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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5258_Библиотеки_им_академика_М_И_Перельмана.pdf
35
Immunosuppressant
Dosing
Monitoring
Pharmacokinetics:
Half-life (t
1/2
)
Bioavailability (F) Adverse effects Comments
mTOR
inhibitors
Sirolimus
(Rapamune
®
)
Dosing:
1–5mg PO daily
Monitoring:
Target levels 5–15ng/
mL (trough)
t
1/2
=60h
(113h in hepatic
impairment)
Nephrotoxicity
Endocrine/metabolic
• Hypertriglyceridemia (45–57%)
• Hypercholesterolemia (20–46%)
• Post-transplant diabetes.
Miscellaneous
• Delayed wound healing (inhibits smooth muscle
proliferation)
• Mouth ulcers
• Rash
• Acne
Hematologic
• Leukopenia, anemia, thrombocytopenia
• HemolyticUremicSyndrome/thrombotic
microangiopathy
Respiratory
• Pneumonitis
• Alveolar hemorrhage
• Pleural effusion
Cardiovascular
• Hypertension
Hepatotoxicity
• Increased transaminases, bilirubin
Gastrointestinal
• Diarrhea
Neuromuscular
• Arthralgia
Contraindicated in pregnancy
mTOR inhibitors may be started as a component of
immunosuppressive regimen to reduce the need for
CNI (as part of a CNI sparing or CNI free regimen
as they have non-nephrotoxic properties), and also
as an adjunctive immunosuppressant for patients
with cancer
Everolimus
(Anitor, Zortress
®
)
Dosing:
0.75–5mg PO Q12h
Monitoring:
Target levels 3–8ng/
mL (trough)
t
1/2
=30h Adverse effects similar to sirolimus Anitor Disperz
®
(tablets for suspension) is NOT
indicated in transplant recipients
a
Drug levels only appropriate to assess adherence; there is no clear relationship between toxicity and exposure; mycophenolic acid (MPA) trough 2–5 mcg/mL, area
under the curve (AUC) 30–60 mcg/mL/h, IBW ideal body weight
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
36
3.4 Monitoring
Because most immunosuppressants have a narrow therapeutic index and blood con-
centrations vary signicantly between individuals, therapeutic drug monitoring is
essential to maintain efcacy while minimizing toxicity [7]. The calcineurin inhibi-
tors (tacrolimus, cyclosporine) and mTOR inhibitors (sirolimus, everolimus) require
routine therapeutic drug monitoring of trough concentrations as described in
Table3.2. A stable patient typically has laboratory studies drawn every 3months
after the rst year, although this will be individualized based on transplant center
protocols and patient factors. Primary care providers should review the most recent
laboratory testing—if there has been no testing in the past 3months, then the patient
and/or primary care provider should contact the transplant center, as the patient is
likely overdue.
Monitoring is done via trough levels, which are drawn just prior to the next
dose—for example, a patient who takes tacrolimus at 9am and 9pm may come to
the lab to have blood drawn between 8 and 9am (or between 8 and 9pm if the labo-
ratory is open). Trough levels correlate reasonably well with the area under the
curve (AUC), with total AUC being an accurate measure of drug exposure [9]. Most
solid organ transplant recipients are accustomed to knowing that they should be
having trough levels drawn. However, if a patient has a non-trough blood level
drawn, as might occur in an urgent care or emergency department visit, then that
level may need to be discussed with the transplant team, and likely would need to
be redrawn as a trough level for accurate interpretation.
The frequency of drug level monitoring should be increased following dose
adjustments, as well as in the following situations that a primary care provider may
encounter (Table3.3) [9].
It is best to alert the transplant team when one of these situations occurs if they
are not already aware. While primary care providers may not be making routine
dose adjustments, they are frequently involved with changes in interacting drugs,
intercurrent illnesses, or changes in nutritional status.
Table 3.3 Indications to increase drug level monitoring in solid organ transplant recipients
• Discontinuation or addition of drugs known to interact with immunosuppressants
• Suspected adverse events or rejection
• Deteriorating graft function
• Route of administration or formulation changes
• If the patient acquires a severe illness such as sepsis that may affect drug absorption/
elimination
• If nonadherence is suspected
L. Sun et al.
37
The clinical utility of concentration monitoring for mycophenolate has been
questioned as studies have uncovered conicting results. There is no high-level evi-
dence of a strong association between troughs and outcome or between troughs and
AUC; therefore, it is not very informative for adjusting doses or predicting toxicity
[9]. Occasionally, providers will obtain mycophenolate levels to assess adherence
due to unexpected acute rejection, validate dose reduction due to adverse gastroin-
testinal side effects, or in case of drug interaction [10].
Adherence can be a signicant issue. As discussed previously (see Chap. 2),
medication nonadherence has been reported in 7–36% of transplant recipients, with
increased rates in younger kidney transplant recipients [11, 12]. Patients who are
poorly adherent to immunosuppressive medications are more likely to experience
graft failure or rejection, and if nonadherence is not discovered, they are at risk of
further harm by changes in their immunosuppressive treatment that may not have
been necessary if their transplant team had known [3, 5]. Being aware of common
side effects (See Table3.2) can guide primary care providers in knowing what ques-
tions to ask.
3.5 Drug-Related Complications
Immunosuppressive medications can cause complications from both direct side
effects (renal insufciency, diabetes, cardiovascular disease and others as discussed
in Chap. 11) as well as persistently low immune defenses (infections and malignan-
cies) [13]. Specic drug-related complications and adverse effects are outlined in
Table3.2.
Infection is a common cause of morbidity and mortality among patients receiv-
ing immunosuppression. The risk of infection following transplantation depends on
the recipient’s degree of immunosuppression, epidemiologic exposures, and conse-
quences of invasive procedures (see Chap. 8) [14].
The risk of malignancy is at least twofold higher in transplant recipients com-
pared to the general population, with variations in risk depending on the type of
cancer [15]. Not only are cancers common, but they tend to be more aggressive and
are associated with increased mortality among transplant recipients than in the gen-
eral population [16] (see Chap. 10).
The incidence of cancer is highest for malignancies related to viral infections,
including non-Hodgkin lymphoma (Epstein–Barr virus), Kaposi sarcoma (human
herpesvirus 8), liver (hepatitis B and hepatitis C viruses), and anogenital cancers
(human papilloma virus), because of impaired immune control of these oncogenic
viruses [14]. Azathioprine and cyclosporine also directly enhance the carcinogenic
effects of ultraviolet (UV) radiation via inhibiting DNA repair and resulting in
apoptosis of keratinocytes [17].
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
38
3.6 Drug Interactions [18, 19]
Interactions affecting drug metabolism are common in solid organ transplant recipi-
ents and typically involve specic elements of the cytochrome P-450 enzyme sys-
tem (CYP) as well as P-glycoprotein (P-gp). The combination of immunosuppressive
drugs, which have a narrow therapeutic index, with medications for the treatment of
common comorbidities such as dyslipidemia, infection, psychiatric conditions, and
hypertension, can lead to life-threatening drug interactions. It is critical for primary
care providers to understand these interactions, their impact on patient care, and
management strategies [18]. A summary of common drug interactions is listed in
Table3.4. Hormonal therapy is addressed in Chaps. 13 and 17.
3.6.1 COVID-19 Drug-Related Concerns
Patients with solid organ transplantation infected with SARS-CoV-2 may show dif-
ferent clinical signs, clinical course, and prognosis due, in part, to use of immuno-
suppressant medications. Primary care, urgent care, and emergency department
providers must be aware of the potential for drug-drug interactions and overlapping
toxicities between treatments for COVID-19 and immunosuppressants. The deci-
sion to treat as an outpatient with nirmatrelvir-ritonavir should be made in discus-
sion with the patient and their transplant team based on clinical stability, anticipated
risk of progression to severe disease, and potential risks of treatment (see Chap. 8).
The patient’s transplant specialist will typically be in charge of making decisions
about stopping or adjusting the doses of immunosuppressive drugs. In general,
patients who are treated with nirmatrelvir-ritonavir should continue taking their
immunosuppressant medications but often modify them based on clinical symp-
toms and laboratory results [20, 21]. See Table3.5 for management recommenda-
tions with the most common COVID-19 treatment, nirmatrelvir-ritonavir (Paxlovid
®
)
and immunosuppressants. The landscape of COVID-19 therapies has changed since
the start of the COVID-19 pandemic; for the most up-to-date treatment consider-
ations, primary care providers may need to consult with an infectious disease spe-
cialist. Inpatient and intravenous therapies are not addressed in this chapter.
L. Sun et al.
39
Table 3.4 Common drug interactions to consider in solid organ transplant recipients
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Antifungal medications
Ketoconazole Strong inhibition of
CYP3A4 leads to ↑
tacrolimus/cyclosporine
levels, consider alternative
azole derivative, if possible
(ketoconazole may be used
for boosting levels)
No interaction Strong inhibition of
CYP3A4. Dose reduction of
mTOR inhibitors is
necessary
Inhibition of 3A4 leads
to mildly ↑
corticosteroid levels,
monitor therapy
Voriconazole Strong inhibition of
CYP3A4 leads to ↑
tacrolimus/cyclosporine
levels, consider alternative
azole derivative, if possible
No interaction Strong inhibition of
CYP3A4. Combination is
contraindicated (if must be
used, 50–90% dose
reduction of sirolimus and
close monitoring)
Inhibition of 3A4 leads
to mildly ↑
corticosteroid levels,
monitor therapy
Fluconazole Weak inhibition of CYP3A4
leads to ↑
No interaction Weak inhibition of
CYP3A4 leads to ↑
tacrolimus/cyclosporine
levels, monitor closely
Inhibition of 3A4 leads
to mildly ↑
corticosteroid levels,
monitor therapy
Itraconazole
Tacrolimus/cyclosporine
levels, monitor closely
(clotrimazole may be used
for boosting levels)
Clotrimazole
(continued)
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
40
Table 3.4 (continued)
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Antibacterial medications
Clarithromycin Strong inhibition of
CYP3A4 leads to ↑
Antibiotic interference with
enterohepatic recirculation of
mycophenolic acid metabolite
leads to mildly ↓
mycophenolate levels, monitor
therapy
P-gp inhibition may
lead to ↑
Inhibition of 3A4 leads
to mildly ↑
corticosteroid levels,
monitor therapy
tacrolimus/cyclosporine
levels, consider alternative
antibiotic
sirolimus/everolimus levels.
Combination with
everolimus is
contraindicated (if must be
used, 50% dose reduction
of everolimus and close
monitoring)
↑ additive risk for QT
prolongation (assess baseline
EKG, monitor routinely if
antibiotic course is
prolonged)
Azithromycin Azithromycin interference
with biliary excretion of
cyclosporine and inhibition
of Pg-p may lead to ↑
Antibiotic interference with
enterohepatic recirculation
of mycophenolic acid
metabolite leads to mildly ↓
mycophenolate levels, monitor
therapy
P-gp inhibition may
lead to ↑
sirolimus/everolimus levels,
consider alternative antibiotic
Inhibition of 3A4 leads
to mildly ↑
corticosteroid levels,
monitor therapy
tacrolimus/cyclosporine
levels, monitor therapy
QT prolongation is a more
signicant risk with
azithromycin (assess
baseline EKG, monitor
routinely if antibiotic course
is prolonged). May be used
with caution if necessary
L. Sun et al.
41
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Erythromycin Moderate inhibition of
CYP3A4 leads to ↑
Antibiotic interference with
enterohepatic recirculation of
mycophenolic acid metabolite
leads to mildly ↓
mycophenolate levels, monitor
therapy
P-gp inhibition may
lead to ↑
Inhibition of 3A4 leads
to mildly ↑
corticosteroid levels,
monitor therapy
cyclosporine levels, if
concomitant use is required,
decrease cyclosporine dose
up to 50%
Sirolimus/everolimus
levels, consider alternative
antibiotic
Trimethoprim/sulfamethoxazole Additive risk for
hyperkalemia (monitor
closely)
No interaction No interaction No interaction
Rifampin Strong induction of
CYP3A4 will lead to ↓
levels of tacrolimus/
cyclosporine
No interaction Strong induction of
CYP3A4 will lead to ↓
levels of siroimus/
everolimus
Induction of 3A4
leads to ↓
corticosteroid levels,
monitor therapy
Avoid if possible, if
concomitant use is required,
increase tacrolimus/
cyclosporine dose twofold
Avoid if possible, if
concomitant use is required,
increase sirolimus/
everolimus dose twofold
Fluoroquinolones Additive risk for QT
prolongation (assess
baseline EKG, monitor
routinely if antibiotic course
is prolonged)
No interaction No interaction Elevated risk of
tendinitis and tendon
rupture, monitor patient
Antiviral medications
(continued)
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
42
Table 3.4 (continued)
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Nirmatrelvir-ritonavir (Paxlovid
®
)
See Table3.5 for management of
immunosuppression while on
concomitant Paxlovid
®
Strong inhibition of
CYP3A4 leads to ↑
tacrolimus/cyclosporine
levels, use alternative
anti-COVID-19 therapy
(e.g., IV remdesivir)
No interaction Strong inhibition of
CYP3A4 leads to ↑
sirolimus/everolimus levels,
use alternative anti-
COVID- 19 therapy
No interaction
If must be used, hold
tacrolimus as soon as
possible and for at least
2–3days following
Paxlovid discontinuation.
Timing and dose for
tacrolimus resumption
should be guided by
continued monitoring of
tacrolimus levels
If must be used, hold
sirolimus/everolimus during
treatment with Paxlovid and
for at least 2–3days
following Paxlovid
discontinuation. Timing and
dose for sirolimus/
everolimus resumption
should be guided by
continued monitoring of
sirolimus/everolimus levels
If must be used, consider
cyclosporine dose reduction
of 80%. Timing of
cyclosporine dose increases
after Paxlovid completion
should be guided by
continued monitoring of
cyclosporine levels
L. Sun et al.
43
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Ganciclovir, valganciclovir No interaction Mycophenolate-glucuronide
inhibits renal tubular secretion
of ganciclovir which leads to ↑
ganciclovir/vaganciclovir
levels and therefore, ↑ risk for
nephrotoxicity neutropenia,
leukopenia. Monitor therapy
No interaction No interaction
Ganciclovir/valganciclovir are
routinely given with MMF in
the transplant recipient
Cardiovascular medications
Lipid lowering agents:
(continued)
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
44
Table 3.4 (continued)
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Simvastatin, lovastatin, atorvastatin Increased statin exposure by
calcineurin inhibitors,
especially c
yclosporine
(inhibits CYP3A4)
No interaction No interaction No interaction
↑ risk of myopathy and
rhabdomyolosis
Pravastatin, rosuvastatin or
uvastatin are preferred,
although other statins have
been used successfully. If
other statins considered,
reduce dose to 50% prior to
starting immunosuppressive
medication and monitor for
myopathy if up-titration
required; discuss with
transplant team (Note: all
heart transplant recipients
receive statin therapy) (see
Chap. 11)
Anti-hypertensive agents:
L. Sun et al.