**6.4. Metabolism of CNIs and major drug interactions**

Both tacrolimus and cyclosporine are metabolized by cytochrome P450 (CYP3a) enzymes that are located in the GI tract and liver. Both drugs are excreted in bile so dosage adjustment is not needed in renal insufficiency. Many medications are metabolized by P450 system and therefore many potential and significant drug interactions with CNI can occur. Classes of drugs that induce CYP3a can reduce CNI levels, such that increased dosing may be required to reach therapeutic and adequate ranges. On the other hand, drugs that block the action of CYP3a can lead to increased levels of CNI, which can lead to acute nephrotoxicity among other side effects. Specific blood pressure medications, antibiotics, anti-fungals, anti-convulsants and HIV medications need to be reviewed for p450 interactions, and both CNI and medications need to be adjusted accordingly. Commonly used medications that affect P450, and the subsequent impact on CNI levels are shown in Table 2.

Table 2 pg. 9

\*Significant increases in CNI level

**Table 2.** CNI-Drug Interactions

**Ritonavir**

**6.5. Adverse effects and toxicities of CNI**

toxicity and its impact on long-term allograft survival.

**Erythromycin Voriconazole Itraconazole Fluconazole**

**\****Significant increases in CNI level*

**\* Ketoconazole Carbamazepine Nicardipine Phenytoin \* Diltiazem Barbiturates Amlodipine Rifabutin \* Verapamil Rifampin**

CNIs have facilitated the success of transplantation and a greater number of patients are living with functioning transplants for longer periods of time. This has made long term CNI exposure and the associated side effects inevitable. Cyclosporine and tacrolimus possess unique side

One of the most significant side effects of CNIs is nephrotoxicity which contributes to chronic allograft dysfunction and late allograft loss. Acute CNI toxicity is functionally mediated by vasoconstriction of the afferent arteriole leading to reduction in renal blood flow and glomer‐ ular filtration rate. Studies demonstrate that CNI increases renin production in the kidney leading to angiotensin II mediated vasoconstriction. [26] Chronic exposure can lead to prolonged vasoconstriction and acute tubular necrosis. Chronic CNI nephrotoxicity can mediate vascular injury, glomerular ischemia, tubular atrophy and chronic interstitial fibrosis. Basic studies do demonstrate that excess production of fibrosing cytokines like transforming growth factor beta (TGF-β) is in part driven by CNI direct role on renin secretion in the kidney. [27] The development of calcineurin minimization and withdrawal protocols as well as the development of new maintenance agents are an attempt to prevent/minimize CNI nephro‐

Other adverse renal manifestations of CNIs include thrombotic microangiopathy, which presents with renal dysfunction, microangiopathic hemolytic anemia and thrombocytopenia. CNI can also cause isolated tubular toxicity which manifests in many forms of electrolyte disturbances. The most prominent and clinically significant of these are renal tubular acidosis (RTA) type 4 (typically associated with metabolic acidosis and hyperkalemia) and hypomag‐

effect profiles which play an important role in agent selection for individual patients.

**Increases CNI level by inhibition of P450** 

**Decreases CNI level by induction of P450**

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Agents that are not often considered in practice, but having an effect on CNI include, steroids which when withdrawn can lead to increases in drug levels of CNIs, and binders such as cholestyramine and sevelamer which can bind CNIs and prevent absorption leading to sub therapeutic levels. Grape fruit juice increases absorption of tacrolimus and hence it is generally recommended to avoid its use with CNIs. Several herbal medications can also alter the metabolism of these drugs.

Because of the sensitive interactions between CNI and antiretrovirals, mangagement of CNI in HIV recipients can be challenging. CNI toxicity and supra therapeutic levels of CNI are common issues in HIV recipients and most likely contributes to allograft dyfunction. Reduced dosing of Tacrolimus is required with some protease inhibitors, particularly Ritonavir, the most potent blocker of CYP3A, and is dosed once to twice a week as opposed to the normal twice a day dosing.


**\****Significant increases in CNI level* \*Significant increases in CNI level

dosing is 1/3rd of the total oral dose, administered as a continuous 24 hour infusion. Patient variability in drug kinetics can be attributed to the heterogeneity of metabolic activity of the enzyme responsible for calcineurin metabolism; the liver enzyme, CYP3A. In general, African Americans may require higher doses of tacrolimus, whereas patients with liver disease and elderly patients may need lower doses. Because of wide patient variability in metabolism, therapeutic drug monitoring is routinely performed with these agents. Most centers check a 12 hr trough level prior to the morning dose. More sophisticated monitoring with area under the curve (AUC) measurements is available but is not routinely performed because of technical and clinical difficulties. During the first 3 months post transplant, our center aims for a 12 hr tacrolimus trough in the range of 8-12 ng/dl, followed by a level of 6-10 ng/dl for months 4 to 12. After the first year, we reduce tacrolimus dosing aiming to achieve maintenance levels of of 4-6 ng/dl. For cyclosporine, a 12 hour trough of 250-350 mg/dl are maintained for the first few months and then target levels are gradually decreased. After the first year post transplan‐ tation the usual cyclosporine trough is between 100-200mg/dl. Targeted drug ranges vary across centers and are driven by center protocols that take into account patient risk, type of

Both tacrolimus and cyclosporine are metabolized by cytochrome P450 (CYP3a) enzymes that are located in the GI tract and liver. Both drugs are excreted in bile so dosage adjustment is not needed in renal insufficiency. Many medications are metabolized by P450 system and therefore many potential and significant drug interactions with CNI can occur. Classes of drugs that induce CYP3a can reduce CNI levels, such that increased dosing may be required to reach therapeutic and adequate ranges. On the other hand, drugs that block the action of CYP3a can lead to increased levels of CNI, which can lead to acute nephrotoxicity among other side effects. Specific blood pressure medications, antibiotics, anti-fungals, anti-convulsants and HIV medications need to be reviewed for p450 interactions, and both CNI and medications need to be adjusted accordingly. Commonly used medications that affect P450, and the subsequent

Agents that are not often considered in practice, but having an effect on CNI include, steroids which when withdrawn can lead to increases in drug levels of CNIs, and binders such as cholestyramine and sevelamer which can bind CNIs and prevent absorption leading to sub therapeutic levels. Grape fruit juice increases absorption of tacrolimus and hence it is generally recommended to avoid its use with CNIs. Several herbal medications can also alter the

Because of the sensitive interactions between CNI and antiretrovirals, mangagement of CNI in HIV recipients can be challenging. CNI toxicity and supra therapeutic levels of CNI are common issues in HIV recipients and most likely contributes to allograft dyfunction. Reduced dosing of Tacrolimus is required with some protease inhibitors, particularly Ritonavir, the most potent blocker of CYP3A, and is dosed once to twice a week as opposed to the normal

induction used and the strength of other agents used for maintenance.

**6.4. Metabolism of CNIs and major drug interactions**

212 Current Issues and Future Direction in Kidney Transplantation

impact on CNI levels are shown in Table 2.

metabolism of these drugs.

twice a day dosing.

Table 2 pg. 9 **Table 2.** CNI-Drug Interactions

#### **6.5. Adverse effects and toxicities of CNI**

CNIs have facilitated the success of transplantation and a greater number of patients are living with functioning transplants for longer periods of time. This has made long term CNI exposure and the associated side effects inevitable. Cyclosporine and tacrolimus possess unique side effect profiles which play an important role in agent selection for individual patients.

One of the most significant side effects of CNIs is nephrotoxicity which contributes to chronic allograft dysfunction and late allograft loss. Acute CNI toxicity is functionally mediated by vasoconstriction of the afferent arteriole leading to reduction in renal blood flow and glomer‐ ular filtration rate. Studies demonstrate that CNI increases renin production in the kidney leading to angiotensin II mediated vasoconstriction. [26] Chronic exposure can lead to prolonged vasoconstriction and acute tubular necrosis. Chronic CNI nephrotoxicity can mediate vascular injury, glomerular ischemia, tubular atrophy and chronic interstitial fibrosis. Basic studies do demonstrate that excess production of fibrosing cytokines like transforming growth factor beta (TGF-β) is in part driven by CNI direct role on renin secretion in the kidney. [27] The development of calcineurin minimization and withdrawal protocols as well as the development of new maintenance agents are an attempt to prevent/minimize CNI nephro‐ toxicity and its impact on long-term allograft survival.

Other adverse renal manifestations of CNIs include thrombotic microangiopathy, which presents with renal dysfunction, microangiopathic hemolytic anemia and thrombocytopenia. CNI can also cause isolated tubular toxicity which manifests in many forms of electrolyte disturbances. The most prominent and clinically significant of these are renal tubular acidosis (RTA) type 4 (typically associated with metabolic acidosis and hyperkalemia) and hypomag‐ nesemia. Proposed mechanisms mediating this effect includes, decreased aldosterone pro‐ duction secondary to cyclosporine, as well as decreased transcription and expression of mineralocorticoid receptor due to prograf.

studies however have shown an association between MPA exposure and clinical outcomes (rejection and toxicity) and therapeutic drug monitoring (TDM) in certain circumstances may be warranted. [30] [31] The APOMYGRE study has shown decreased incidence of acute

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When a serious infection develops, MMF or MPA is typically held since the drug's impact on lymphocyte proliferation is reversible and the immunosuppressive effects disappear within a few days. Intravenous formulations are available for MMF and intravenous dosing is the same as oral dosing with 1:1 conversion. Dose adjustment is not necessary in renal insufficiency. These drugs are not dialyzable. Use of MMF in pregnancy is contraindicated since it is associated with congenital malformations in the fetus especially facial abnormalities.[33] Mycophenolate should be discontinued before planned pregnancy in both male and female

Mycophenolate moefetil is rapidly absorbed and hydrolysed to yield the active component MPA mainly in the liver, which is detectable in peripheral blood within 1-2 hours. MPA is then converted to 7-0-MPA glucuronide also referred to as MPAG (an inactive metabolite) by UDPglucuronosyl transferase (UDPGT) in the liver and intestine. MPAG is excreted through the bile and urine. Both MPA and MPAG are protein bound. So factors such as low albumin concentra‐ tion and high urea levels can decrease protein binding and lead to rapid clearance of the drug. MPAG accumulation in renal failure displaces MPA from protein binding and can lead to an in‐ crease in the free fraction of the drug. Once MPAG is excreted in the bile it can be converted back to MPA by bacterial glucuronidases and lead to increased levels of MPA (enterohepatic recircu‐ lation). This leads to a second peak in the drug concentration 6 to 12 hours after administration which contributes to more than 30% of the area under the curve. Cyclosporine leads to inhibi‐ tion of this second peak by blocking the transporters involved in biliary excretion of MPAG. So typically patients on cyclosporine need higher doses of MMF or MPA compared to patients on tacrolimus. Antibiotic therapy is also known to have a similar impact by inhibiting bacterial

There is no significant drug interaction with medications that induce or block the CYP3A pathway. When used in combination with sirolimus both agents can lead to cytopenias. Generally co administration with antacids and cholestyramine should be avoided as they

The main dose limiting toxicity of MMF or enteric coated MPA is related to gastrointestinal (GI) side effects. More than one third of patients develop diarrhea and in addition some patients have nonspecific GI intolerance in the form of dyspepsia, nausea and vomiting. Indeed, there is evidence demonstrating a correlation between drug exposure and GI toxicity. [31] Most of these side effects are handled with either dose reduction or splitting the dose into 3 to 4 divided doses. Although patients may tolerate enteric coated MPA better, studies

rejection with individualized MMF dosing based on drug exposure. [32]

proliferation in the gut and hence inhibiting enterohepatic recirculation.

transplant recipients.

**6.9. MMF exposure and metabolism**

interfere with absorption of MMF.

**6.10. Toxicity**

Since calcineurin is a ubiquitous enzyme, there are other non-renal toxicities associated with CNI use. Tacrolimus is associated with neurotocity, GI side effects and pancreatic islet toxicity. Neurotoxicity can be as benign as tremors, but in some cases can be quite severe and lead to seizures and altered mental status. Finally, Tacrolimus use has been associated with posterior reversible encephalopathy syndrome (PRES) which can present with various neurological manifestations.[28] Another important clinical issue is the development of new onset posttransplant diabetes, or worsening diabetes post-transplant, particularly with tacrolimus. Neuro and pancreatic toxicity of tacrolimus are clinically handled by either dose reduction or conversion to cyclosporine. Cyclosporine use however can cause gingival hyperplasia, hirsutism, hypercholesterolemia, hypertension, salt retention and an increased incidence of gout. Both CNIs have been linked to increased risk of infectious complications as well as post transplant malignancies. Differences in adverse effects among the CNIs as well as other maintenance agents are shown in Table 3.

The current challenge is to mitigate the side effects of CNIs without sacrificing overall graft outcomes. Several novel protocols are recently designed and studied to overcome CNI toxicity. We have summarized these in the section of new evolving protocols.
