Toxicity and efficacy of sirolimus: Relationship to whole-blood concentrations

CLINICALTHERAPEUTICS’IVOL.

22, SUPPL. B, 2000

Toxicity and Effkacy of Sirolimus: Whole-Blood Concentrations Herwig-Ulf

Meier-Kriesche,

Relationship

to

MD, and Bruce Kaplan, MD

Depurtmrnt of Internal Medicine, Division of Nephrology, University of Michigun Medical School, Ann Arbor, Michigun

ABSTRACT Background: Sirolimus is a novel macrolide immunosuppressivedrug with a mechanism of action distinct from that of both cyclosporine and tacrolimus. Recent clinical studies have demonstrateda decreasein acute rejection episodesin renal transplant patients receiving sirolimus compared with controls. The major toxicities associatedwith sirolimus treatment are thrombocytopenia and hyperlipidemia. In addition, concern has been raisedby the higher serumcreatinine levels noted in patients receiving sirolimus and cyclosporine compared with controls receiving cyclosporine and azathioprine. Objective: The objective of the presentreview is to summarize the efficacy and toxicity data for sirolimus. Special consideration is given to evidence that links these effects to dose or whole-blood concentrations of sirolimus. Results: The literature indicatesthat trough concentrations of sirolimus >I 5 ng/mL appear to be associatedwith a greater risk of both thrombocytopenia and hyperlipidemia, whereas trough sirolimus concentrations 46 ng/mL have been associated with an increasedincidence of acute rejection. Conclusion: The evidence to date supports target trough sirolimus concentrations of 6 to IS ng/mL in most patients. In higher-risk groups and patients receiving cyclosporinesparing regimens, higher concentrations may be necessaryto achieve similar efficacy. Key words: sirolimus, toxicity, efficacy, concentrations, pharmacokinetics. (Clin Ther. 2000;22[Suppl B]:B93-B 100)

Accepted Printed

for publication December in the USA. Reproduction

0149-291

s/00/$l9.00

3, 1999. in whole or part

is not permitted

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CLINICAL

INTRODUCTION Sirolimus* is a potent macrolide immunosuppressant.’ Extensive clinical studies over the past several years have documented its efficacy in decreasing acute rejection in renal transplant recipients when given in conjunction with cyclosporine and corticosteroids.2-6 The objective of these studies was to determine whether the addition of sirolimus to these 2 drugs would improve the efficacy of this regimen without causing additional side effects or toxicity.‘-” In addition, several lines of evidence suggest that combining sirolimus with cyclosporine and corticosteroids may allow a decrease in the dose (or even withdrawal) of 1 or both of these agents and thus decrease the toxicities associated with these agents.‘-” In general, the initial expectations for this combination have been met. However, as is the case with most potent therapies, toxicities and adverse events have been identified with sirolimus. The objective of the present review is to summarize the efficacy and toxicity data for sirolimus. Special consideration is given to evidence that links these effects to dose or whole-blood concentrations of sirolimus. PHARMACOKINETIC CHARACTERISTICS The pharmacokinetic characteristics of sirolimus have been discussed extensively elsewhere.“‘.” The relative bioavailability of sirolimus is low (-lS%).‘2 After oral dosing, the pharmacokinetic profile of sirolimus is characterized by a relatively short time to maximum concentra‘Trademark: Rapamune”’ (Wyeth-Ayerst ries. Philadelphia. Pennsylvania).

B94

Laborato-

THERAPEIJTICS’

tion of 1 to 3 hours and a long terminal elimination half-life of -60 hours. Sirolimus is extensively distributed to various tissues and organs, and has a large steady-state volume of distribution of -7 to 15 L/kg. Studies in rats have reported considerable accumulation of sirolimus in the heart, kidney, intestine, and testes.‘j,‘J Coadministration of cyclosporine may increase tissue distribution of sirolimus.” In vitro, it appears that the primary route of metabolism of sirolimus is the cytochrome P-450 (CUP) 3A family of isozymes. ” Because both cyclosporine and sirolimus are substrates for CYP 3A4, as well as for the p-glycoprotein transporter system, interactions between these 2 drugs have been assessed in detail.” There is some evidence that sirolimus may increase cyclosporine concentrations when the 2 drugs are coad’ninistered.‘” Furthermore, cyclosporine has been noted to have a more marked effect on sirolimus concentrations. In rats, sirolimus concentrations were increased when the 2 drugs were coadministered.‘” In humans, the quantitative effects of these interactions are less clear. One study in stable renal transplant recipients Ix demonstrated that the relative timing of administration of the 2 drugs had significant effect on the extent of the interaction between cyclosporine and sirolimus. When cyclosporine and sirolimus were administered together, the mean area under the curve (AUC) for sirolimus was -50% higher than when the drugs were administered 4 hours apart (P < O.Ol), whereas the timing of administration seemed to have no effect on cyclosporine concentration. Ix Most data on the relationship between sirolimus concentrations and effects have been based on trough values, and a strong correlation has been reported between

H.-U.

MEIER-KRIESCHE

AND

B. KAPLAN

sirolimus concentrations 24 hours after the last dose (C24) and AUC.‘” Thus, current recommendations for monitoring sirolimus pharmacokinetic/pharmacodynamic relationships are based on trough or C24 con centrations. In the clinical situation, there may be little role for full AUC monitoring. EFFICACY Phase 111studieszO have clearly demonstrated that sirolimus decreases the incidence of acute rejection in renal transplant recipients. These studies compared a regimen of cyclosporine, sirolimus, and prednisone with either cyclosporine, azathioprine, and prednisone or cyclosporine, placebo, and prednisone. Based on prior phase II studies,3 2 doses of sirolimus were compared (2 and 5 mg QD). The results demonstrated that biopsy-proven acute rejection was significantly decreased in both the 2- and 5-mg sirolimus groups (P < 0.05) (table). Definitive data regarding the relation of sirolimus concentrations to the incidence of acute rejection are not yet available. Subanalysis of the data has raised a question of whether the benefit seen in the entire population extended to the subgroup of black transplant recipients.21x22 The poorer results in black patients could not be ascribed to a difference in pharmacoki-

netic behavior. It was noted, however, that cyclosporine concentrations were lower in several black patients compared with white patients. This analysis2’ also indicated that black patients had somewhat better results with the S-mg dose. Further studies may be warranted to determine the optimal dose and concentration of sirolimus in black renal transplant recipients. In large animal studies,23*24trough levels > IO mg/L were necessary to protect against rejection. In human renal transplant recipients, a report from 1 center indicated a relationship between the dose and absorption of sirolimus and the occurrence of acute rejection. I7 Another report, 2s based on the phase 111study data, indicated that trough sirolimus levels did correlate with the occurrence of acute rejection. In this analysis, patients who experienced an episode of acute rejection had a mean sirolimus concentration of 56 kg/L, whereas patients who experienced no rejection had trough sirolimus concentrations of 2 IO p.g/L. TOXICITY The primary treatment-emergent toxicities associated with sirolimus therapy are thrombocytopenia, leukopenia, anemia, and hyperlipidemia. The results of a study from the University of Texas at Houston demonstrated the relationship between

Table. Results of phase III study of sirolimus in renal transplant recipients.20 Study

Group

Sirolimus 2 mg Sirolinius 5 mg Azathioprine *P < 0.05 compared

Acute Rejection (%b)

Graft Survival (% )

Patient Survival (%)

IS’ II* 24

94.7 92.7 98. I

97.2 96.0 94.4

with azathioprine.

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CLINICALTHERAPEUTICS

sirolimus concentration and these toxicities (figure).2” In general, theselaboratory abnormalitiescorrelated in a linear fashion with increasing trough concentrations of sirolimus.This effect wasmost apparentin both the platelet count and serum triglyceride leveL2’ Platelet counts were generally 25% lower in patients with trough sirolimus levels of >I5 kg/L compared with patientswith trough levels of I5 kg/L compared with patients with trough concentrations of <.5 kg/L (P < 0.01). In contrast, the hematocrit and white blood cell count were not as strongly correlated with trough sirolimus level. The investigators noted that theselaboratory abnormalitiesseemed to improve with doseadjustment.2h There is some controversy concerning the possiblepotentiation of cyclosporineinduced nephrotoxicity by sirolimus. Both animal and human studies have failed to demonstrate any histologic or hemodynamic deleteriouseffect of sirolimuson the kidney (when sirolimus was administered without cyclosporine).2xIn I study,2” sirolimus given alone produced no renal vasoconstriction or decreasein the glomerular filtration rate or renal blood flow. However, possibletubular toxicity was inferred from a finding of renal magnesiumwasting.2” One group of investigatorsworking with a salt-depletedSprague-Dawleyrat model of cyclosporine nephrotoxicity noted that sirolimus increasedcyclosporine-induced histologic lesions.“0However, these investigators did not measureconcentrationsof sirolimus; thus, it is difficult to ascertain whether this was a pharmacodynamic or pharmacokinetic potentiation. A study in the Wistar-Furth rat suggestedthat the observeddecreasein glomerularfiltration rate B96

could be ascribedto sirolimus-relatedincreasesin cyclosporine concentrations.3’ Likewise, resultsof the phaseIll studies2” indicated that patients in the sirolimus group tended to have higher serumcreatinine levels than patients in the control group. The decreasedrenal function seen in the sirolimus group has yet to be explained adequately. Determining whether the decreasein creatinineclearanceseenin the sirolimus group was causedby an effect on cyclosporine concentrations or a pharmacodynamiceffect will require further analysis. CONCLUSIONS Sirolimus is an effective and potent immunosuppressive agent.When usedin conjunction with cyclosporineand corticosteroids, it reduces the incidence of acute rejection in renal transplantrecipientswithout producingan increasein overall adverse events.‘A The major treatment-emergent toxicities associatedwith sirolimus appear to be increasesin triglyceride levels anddecreasesin plateletcount. Whether sirolimus potentiatescyclosporine nephrotoxicity is asyet uncertain. Given the findings to date. it is reasonable to draw some tentative conclusions about the pharmacokinetic behavior and effects of sirolimus. Because there is a strong correlation between trough sirolimus concentrationsand AUC, current recommendations for monitoring sirolimus pharmacokineticipharmacodynamic relationships are for trough or C24 concentrations. Additionally, there may be little role for full AUC monitoring in the clinical situation. There is controversy regarding the correlation between trough levels of sirolimus and the incidenceof acute rejection in humans.However, the data suggest

H:U.MEIER-KRIESCHEAND

B.KAPLAN

A

40 i1 -0

30

.E. E 20 :: 5 f IO I 0 <5

5-10

IO-15

>I5

Sirolimus (ng/mL)

6

+ "0 F x E s 0 H 2 m 11

250 200 150 100 50 0 4

5-10

IO-15

>I5

Sirolimus (ng/mL)

L

8 E 2 0 = Q-oi 2J4

6

-0X

ma,

2 <5

5-10

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215

Sirolimus (ng/mL)

<5

5-10

10-15

>I5

Sirolimus (ng/mL)

Figure. The relationship between sirolimus concentrations and specific toxicities.26 B97

CLINICAL

that concentrations% pg/L may be necessary for sirolimus to provide its full protective effect when coadministered with full-dose cyclosporine and corticosteroids. In cyclosporine- or corticosteroid-sparing protocols, trough sirolimus levels will in all likelihood need to be somewhathigher. It is possible that trough concentrations may need to be higher in black patients than in white ones. The toxicity of sirolimus appears to be most marked at trough concentrations >I5 kg/L. This is particu-

larly true in the case of hypertriglyceridemia

and thrombocytopenia.

Sirolimus is a promising therapeutic option in renal transplant recipients. As this drug is used and investigated further, a better understanding of its pharmacokinetic and pharmacodynamic behavior will be gained. In this regard, a prospective,

concentration-controlled clinical trial in renal transplant patients would be invaluable in developing the scientific basis for therapeutic

drug monitoring

of sirolimus.

ACKNOWLEDGMENT This study was performed

with the finan-

cial support of Wyeth-Ayerst Research Laboratories, Princeton, New Jersey. Address correspondence to: Bruce Kaplan, MD, University of Michigan Medical Center, Department of Internal Medicine, 3914 0364, Ann Arbor,

Taubman Center, MI 48 109-0364.

Box

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