Immunosuppresants Flashcards
What are the 4 immunosuppressant drugs?
Cyclosporine microemulsion (CSA)
Tacrolimus (TAC)
Sirolimus (SRL)
Everolimus (EVR)
What is the brand name of CSA?
Neoral
What is the brand name of TAC?
Prograf, Envarsus XR, Astagraf XL
What is the brand name of SRL?
Rapamune
What is the brand name of EVR?
Zostress
What is the indication for the immunosuppressant drugs?
Prevention of allograft rejection
What is the conversion ratio from PO to IV for CSA?
3:1 conversion ratio PO:IV
What CSA medication is the original formulation, has poor absorption and has a variable PK in patients?
Oral Sandimmune
What CSA medication is a microemulsion, has improved absorption and less variability in PK for patients
Oral Neoral
What CSA medication is considered therapeutically interchangeable with Oral Neoral?
Gengraf (generic CSA formulation)
What is the bioavailability (F) in Neoral?
F = 5 to 70%
What is the volume of distribution (Vd) in Neoral?
Vd = 3 to 7 L/kg
What does Neoral bind to in the blood affecting Vd? By how much percent?
Erythrocytes; 70%
What does Neoral bind to in plasma affecting Vd?
Lipoproteins
What is Neoral metabolized by?
Hepatic and intestinal CYP3A4
What is Neoral transported by after being metabolized?
P-gp
Can variations of intestinal P-gp and CYP3A4 affect F for CSA?
YES
How is Neoral eliminated?
Eliminated by kidneys
What is the t 1/2 of Neoral?
12 to 16 hours
What are two strategies to monitor CSA?
- Pre-dose trough whole blood concentration (C0)
2. Single point sampling 2 hours after drug administration (C2)
Which strategy to monitor CSA is thought to be a bit less inaccurate?
C2
Roughly what is the initial dose of CSA?
4 mg/kg PO q12h
CSA should be titrated based off what?
Steady-state trough (C0) blood levels
For the first 6 months of post-transplant of a liver or kidney organ, what should the therapeutic C0 level be for CSA?
200-250 ng/mL
For the first 6 months of post-transplant of a heart or lung organ, what should the therapeutic C0 level be for CSA?
250-300 ng/mL
In the first month of post-transplant, how many times a week should the trough (C0) levels be monitored for CSA?
3 times a week
In the next two months from the first month of post-transplant, how many times a week should the C0 levels be monitored for CSA?
2 times a week
In the next 3 months from the three months of post-transplant, how many times a week should the C0 levels be monitored for CSA?
once a week
How many times should the C0 levels be monitored when a patient has passed 6 months from their post-transplant or had any dose changes to CSA?
Once a month
To achieve therapeutic C0 levels in CSA, how should doses be adjusted?
25 to 50 mg PO q12h
What is the conversion ratio from PO to IV for TAC?
5:1 conversion ratio from PO:IV
What is the name of the TAC medication that has poor absorption and highly variable PK?
Prograf
What is the name of the TAC medication that is an extended release tablet?
Envarsus XR
What is the name of the TAC medication that is an extended release capsule?
Astagraf XL
What is the F for Prograf?
F = 5 to 67%; mean 27%
What is the F for Envarsus XR?
F = about 50% higher than Prograf
(T/F) - Astagraf is better taken with food and in the morning hours for better bioavailability
FALSE - it’s better taken in the morning hours and with an EMPTY stomach
What is the Vd of Prograf, Envarsus XR, and Astagraf XL?
Vd = 5 to 6 L/kg
What do the 3 TAC drugs bind to in blood? What’s the percentage?
Erythrocytes by 70 to 80%
What do the 3 TAC drugs bind to in plasma? What’s the percentage?
Albumin and alpha-1 acid glycoprotein by 88%
How are the 3 TAC drugs metabolized?
Hepatic and intestinal CYP3A4
How are the 3 TAC drugs transported after being metabolized?
By the P-gp
(T/F) - Variations in the P-gp and CYP3A4 can affect the bioavailability in the 3 TAC drugs
TRUE
How is Prograf eliminated and what is the half life mean?
Minimal renal elimination; t 1/2 = 12 hours
How is Envarsus XR eliminated and what is the half life?
Minimal renal elimination; t 1/2 = 31 +/- 8 hours
How is the Astagraf XL eliminated and what is the half life?
Minimal renal elimination; t 1/2 = 38 +/- 3 hours
What are two strategies for TAC monitoring?
- High correlation between trough (C0), Cmax, and AUC 0-4
2. Pre-dose trough whole blood concentration (C0) is the standard care
What is the initial dosing for Prograf?
0.05 mg/kg PO q12h
What is the conversion dose of Prograf to Envarsus XR?
80% of Prograf taken QD
What is the conversion dose of Prograf to Astagraf XL?
Same as Prograf taken QD
What is the target therapeutic C0 level of TAC?
5 to 15 ng/mL
The target therapeutic C0 level of TAC in a liver or kidney transplant is what? For how long should it be that range?
8 to 10 ng/mL for 6 months
The target therapeutic C0 level of TAC in a heart or lung transplant is what? For how long should it be that range?
10 to 15 ng/mL for 6 months
How should C0 levels be monitored for Prograf during the 6 months?
First month: 2/3 x weekly
Second and third month: 2 x weekly
Fourth, fifth, and sixth month: once a week
(T/F) - After the 6 months from post-transplant or any dose adjustments to Prograf, C0 levels should be monitored once every two weeks
FALSE - once a month
How should C0 levels be monitored for Envarsus XR and Astagraf XL after post-transplant?
Three months: once a week
Monthly after first three months
How is the dose of Prograf adjusted to reach therapeutic levels?
0.5 to 2 mg PO q12h
Is SRL available intravenously?
NO
What is the SRL brand name that has poor absorption, highly variable PK, and also known as rapamycin?
Rapamune
CSA has been administered in a patient and Rapamune has been assigned to that patient. When do you administer Rapamune? Why?
4 hours after CSA due to an interaction
What is the F of Rapamune?
F = 15% (poorly absorbed)
What is the Vd of Rapamune?
Vd = 4 to 20 L/kg ( ~12 L/kg)
What is Rapamune highly bound to in the blood? By how much percent?
Erythrocytes; 95%
What is Rapamune highly bound to in the plasma? By how much percent?
Lipoproteins; 40%
What is Rapamune metabolized by and how is it transported?
CYP3A4 and transported by P-gp
How is Rapamune eliminated? & what is the half-life?
Minimal renal elimination; t 1/2 = 57 to 63 hours
Can Rapamune be given as a LD, MD or both?
BOTH
What are two strategies for SRL monitoring?
- High correlation between C0 and AUC
2. Whole blood trough C0 monitoring is standard of care
What is the dose for SRL in a low-moderate immunological risk (kidney or liver transplant)?
2 mg QD
What is the dose for SRL in a high immunological risk (heart or lung transplant)?
5 mg QD
What is the therapeutic C0 levels for SRL?
5 to 15 ng/mL
How would you monitor the C0 levels for SRL?
First month: once a week
Next 3 months or any dose adjustments: monthly
How is the SRL dose adjusted?
0.5 to 1 mg/day
What EVR brand drug has variable oral bioavailability and interindividual PK variability?
Zostress
(T/F) - EVR tablets and dispersible tablets are interchangeable
TRUE
What is the EVR brand name that is ONLY indicated for subependymal giant cell astrocytoma (SGCA)
Afinitor Disperz
What is the F of EVR?
F = 30% (reduces w/ meals)
What is the Vd of EVR?
Vd = 2 to 5 L/kg
What is EVR bounded to in plasma? What is the percentage?
Protein - 70%
How is EVR metabolized?
CYP3A4 and P-gp
How is EVR eliminated?
Feces (80%) and minimal renal excretion (5%)
What is the half-life of EVR?
T 1/2 = 30 hours
What are 2 strategies for EVR monitoring?
- High correlation between trough (C0), Cmax, and AUC 0-4
2. Predose trough whole blood concentration (C0) is the standard care
What is the dose of EVR for liver transplant?
1 mg BID
What is the dose of EVR for renal transplant?
0.7 mg BID
What is the therapeutic trough level range for EVR?
3 to 8 ng/mL
How are trough levels monitored for EVR?
One month: 1-2 x week
After one month: clinically as indicated
How are EVR doses adjusted to reach therapeutic trough levels?
0.25 to 0.5 mg PO q12h
