Describe the conversion of tacrolimus IR to Astragraf XL

1:1 conversion between IR and Astragraf XL

Describe the conversion of tacrolimus IR to Envarsus XR

Greater bioavailability than IR = once daily dose that is 80% of the total daily dose of IR tacrolimus

Round up or down to the nearest whole mg

After switching a tacrolimus formulation, when should trough levels be checked?

After 7 days

What strengths does Prograf come in?

0.5, 1, 5 mg capsules

What strengths foes Envarsus XR come in?

0.75 mg, 1, 4 mg ER 24-hour capsules

Which CNI has a greater likelihood of causing HTN and dyslipidemia?

Cyclosporine

Which CNI has a greater likelihood of causing new-onset diabetes?

Tacrolimus

Which CNI has a greater likelihood of causing neurotoxicity?

Tacrolimus

Which CNI can cause alopecia?

Tacrolimus

Which CNI can cause gingival hyperplasia and hirsutism?

Cyclosporine

Compare tremor with ER tacrolimus versus IR tacrolimus

Less tremor with ER versus IR

What are side effects of both tacrolimus and cyclosporine?

NEPHROTOXICITY, anemia, thrombocytopenia, leukopenia, heparotoxicity, electrolyte abnormalities

Describe acute CNI nephrotoxicity

Early, dose-dependent and reversible

Describe chronic CNI nephrotoxicity

More common

Increased SCr/BUN, hyperkalemia, hyperuricemia, mild proteinuria

Leading cause of renal dysfunction post kidney transplant

Describe the mechanism of CNI nephrotoxicity

Increased afferent arteriole vasoconstriction, decreasing renal blood flow by up to 40%, decreasing GF by 30% with increased proximal tubular sodium reabsorption and reduction in urinary sodium and potassium excretion

What are risk factors for CNI toxicity?

A low C/D ratio = fast metabolizer

How can CNI nephrotoxicity be prevented?

Delay use of CNIs immediately post transplant by using induction regimen

Close CNI drug level monitoring

Avoid other nephrotoxic drugs

What decreases bioavailability of tacrolimus?

Food

Administer IR with or without meals consistently

Administer with food for GI intolerance

When should once daily tacrolimus be dosed?

Dose in morning

When should twice daily tacrolimus be dosed?

12 hours apart (can have different doses AM vs PM, but no more than 0.5-1 mg)

How should extended release tacrolimus be administered?

On an empty stomach 1 hour before or 2 hours after a meal

What increases the initial absorption rate and speeds the release of tacrolimus from ER tablets?

Alcohol = advise patients on ER tacrolimus not to take the medication with alcoholic beverages

What is the formula for tacrolimus dosing adjustments?

PROPORTION

(new dose/new Css) = (old dose/old Css)

What is a lower C/D ratio (fast metabolizer phenotype) linked to a higher incidence of?

Early nephrotoxicity and BK nephropathy

Acute rejection

Infection

Describe the metabolism of tacrolimus

CYP3A5 substrate > CYP3A4 substrate

WEAK inhibitor of CYP3A4

WEAK inhibitor of P-gp

Inhibits OATPs (questionable clinical relevance)

Describe the metabolism of cyclosporine

CYP3A4 substrate

MODERATE inhibitor of CYP3A4

Inhibitor of P-gp

Inhibitor of OATP1B1 and OATP1B3

Inhibitor of MRP2, BCRP, NTCP

How should tacrolimus maintenance therapy be initiated in patients with the CYP3A5*1/*1 or CYP3A5*1/*3 genotype?

Initiate maintenance dose with 1.5-2 times recommended dose not to exceed 0.3 mg/kg/day

How should tacrolimus maintenance therapy be initiated in poor metabolizers?

Initiate maintenance dose with usual dose

When is cyclosporine used for maintenance immunosuppression over tacrolimus?

Tacrolimus neurotoxicity

Hyperkalemia

Alopecia

What happens to MMF levels if you switch from tacrolimus to cyclosporine and why?

MMF levels would decrease because cyclosporine lowers MMF levels (increases costs), while tacrolimus does not

When should C2 concentrations be drawn in patients taking tacrolimus?

15 min before next dose or after the 2 hour post-dose time

Describe the clearance and half-life of tacrolimus and cyclosporine in patients with liver failure

Lower clearance and prolonged half-life

Describe the clearance of tacrolimus and cyclosporine in pediatric patients

Higher clearance

What are examples of CYP3A4 inducers?

Phenytoin

Phenobarbital

Carbamazepine

Rifampin

Rifabutin

St. John's Wort

How will CYP3A4 inducers effect CNI and mTOR levels?

Increases metabolism = decreases concentrations

What are examples of CYP3A4 inhibitors?

Fluconazole

Isavuconazole

Posaconazole

Voriconazole

Diltiazem

Verapamil

Erythromycin

Clarithromycin

Ritonavir

Darunavir

Amiodarone

Cobicistat

How will CYP3A4 inhibitors effect CNI and mTOR levels?

Decreases metabolism = increases concentrations

How should cyclosporine be dose adjusted when used with fluconazole 100-200 mg daily?

Monitor concentrations

How should tacrolimus be dose adjusted when used with fluconazole 100-200 mg daily?

100 mg = monitor concentrations

200 mg = reduce dose by 1/4

How should cyclosporine be dose adjusted when used with fluconazole 400-800 mg daily?

Reduce dose by 1/4

How should tacrolimus be dose adjusted when used with fluconazole 400-800 mg daily?

Reduce dose by 1/2

How should cyclosporine be dose adjusted when used with posaconazole?

Reduce dose by 1/4

How should tacrolimus be dose adjusted when used with posaconazole?

Reduce dose by 2/3

How should cyclosporine be dose adjusted when used with voriconazole?

Reduce dose by 1/2

How should tacrolimus be dose adjusted when used with voriconazole?

Reduce dose by 2/3

What are the max statin doses that can be used with cyclosporine?

5 mg rosuvastatin

20 mg pravastatin

40 mg fluvastatin

What are the max statin doses that can be used with tacrolimus?

20 mg atorvastatin (questionable = can still use 40-80 mg)

5 mg rosuvastatin (questionable = can still use 20-40 mg)

20 mg pravastatin

40 mg fluvastatin

Which statins should be avoided with cyclosporine and tacrolimus?

Simvastatin, lovastatin, and pitavastatin

Describe the DDI between tacrolimus and estrogen/progesterone or estrogen

Increases concentration of tacrolimus

Monitor and adjust

What other agents can tacrolimus interact with (non-PK)?

Agents that increase the risk of hyperkalemia

Agents that increase risk of hypoglycemia

Agents that increase the risk of nephrotoxicity

Avoid concomitant drugs that prolong the QT interval (if unavoidable monitor 12-lead ECG for QT prolongation)

What foods can increase tacrolimus levels?

Grapefruit, grapefruit juice, products containing grapefruit juice

Pomelo, Seville oranges, tangelos, Ugli fruit, pomegranate, star fruit

Ginger

Tumeric

What is the BBW of sirolimus?

Liver transplant

What is the BBW of belatacept?

Post-transplant lymphomphoproliferative disorder (PTLD)

Liver transplant

When is belatacept contraindicated?

In transplant patients with an unknown EBV status or those that are EBV seronegative due to increased risk of developing PTLD

What screening should be done prior to belatacept initiation?

TB screening (usually part of pre transplant evaluation)

What is the role of belatacept in transplant patients?

Renal sparing

Lack of metabolic adverse effects

Adherence

What formulations of mycophenolate are available?

Mycophenolate mofetil (ester prodrug)

Enteric-coated mycophenolate sodium

Mycophenolate mofetil (ester prodrug)

CellCept

Enteric-coated mycophenolate sodium

Myfortic

What are equivalent doses of CellCept and Myfortic?

180 mg Myfortic = 250 mg CellCept

360 mg Myfortic = 500 mg CellCept

After how long should mycophenolate doses be reduced?

After about 2 weeks

What are ADEs of mycophenolate?

GI, myelosuppression, teratogenicity

How should mycophenolate tablets/capsules be taken?

Do not break, open, crush, or chew

What drugs interact with mycophenolate?

Cyclosporine

PPIs

Aluminum/magnesium containing antacids

Antivirals

Hormonal contraceptives

When should azathioprine be used?

When severe GI ADEs to MMF/MPA

Instead of mycophenolate, sirolimus, everolimus during pregnancy

What inactivates azathioprine?

TMPT = check TMPT level first to avoid azathioprine toxicity

When should azathioprine be dose adjusted?

Renal dose adjustment

What is a notable DDI with azathioprine?

Severe leukopenia with XO inhibitors like allopurinol or febuxostat