case report drug interaction between sirolimus and...

Case ReportDrug Interaction between Sirolimus and Ranolazine in a KidneyTransplant Patient

Joanna C Masters1 Mita M Shah23 and Ashley A Feist2

1 Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego La Jolla CA 92093 USA2University of California San Diego Medical Center Center for Transplantation La Jolla CA 92037 USA3University of California San Diego Medical Center Department of Medicine Division of Nephrology and HypertensionSan Diego CA 92103 USA

Correspondence should be addressed to Ashley A Feist aafeistucsdedu

Received 17 September 2013 Accepted 16 October 2013 Published 2 January 2014

Academic Editors P A Andrews D Capone R Grenda and H P Tan

Copyright copy 2014 Joanna C Masters et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Purpose The case of a kidney transplant recipient who experienced a probable drug interaction between sirolimus and ranolazineis reported Summary The narrow therapeutic window of immunosuppressive therapy in transplant recipients requires closemonitoring for potential drug-drug interactions The patient a 57-year-old Caucasian male kidney transplant recipient wasstable for years on sirolimus as his primary immunosuppressive agent and had a history of chronic angina for which he wasprescribed ranolazine Upon addition and dose escalation of ranolazine whole blood sirolimus levels more than tripled risingto immeasurably high concentrations After holding sirolimus on multiple occasions and reducing dosage more than 50 bloodlevels returned to therapeutic range while continuing ranolazine Conclusion Since ranolazine is a documented P-GP and CYP3Ainhibitor and sirolimus a known substrate for both pathways it is proposed that ranolazine inhibition of P-GP and CYP3A4contributed to the significant elevation in sirolimus exposure No alternative causes for the rise in sirolimus exposure were foundand assessment with the Drug Interaction Probability Scale finds this interaction to be probable Clinicians should be aware of thepotential for this interaction to cause elevated sirolimus exposure and subsequent increase in clinical effect or toxicity in this caseoverimmunosuppression

1 Introduction

Immunosuppressive agents used in solid organ transplanthave narrow therapeutic windows making drug-drug inter-actions amajor concern As new drugs are brought tomarketclinically significant drug interactions may be identified thathave not been previously reported in the literature Thiscase report describes a possible drug interaction betweensirolimus and ranolazine in a kidney transplant patient lead-ing to supratherapeutic blood concentrations of sirolimus

Ranolazine is a piperazine derivative approved for treat-ment of refractory angina however its exact mechanismof action is unclear Ranolazine is metabolized primarilyby intestinal and liver enzymes CYP3A (cytochrome P450family 3A) and to a lesser extent CYP2D6 resulting in activemetabolites with less than 5 of compounds excreted inthe urine It is reported to be a mild inhibitor of CYP3A

Ranolazine is also a substrate and moderate inhibitor of p-glycoprotein (P-GP) an active transporter that serves as anintestinal efflux pump [1 2]

The immunosuppressant sirolimus is amammalian targetof rapamycin (mTOR) inhibitor which is used in transplantpatients in place of or along with calcineurin inhibitors suchas cyclosporine and tacrolimus Sirolimus is metabolizedprimarily by CYP3A4 and about 2 is excreted in urineSirolimus is also a substrate and mild inhibitor of the P-GP efflux pump [3] Due to the narrow therapeutic windowdrug interactions through CYP or P-GP mechanisms are ofconcern and increased knowledge about such interactionscan prevent unnecessary toxic accumulation of sirolimus andsignificant adverse events

The purpose of this paper is to report a probable druginteraction between sirolimus and ranolazine leading toelevations in sirolimus blood levels To further assess this

Hindawi Publishing CorporationCase Reports in TransplantationVolume 2014 Article ID 548243 4 pageshttpdxdoiorg1011552014548243

2 Case Reports in Transplantation

interaction an advanced literature search of the PubMeddatabase was performed using the search terms ranolazineand sirolimus No results were reported This lack of pub-lished information regarding concomitant use of these twoagents highlights the importance of presenting this casereport

2 Case Report

A 57-year-old Caucasian male presented to the long-termkidney transplant clinic for routine follow-up The patientrsquosmedical history was significant for type 1 diabetes mellitussince the age of ten leading to complications of coronaryartery disease with chronic angina and end-stage renaldisease Four years prior to presentation the patient receiveda simultaneous pancreas and kidney transplant The patientunderwent pancreatectomy shortly after transplantation dueto graft thrombosis but the kidney allograft continuedto function Additionally he underwent a redo coronaryartery bypass graft (CABG) one year after transplant Dueto an intolerance of mycophenolate mofetil and tremoron therapeutic-dose tacrolimus he has been maintainedon an immunosuppressive regimen of sirolimus low-dosetacrolimus and prednisone since shortly after transplan-tation His renal function has been stable with a serumcreatinine ranging from 13 to 17mgdL

The patient had remained adherent and stable onsirolimus for several years with whole blood levels of 8ndash12 ngmLondoses of 5 to 7mgbymouth daily Approximatelyseven months prior to presentation to our transplant clinicthe sirolimus dose was increased from 6mg to 7mg dailyOne week later the patient presented to his cardiologist withworsening angina and was started on ranolazine 500mg bymouth twice daily (Figure 1) Four months after the additionof ranolazine sirolimus trough concentration was measuredto be 191 ngmL higher than previous values but still withinthe target therapeutic range No changes were made to hisimmunosuppressive regimen at this time Due to ongoingangina shortly thereafter the ranolazine dose was increasedtwofold to 1 gram twice daily No other significant changesin his medication profile were made throughout this timeperiod

One month following this ranolazine dose increase thepatient presented to the emergency department for paindehydration and malaise following a recent oral surgery Inthe emergency department the sirolimus level was found tobe greater than 60 ngmL which is beyond the upper limitof detection of the assay A repeat level confirmed this valueAfter consultationwith the transplant nephrology service thesirolimuswas held for four days until concentrations reached155 ngmL All other laboratory values were within normallimits including renal and hepatic function tests Sirolimuswas then restarted at a decreased dose of 6mg daily howeverrepeat levels were once again above the therapeutic targetand therefore the dose was further reduced one week later to5mgdaily (see Figure 1 for detailed timeline) At this time theetiology of the elevated sirolimus levels was unclear and hadnot been associated with a possible drug-drug interaction

0

10

20

30

40

50

60

70

Siro

limus

(ng

mL)

No ranolazine

Time (relative to clinic visit)

012345678910

Siro

limus

dos

e (m

gda

y)

SirolimusSirolimus dose

minus1

mo

minus2

mo

minus3

mo

minus4

mo

minus5

mo

minus6

mo

minus7

mo

minus8

mo

minus9

mo

minus10

mo

Clin

ic

+1

mo

Ranolazine(500mg BID)

Ranolazine(1g BID)

lowast

Figure 1 Timeline of sirolimus dosing and whole blood concen-trations with ranolazine titration 998771 level above limit of detectionuarr sirolimus held for 1 day lowast patient presents to emergencydepartment

In following month the patient presented for follow-up to our kidney transplant clinic His medication list atpresentation included sirolimus 5mg daily with a targettrough concentration of 10ndash20 ngmL low-dose tacrolimus1mg daily prednisone 5mg daily clopidogrel 75mg dailyaspirin 325mg daily ranolazine 1 gram twice daily amlodip-ine besylate 10mg daily lisinopril 10mg daily metoprololtartrate 100mg twice daily furosemide 20mg twice dailynitroglycerin sublingual spray 04mg as needed for chestpain hydromorphone hydrochloride 4mg every 4 hours asneeded for pain vitamin D 5000 IU daily and insulin lisproadministered via insulin pump The patient reported takingall medications as prescribed and the only major medicationchanges in the recent past were titration of ranolazine andsirolimus as described previously At this visit his steady-state sirolimus trough level was elevated to 334 ngmL Closereview of his recent sirolimus levels and dosing history wasmade by the clinical pharmacist and transplant nephrologistand an association between the addition of ranolazine andthe highly elevated sirolimus levels was identified A druginteraction was suspected between ranolazine and sirolimusbased on ranolazinersquos moderate P-GP inhibition and mildCYP3A inhibition The patient was instructed to hold twodoses of sirolimus and reduce his daily dose to 3mg there-after with close monitoring of his sirolimus levels He wouldcontinue on ranolazine 1 gram twice daily as instructed by hiscardiologist and was advised to notify the transplant clinic ofany future changes in ranolazine therapy

The patient returned for labs in two weeks at which timehis sirolimus level was 192 ngmL He was then instructed tocompletely discontinue his low-dose tacrolimus due to therisk of potential overimmunosuppression Six months laterhis sirolimus levels have remained within the target rangeon 2-3mg daily and he has continued on the same dose ofranolazine 1 gram twice daily

Case Reports in Transplantation 3

3 Discussion

Ranolazine is reported to be a moderate inhibitor of P-GP and the manufacturer includes a caution that dosereductionmay be needed in agents transported byP-GPwhenused in combination with ranolazine Ranolazine is also aCYP3A inhibitor and package information contains a genericcaution for use with drugs with narrow therapeutic windowsincluding sirolimus tacrolimus and cyclosporine Howeverno published reports were found on the specific druginteraction or magnitude of interaction between sirolimusand ranolazine Two published case reports describe aninteraction between tacrolimus and ranolazine in transplantrecipients proposing that both the weak CYP3A inhibi-tion and the moderate P-GP inhibition were responsiblefor observed elevated tacrolimus levels which in one caserequired a 70 decrease in tacrolimus dose [4 5] Anothercase report suggests that the same dual P-GP and CYP3Ainhibitionwas responsible for increased simvastatin exposureupon addition of ranolazine which resulted in toxicity ofrhabdomyolysis [6] Ranolazine concentrations were notmeasured for this patient during the reported time periodand therefore systemic ranolazine levels cannot be assessedin this case

Of note this patient was also concurrently on tacrolimusHowever he was on a low dose given once daily with levelsbelow the limit of detection of the assay and hadno changes intacrolimus dose during the timeperiod detailed in this reportAfter the addition of ranolazine tacrolimus levels increasedto the detectable range but still remained subtherapeutictherefore requiring no dose adjustment For this reason thedrug interaction between ranolazine and tacrolimus whichhas been reported previously [4 5] was not a primary focusof this case report

Drugs such as ranolazine that have both CYP and P-GP inhibition have the potential to create large increasesin systemic concentrations of agents that are substrates ofboth such as sirolimus An increase in bioavailability throughinhibited P-GP efflux in addition to a decrease in first-passmetabolism and systemic clearance through inhibition ofCYP enzymes may result in sirolimus blood levels several-fold above the target systemic concentration Such an eventwas described in a patient whose sirolimus levels increasedmore than eightfold upon addition of clarithromycin apotent inhibitor of both P-GP and CYP3A [7] Sirolimusblood levels far above the therapeutic window can havedire consequences for the patient including complicationsof overimmunosuppression leading to serious infectionsPatients on immunosuppressants such as sirolimus andconcomitant dual CYP and P-GP inhibitors require closermonitoring of systemic drug levels particularly after anyrelevant medication andor dose changes Patients shouldbe clearly instructed to report any changes instituted byother providers to the transplant clinic team for appropriatefollow-up including up-to-date drug levels and increasedmonitoring if necessary

Alternative explanations do exist for the phenomenondescribed here however upon review we have determinednone to be highly probable in this patient case Of course

we assume that the patient was adherent to the prescribedsirolimus regimen as this is what he reported during dis-cussion with providers and there was no evidence of changesin prescription refill patterns that would suggest overdosingThe presence of other concomitant medications resulting in adrug interaction with sirolimus andor ranolazine would alsocontribute to supratherapeutic sirolimus exposure We couldidentify no other alterations in medication regimen withthe potential to significantly impact ranolazine or sirolimusexposure The patientrsquos hepatic function remained normalthroughout this time making acute hepatic impairmentan unlikely explanation for impaired sirolimus clearanceHigh fat meals have been shown to increase the mean totalexposure (AUC) of sirolimus by 23 to 35 [3] however anunreported change in dosing timewith regard tomeals or anydietary changes is also not likely to explain themagnitude andthe duration of change in sirolimus level seen in this case

There is also a possibility that the degree of the P-GPinteraction between ranolazine and sirolimus and subsequentincrease in sirolimus bioavailability is impacted by dosingtimes Simultaneous administration of sirolimus and modi-fied cyclosporine a known CYP3A4 and P-GP inhibitor hasbeen shown to increase the mean maximum concentration(119862max) of sirolimus by 512 andAUCby 148 comparedwithadministration of sirolimus alone However administeringsirolimus four hours after modified cyclosporine as directedby the package insert results in only a 33 increase in both119862max and AUC [3] Perhaps a similar phenomenon could beobservedwith ranolazine and sirolimus and thusminimizingthe amount of ranolazine present in the gut to inhibit P-GP efflux could reduce the extent of increase in sirolimusexposure

4 Conclusion

In this case we observed that upon the addition of ranolazine1 gram twice daily sirolimus dosing had to eventually bereduced by greater than fifty percent Based on the sequenceof events and knownmechanisms listed above we believe thatthe doubling of the daily ranolazine dosewas the precipitatingfactor in the significant elevation of sirolimus trough levelsThe phenomenon observed here did not represent an acuteevent but a sustained interaction that persisted while thepatient continued on ranolazine No reasonable alternativecauses for the magnitude of increase in sirolimus exposurecould be foundThe combination of inhibition of P-GP effluxand CYP3A4 enzymatic clearance by ranolazine explainsthe mechanism that may have caused the great increase insirolimus concentration that occurred shortly thereafter

This is the first published report of a drug interac-tion between ranolazine and sirolimus resulting in ele-vated sirolimus exposure The patient was able to continuetreatment on both sirolimus and ranolazine once doseswere appropriately adjusted based on frequent blood levelmeasurements We determined the patient experienced aprobable drug interaction through evaluation with the DrugInteraction Probability Scale (DIPS)This scale is a tool whichaids in objective assessment of causation in patient cases


involving suspected drug interactions [8] Further study isneeded to improve understanding of the mechanism andextent of the drug interaction as well as methods to reducethe severity such as dose separation Transplant recipientstaking sirolimus should be instructed to report any medica-tion changes to the providersmanaging their transplantmed-ications and take care to monitor for any signs of infectionor other new adverse effects Furthermore other providersshould be encouraged to check for any potential interactionswith narrow therapeutic range immunosuppressants beforeadding or removing medications for comorbid conditions

Conflict of Interests

All authors state there is no conflict of interests that anyauthor should disclose No resultsdatafigures in this paperhave been published elsewhere nor are they under consider-ation by another publisher

References

[1] Ranexa (Ranolazine) Package Insert Gilead Sciences FosterCity Calif USA 2011

[2] M Jerling ldquoClinical pharmacokinetics of ranolazinerdquo ClinicalPharmacokinetics vol 45 no 5 pp 469ndash491 2006

[3] Rapamune (Sirolimus) Package Insert Wyeth PharmaceuticalsPhiladelphia Pa USA 2011

[4] D A Pierce and A M Reeves-Daniel ldquoRanolazine-tacrolimusinteractionrdquo Annals of Pharmacotherapy vol 44 no 11 pp1844ndash1849 2010

[5] H PatniM Gitman A Hazzan andK D Jhaveri ldquoRanolazinetacrolimus and diltiazemmight be a hazardous combination ina transplant patientrdquo Renal Failure vol 34 no 2 pp 251ndash2532012

[6] A C Hylton and T O Ezekiel ldquoRhabdomyolysis in a patientreceiving ranolazine and simvastatinrdquo American Journal ofHealth-System Pharmacy vol 67 no 21 pp 1829ndash1831 2010

[7] D Capone G Palmiero A Gentile et al ldquoA pharmacokineticinteractions between clarithromycin and sirolimus in kidneytransplant recipientrdquoCurrent DrugMetabolism vol 8 no 4 pp379ndash381 2007

[8] J R Horn P D Hansten and L Chan ldquoProposal for a new toolto evaluate drug interaction casesrdquo Annals of Pharmacotherapyvol 41 no 4 pp 674ndash680 2007

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interaction an advanced literature search of the PubMeddatabase was performed using the search terms ranolazineand sirolimus No results were reported This lack of pub-lished information regarding concomitant use of these twoagents highlights the importance of presenting this casereport

2 Case Report

A 57-year-old Caucasian male presented to the long-termkidney transplant clinic for routine follow-up The patientrsquosmedical history was significant for type 1 diabetes mellitussince the age of ten leading to complications of coronaryartery disease with chronic angina and end-stage renaldisease Four years prior to presentation the patient receiveda simultaneous pancreas and kidney transplant The patientunderwent pancreatectomy shortly after transplantation dueto graft thrombosis but the kidney allograft continuedto function Additionally he underwent a redo coronaryartery bypass graft (CABG) one year after transplant Dueto an intolerance of mycophenolate mofetil and tremoron therapeutic-dose tacrolimus he has been maintainedon an immunosuppressive regimen of sirolimus low-dosetacrolimus and prednisone since shortly after transplan-tation His renal function has been stable with a serumcreatinine ranging from 13 to 17mgdL

The patient had remained adherent and stable onsirolimus for several years with whole blood levels of 8ndash12 ngmLondoses of 5 to 7mgbymouth daily Approximatelyseven months prior to presentation to our transplant clinicthe sirolimus dose was increased from 6mg to 7mg dailyOne week later the patient presented to his cardiologist withworsening angina and was started on ranolazine 500mg bymouth twice daily (Figure 1) Four months after the additionof ranolazine sirolimus trough concentration was measuredto be 191 ngmL higher than previous values but still withinthe target therapeutic range No changes were made to hisimmunosuppressive regimen at this time Due to ongoingangina shortly thereafter the ranolazine dose was increasedtwofold to 1 gram twice daily No other significant changesin his medication profile were made throughout this timeperiod

One month following this ranolazine dose increase thepatient presented to the emergency department for paindehydration and malaise following a recent oral surgery Inthe emergency department the sirolimus level was found tobe greater than 60 ngmL which is beyond the upper limitof detection of the assay A repeat level confirmed this valueAfter consultationwith the transplant nephrology service thesirolimuswas held for four days until concentrations reached155 ngmL All other laboratory values were within normallimits including renal and hepatic function tests Sirolimuswas then restarted at a decreased dose of 6mg daily howeverrepeat levels were once again above the therapeutic targetand therefore the dose was further reduced one week later to5mgdaily (see Figure 1 for detailed timeline) At this time theetiology of the elevated sirolimus levels was unclear and hadnot been associated with a possible drug-drug interaction

0

10

20

30

40

50

60

70

Siro

limus

(ng

mL)

No ranolazine

Time (relative to clinic visit)

012345678910

Siro

limus

dos

e (m

gda

y)

SirolimusSirolimus dose

minus1

mo

minus2

mo

minus3

mo

minus4

mo

minus5

mo

minus6

mo

minus7

mo

minus8

mo

minus9

mo

minus10

mo

Clin

ic

+1

mo

Ranolazine(500mg BID)

Ranolazine(1g BID)

lowast

Figure 1 Timeline of sirolimus dosing and whole blood concen-trations with ranolazine titration 998771 level above limit of detectionuarr sirolimus held for 1 day lowast patient presents to emergencydepartment

In following month the patient presented for follow-up to our kidney transplant clinic His medication list atpresentation included sirolimus 5mg daily with a targettrough concentration of 10ndash20 ngmL low-dose tacrolimus1mg daily prednisone 5mg daily clopidogrel 75mg dailyaspirin 325mg daily ranolazine 1 gram twice daily amlodip-ine besylate 10mg daily lisinopril 10mg daily metoprololtartrate 100mg twice daily furosemide 20mg twice dailynitroglycerin sublingual spray 04mg as needed for chestpain hydromorphone hydrochloride 4mg every 4 hours asneeded for pain vitamin D 5000 IU daily and insulin lisproadministered via insulin pump The patient reported takingall medications as prescribed and the only major medicationchanges in the recent past were titration of ranolazine andsirolimus as described previously At this visit his steady-state sirolimus trough level was elevated to 334 ngmL Closereview of his recent sirolimus levels and dosing history wasmade by the clinical pharmacist and transplant nephrologistand an association between the addition of ranolazine andthe highly elevated sirolimus levels was identified A druginteraction was suspected between ranolazine and sirolimusbased on ranolazinersquos moderate P-GP inhibition and mildCYP3A inhibition The patient was instructed to hold twodoses of sirolimus and reduce his daily dose to 3mg there-after with close monitoring of his sirolimus levels He wouldcontinue on ranolazine 1 gram twice daily as instructed by hiscardiologist and was advised to notify the transplant clinic ofany future changes in ranolazine therapy

The patient returned for labs in two weeks at which timehis sirolimus level was 192 ngmL He was then instructed tocompletely discontinue his low-dose tacrolimus due to therisk of potential overimmunosuppression Six months laterhis sirolimus levels have remained within the target rangeon 2-3mg daily and he has continued on the same dose ofranolazine 1 gram twice daily


3 Discussion







4 Conclusion







References














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Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















3 Discussion







4 Conclusion







References














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Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References














of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















case report drug interaction between sirolimus and...

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