- Email: [email protected]
Requirements for therapeutic Drug monitoring of sirolimus, an immunosuppressive agent used in renal transplantation
CLINICAL THERAPELJTICS /VOL. 22, SUPPL. B, 2000
Requirements for Therapeutic Drug Monitoring of Sirolimus, an Immunosuppressive Agent Used in Renal Transplantation Launa J. Aspeslet, PhD, and Randall W. Yatscoff, PhD Isotrchnika
Inc., Ednontnrz, Alhertcr, Ctrn~~du
ABSTRACT Background: On September 15, 1999, sirolimus received approval from the US Food and Drug Administration (FDA) for marketing as an immunosuppressive agent. As with any chronically administered medication, the question arises whether therapeutic drug monitoring (TDM) is required for optimal therapy. In the case of sirolimus, there are data to suggest that TDM may be beneficial in some patients. Objective: To assess the need for monitoring sirolimus concentrations, this paper reviews the following factors influencin g the usefulness of TDM: wide pharmacokinetic variability; toxicity; suspected noncompliance; suspected drug interactions; and specific demographic characteristics. Data supporting the correlation between sirolimus concentration and immunosuppressive efficacy are also discussed. Results: The available literature on sirolimus suggests that TDM may be required in some cases. Studies have shown that there is wide interindividual variability in the pharmacokinetic behavior of drugs in transplant patients; that there is a relationship between blood concentrations of sirolimus and adverse events; and that coadministration of cyclosporine alters the pharmacokinetics of sirolimus. Additionally, the correlation between sirolimus concentration and immunosuppressive efficacy in phase III trials suggests a benefit in transplant patients when sirolimus concentrations reach appropriate levels. Finally, noncompliance is a common occurrence in the transplant population, and monitoring is often necessary in suspected noncompliers. Conclusion: Although additional clinical studies are needed, it appears that TDM is an important aspect of treatment with sirolimus. Key words: sirolimus, therapeutic drug monitoring, renal transplantation. (Clirr Tlwr. 2000;22[SuppI B]:B86-B92) Accepted for pubkcation March Printed in the USA. Reproduction
B86
8, 2000. in whole
or part
IS not permitted.
L.J. ASPESLET
AND
R.W.
YATSCOFF
INTRODUCTION On September 15, 1999, sirolimus* received approval from the US Food and Drug Administration (FDA) for marketing as an immunosuppressive agent for the prophylaxis of acute rejection in renal transplant patients. With a potential for widespread use of this drug, the question arises regarding the need for therapeutic drug monitoring (TDM) of sirohmus. To answer this question, it is necessary to examine the situations in which TDM is useful. Generally, TDM is valuable when: (I) the drug shows wide interindividual pharmacokinetic vatiability; (2) signs of toxicity are difficult to recognize clinically; (3) pathophysiologic factors may affect drug pharmacokinetics; (4) there is no correlation between dose and result; (5) noncompliance is suspected; or (6) drug interactions are suspected. Furthermore, for TDM to be useful, a clear relationship between drug concentration and effects must be shown. Although many of the above situations have not been thoroughly investigated with regard to sirolimus, this chronic immunosuppressive drug, like many other immunosuppressants, may require TDM in a number of circumstances. This paper reviews the situations on which data are available in the peer-reviewed literature, and examines the relationship between sirolimus concentration and immunosuppressive efficacy that makes TDM a useful component of immunosuppressive therapy with this drug. PHARMACOKINETIC
VARIABILITY
Key pharmacokinetic data in renal transplant patients were obtained from a phase ‘Trademark: Rapamune” (Wyeth-Ayerst ries. Philadelphia. Pennsylvania).
Laborato-
I clinical trial.’ This study was a doubleblind, ascending multiple-dose study conducted in 40 stable renal transplant patients who were receiving steady-state regimens of cyclosporine and prednisone. Nine doses of sirolimus were used, ranging from 0.5 to 6.5 mg/m2 every 12 hours. The pharmacokinetic parameters of sirolimus, determined by electrospray highperformance liquid chromatography-mass spectrometry (HPLC-MS), were calculated for all dose groups. The mean (k SD) time to maximum blood concentration (T,,,,) was 1.4 + 1.2 hours; the terminal half-life was 62.3 f 16.2 hours; the oral dose clearance was 208.0 + 95.0 mL/h per kg; the steady-state volume of distribution was 12.0 + 4.6 L/kg; and the blood-plasma ratio was 38.0 + 12.8. The interindividual variabilities in clearance, volume of distribution, and bloodplasma ratio of sirolimus showed -4.5fold ranges. This large pharmacokinetic variability is similar to that seen with other immunosuppressive drugs for which TDM is employed, namely cyclosporine, tacrolimus, and mycophenolate mofetil. The investigators in the phase I study] postulated that the large interindividual variation in clearance of sirolimus was due mainly to the combined action of the cytochrome P-450 (CUP) 3A4 isozyme responsible for the metabolism of sirolimus and the multidrug efflux pump, p-glycoprotein. Both CYP 3A4 and pglycoprotein are located in the enterocytes of the small intestine.* A study examining small-intestinal biopsy samples from 20 patients found an 1I -fold variation in the intestinal content of CYP 3A4.” Also important is the finding that the activity of both intestinal CYP 3A4 and p-glycoprotein is affected by coadB87
CLINICAL
ministration of other drugs, particularly cyclosporine.3,” This same study’ found a linear relationship between steady-state blood trough concentrations of sirolimus and area under the concentration-time curve (AUC) in the dosage range from 0.5 mg/m2 to 3.5 mg/m* every 12 hours. This finding suggests that monitoring of trough blood concentrations could be used to adjust the dosages of patients within this range. In addition, the ranges of the individual pharmacokinetic parameters were highly overlapped between dose groups, suggesting that pharmacokinetic parameters are not dose dependent. Results of the phase I study’ also suggest that due to the long half-life of sirolimus, a loading dose is necessary to achieve therapeutic steady-state concentrations rapidly. The study demonstrated that a loading dose -3 times greater than the maintenance dose could be administered, to a maximum single dose of 60 mg (based on available data). In such a situation, it may be useful to monitor trough sirolimus concentrations to ensure that a target concentration is achieved after administration of the loading dose. TOXICITY A clinical study in which 20 renal transplant patients were administered various doses of sirolimus found a correlation between adverse events and whole-blood trough sirolimus concentrations 2 I5 ng/mL, as determined by HPLC.S Similar conclusions were drawn from a phase II clinical study conducted in renal transplant patients receiving either cyclosporine (n = 42) or sirolimus (n = 41).” In the latter study, patients were given an initial loading dose of sirolimus I6 to 24 mg/m2 per day, followed by 8 to 12 mg/m* B88
THERAPEUTICS’
per day, adjusted to achieve a target trough level of 30 ng/mL for 8 weeks. Thereafter, daily dosing was reduced to maintain a target trough level of I5 ng/mL, as determined by HPLC. A strong relationship was observed between trough sirolimus concentrations and adverse effects. The abnormalities, primarily thrombocytopenia, leukopenia, hypertriglyceridemia, and cholesterolemia, were noted to improve when trough sirolimus concentrations were in the range from IO to 20 ng/mL. COMPLIANCE TDM is often used to monitor compliance. Because immunosuppression following transplant surgery is chronic therapy and maintenance of trough drug levels is a necessity for the prevention of acute rejection, patients must adhere to the daily drug regimen. However, the literature indicates that not all transplant patients do so, and this lack of adherence can lead to graft loss and possibly death. One study in pediatric heart and heart-lung transplant recipients7 found that one third of individuals examined (n = 53) showed unsatisfactory adherence to the treatment regimen, due in part to family dynamics. A larger multicenter study in 1402 renal transplant recipients” found that 22.4% of patients reported noncompliance. A logistic regression model that included age, occupation, time since transplantation, and medication-related beliefs (ie, efficacy and importance of immunosuppressant therapy) was most predictive of the likelihood of compliance. Donor type and history of diabetes or infection became predictive factors in the multivariate model only when the belief-related variables were excluded.
L.J. ASPESLET
AND R.W. YATSCOFF
DRUG INTERACTIONS Cyclosporine Coadministered cyclosporine and sirolimus are an effective combination for the prophylaxis of rejection. However, the combination of these 2 agents creates a potential for drug interactions. The bioavailability of both relies on intestinal CYP 3A4 isozymes, p-glycoprotein, and membranepermeability, in addition to hepatic first-pass effects.2,y,‘0 Thus, each drug could affect metabolismof the other, leading to increasedlevels of I or both. Such an interaction wasnot immediately apparentin clinical studies.In the phaseI study examining the pharmacokinetic effects of the coadministration of cyclosporineand sirolimus in stable renal transplant patients,’ sirolimus did not produce any significant changesin the AUC of cyclosporine over the 2-week study period. However, patients in this study received cyclosporine -3 hours after sirolimus.Another study involved stablerenal transplant patients who had been receiving a combination of sirolimus, cyclosporine microemulsion formulation, and prednisonefor 23 months.” Dosesof the drugs were kept constantthroughout the study, and only the timing of dosing was varied. This study found that the timing of cyclosporine administration affected sirolimus blood concentrations,whereasthe timing of sirolimus administration did not affect cyclosporine concentrations.AUC and trough concentrations of sirolimuswere significantly higher when the drug was administeredconcomitantly with cyclosporine microemulsion,as opposedto when the drugs were administered 4 hours apart. Conversely, in a study examining sirolimus in liver transplantpatients,12the combination of sirolimus and
cyclosporine appeared to cause a mutual increasein blood concentrations.Theseauthors noted that formal multiple-dosepharmacokinetic studiesare neededto confirm this observation in the hepatic transplant population. There is the possibility that concomitant administrationof the 2 drugsmay produce hyperlipidemic effects. When the drugs are administeredalone, theseeffects are manifested in increasedtriglyceride levels with cyclosporine treatment and increasedcholesterol levels with sirolimustreatment.‘” Prednisolone Prednisolone is often administered in combination with cyclosporine and sirolimus. When a rabbit model was usedto investigate the concomitant administration of sirolimus with prednisolone,“’ it was concluded that at therapeutic concentrations, the 2 drugs do not demonstratea significant pharmacokinetic interaction. Other Drugs Other drugs that are likely to be prescribedconcomitantly with sirolimuswere investigated for possible effects on the pharmacokinetic behavior of sirolimus. Diltiazem and ketoconazole increased sirolimus maximum concentration (CmZlx), T m;,x,and AUC. Rifampin, on the other hand, decreasedsirolimus ClllaTand ALJC. Acyclovir, digoxin, glyburide, nifedipine, and norgestreliethinyl estradiol did not alter sirolimus pharmacokinetics.‘,‘5 DEMOGRAPHIC CHARACTERISTICS Although specific demographic characteristics are not included among the facB89
CLINICAL
tors calling for TDM, they play an important role in the use of sirolimus as an immunosuppressive agent. In the phase 1 study in stable renal transplant patients,’ the pharmacokinetic parameters of sirolimus, as determined by HPLC-MS, were compared in black (n = 9) and nonblack patients (n = 17). Significant differences were noted in terms of T,,,,,, and clearance (Cl). In black patients, T,,,:,, was increased 2000/o, and Cl was increased 45%. These results suggest that there may be a reduced rate and extent of absorption in black patients. However, a recent report that examined the effect of race on the efficacy and safety of sirolimus in a subset of patients enrolled in a phase 111 trial’” did not reach the same conclusions. This study found that at 6 months posttransplantation, there were no significant differences in pharmacokinetic parameters between black and nonblack patients. Experimental details such as the numbers of black and white patients in the study and the analytical method used will be important to interpretation of these data. The phase I study’ also compared the pharmacokinetic parameters of sirolimus in men and women, and found no significant differences.
THERAPELJTICS’
treated de novo with a combination regimen of cyclosporine, sirolimus, and prednisone.‘* Results indicated that the incidence of chronic rejection was inversely proportional to the sirolimus dose and correlated with lower sirolimus absorption. as determined by dose-corrected AUC. A phase II study of sirolimus as base therapy in renal transplant patients6 indicated that trough sirolimus concentrations maintained at 30 ng/mL for the first 8 weeks and then maintained at trough levels of IS ng/mL were sufficient to prevent acute rejection. Statistical analysis of the phase III clinical trial in which sirolimus was administered in combination with cyclosporine emulsion and steroids has revealed a correlation between acute rejection episodes and trough sirolimus concentration.” The emerging data from clinical trials indicate that there is a relationship between sirolimus concentrations and immunosuppressive efficacy, suggesting the usefulness of TDM with this drug. The data support the use of monitoring as a guide to dosage adjustment to achieve maximum immunosuppressive efficacy while minimizing toxicity. CONCLUSIONS
DRUG CONCENTRATIONS VERSUS EFFECT In situations in which TDM is useful, it is necessary to show a correlation between blood drug concentrations and outcomes. To date, few studies have been published that examine the correlation between blood concentrations of sirolimus and efficacy in transplant patients. (This is partly due to the low frequency of acute rejection episodes.“) One single-center study examined 120 renal transplant patients B90
Review of the available literature supports the desirability of TDM for sirolimus based on the drug’s emerging pharmacokinetic and pharmacodynamic characteristics, as follows. A relationship between blood concentrations of sirolimus and toxic events has been observed in transplant patients. Drug interaction studies have demonstrated the ability of cyclosporine to alter the pharmacokinetics of sirolimus when the 2 drugs are coadministered. Finally, recent analyses of the
L.J. ASPESLET
AND R.W. YATSCOFF
phase III clinical trial data suggest that there is a therapeutic window in transplant patients.‘” Routine TDM is not an absolute requirement for the use of sirolimus. However, results have indicated that it may be necessary in some cases. This is similar to the approach for mycophenolate mofetil, but differs from those for both cyclosporine and tacrolimus, in which TDM is considered an essential part of patient management. Based on an informal survey of several transplant centers by the authors (Yatscoff RW, unpublished data, l999), it appears that centers currently using sirolimus are conducting TDM of this drug. Consequently, as automated assays become available, the use of TDM of sirolimus is likely to increase. This, in conjunction with data from ongoing clinical trials, will permit more thorough examination of the variables discussed in this paper.
Address correspondence Aspeslet, PhD, Isotechnika 108th Avenue, Edmonton, T5S lE8.
3. Hebert MF, Roberts JP, Prueksaritanont
T, Benet LZ. Bioavailability of cyclosporin with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. C/i/l Phurmacd Ther. lYY2;52:453+4S7.
4.
Huang JD, Su SF. Effect of quinidine on digoxin absorption in the rat: Interaction on P-glycoprotein in the small intestine. FASEB /. lYY5;Y:A6Yl. Abstract.
5.
Kahan B. Sirolimus: A new agent for clinical renal transplantation. Trmsplnnt Proc. lYY7;29:48-50.
6.
Groth CC. BIckman L, Morales J-M, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation. Trafzsplantdon. lYYY;67: 1036-1042.
7
Serrano-lkkos E, Lask B. Whitehead B, Eisler I. Incomplete adherence after pediatric heart and heart-lung transplantation. J Heart Lung Trmspht. 1998; 17: I I771183.
8.
Greenstein S, Siegal B. Compliance and noncompliance in patients with a functioning renal transplant: A multicenter study. Tr~/,lJp/rntcEtio,t. 1 YY8;66: I7 18-l 726.
9.
Gomez DY, Wacher VJ, Tomlanovicb SJ, et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Phnrrn~~col Ther. lYY5;S8:lS-19.
to: Launa
J. Inc., 17208 AB, Canada
REFERENCES I. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin P/2arwfcol. 199737: 40541.5. 2. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P4SO 3A and Pglycoprotein: Implications for drug delivery and activity in cancer chemotherapy, Mol Carcinog. 1995; 13: 129-l 34.
IO. Wu CY, Benet LZ. Hebert MF, et al. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine. C/itl Phnrmc~cd Ther. lYYS;S8:4Y2~Y7. Il.
Kaplan B, Meier-Kriesche H-U, Napoli KL, Kahan BD. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. C/in Plwrmacol Ther. I YY8;63:4Y-53.
CLINICAL
12. Watson CJE, Friend PJ, Jamieson NV, et al. Sirolimus: A potent new immunosuppressant for liver transplantation. Tvctnsplrrtttcrtiott.
1999;67:505-509.
13. Murgia MC, Jordan S, Kahan BD. The side effect profile of sirolimus: A phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidttev Ittt. 1996;49:209-2 16. 14. Ferron GM, Jusko WJ. Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in rabbits. Plrarttrncd Rrs. 1998: IS: I XXX-l 894. IS. RapamuneG oral solution clinical pharmacokinetics. 1JS Food and Drug Administration Web site. Available at: www.fda. govlohrmsldocketslac199/slidesi3529slel index.htm. Accessed October 28, l99Y. 16. Neylan JF, Wickersham P, Jaffe J. Effect of race on efficacy and safety of sirolimus
B92
THERAPEUTICS
VI, AZA plus standard immunotherapy in renal transplantation. Presented at: American Society of Transplantation 18th Annual Meeting; May IS- 19, 1999; Chicapo. III. Abstract 924. 17. Kelly PA, Gruber SA. Behbod F. Kahan BD. Sirolimus, a new, potent immtmosuppressive agent. P/rtrrtrrcrt~ot/?rrcrl~~. 1997: 17:114X-I 1.56. IX. Kahan BD, Napoli KL, Mosheim M, et al. Pharmacokinetic and pharmacodynamic correlations of cyclosporine (CSA) and rapamycin (RAPA) in 120 patients treated for at least 2 years at a single center. Presented at: American Society of Transplantation 18th Annual Meeting: May 15-19, 1999; Chicago. III. Abstract 788. 19. MacDonald AS. Scarola J. Zimmerman J. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clitt Thclr. 2000:22(Suppl B):BIOI-Bl2l.
Requirements for Therapeutic Drug Monitoring of Sirolimus, an Immunosuppressive Agent Used in Renal Transplantation Launa J. Aspeslet, PhD, and Randall W. Yatscoff, PhD Isotrchnika
Inc., Ednontnrz, Alhertcr, Ctrn~~du
ABSTRACT Background: On September 15, 1999, sirolimus received approval from the US Food and Drug Administration (FDA) for marketing as an immunosuppressive agent. As with any chronically administered medication, the question arises whether therapeutic drug monitoring (TDM) is required for optimal therapy. In the case of sirolimus, there are data to suggest that TDM may be beneficial in some patients. Objective: To assess the need for monitoring sirolimus concentrations, this paper reviews the following factors influencin g the usefulness of TDM: wide pharmacokinetic variability; toxicity; suspected noncompliance; suspected drug interactions; and specific demographic characteristics. Data supporting the correlation between sirolimus concentration and immunosuppressive efficacy are also discussed. Results: The available literature on sirolimus suggests that TDM may be required in some cases. Studies have shown that there is wide interindividual variability in the pharmacokinetic behavior of drugs in transplant patients; that there is a relationship between blood concentrations of sirolimus and adverse events; and that coadministration of cyclosporine alters the pharmacokinetics of sirolimus. Additionally, the correlation between sirolimus concentration and immunosuppressive efficacy in phase III trials suggests a benefit in transplant patients when sirolimus concentrations reach appropriate levels. Finally, noncompliance is a common occurrence in the transplant population, and monitoring is often necessary in suspected noncompliers. Conclusion: Although additional clinical studies are needed, it appears that TDM is an important aspect of treatment with sirolimus. Key words: sirolimus, therapeutic drug monitoring, renal transplantation. (Clirr Tlwr. 2000;22[SuppI B]:B86-B92) Accepted for pubkcation March Printed in the USA. Reproduction
B86
8, 2000. in whole
or part
IS not permitted.
L.J. ASPESLET
AND
R.W.
YATSCOFF
INTRODUCTION On September 15, 1999, sirolimus* received approval from the US Food and Drug Administration (FDA) for marketing as an immunosuppressive agent for the prophylaxis of acute rejection in renal transplant patients. With a potential for widespread use of this drug, the question arises regarding the need for therapeutic drug monitoring (TDM) of sirohmus. To answer this question, it is necessary to examine the situations in which TDM is useful. Generally, TDM is valuable when: (I) the drug shows wide interindividual pharmacokinetic vatiability; (2) signs of toxicity are difficult to recognize clinically; (3) pathophysiologic factors may affect drug pharmacokinetics; (4) there is no correlation between dose and result; (5) noncompliance is suspected; or (6) drug interactions are suspected. Furthermore, for TDM to be useful, a clear relationship between drug concentration and effects must be shown. Although many of the above situations have not been thoroughly investigated with regard to sirolimus, this chronic immunosuppressive drug, like many other immunosuppressants, may require TDM in a number of circumstances. This paper reviews the situations on which data are available in the peer-reviewed literature, and examines the relationship between sirolimus concentration and immunosuppressive efficacy that makes TDM a useful component of immunosuppressive therapy with this drug. PHARMACOKINETIC
VARIABILITY
Key pharmacokinetic data in renal transplant patients were obtained from a phase ‘Trademark: Rapamune” (Wyeth-Ayerst ries. Philadelphia. Pennsylvania).
Laborato-
I clinical trial.’ This study was a doubleblind, ascending multiple-dose study conducted in 40 stable renal transplant patients who were receiving steady-state regimens of cyclosporine and prednisone. Nine doses of sirolimus were used, ranging from 0.5 to 6.5 mg/m2 every 12 hours. The pharmacokinetic parameters of sirolimus, determined by electrospray highperformance liquid chromatography-mass spectrometry (HPLC-MS), were calculated for all dose groups. The mean (k SD) time to maximum blood concentration (T,,,,) was 1.4 + 1.2 hours; the terminal half-life was 62.3 f 16.2 hours; the oral dose clearance was 208.0 + 95.0 mL/h per kg; the steady-state volume of distribution was 12.0 + 4.6 L/kg; and the blood-plasma ratio was 38.0 + 12.8. The interindividual variabilities in clearance, volume of distribution, and bloodplasma ratio of sirolimus showed -4.5fold ranges. This large pharmacokinetic variability is similar to that seen with other immunosuppressive drugs for which TDM is employed, namely cyclosporine, tacrolimus, and mycophenolate mofetil. The investigators in the phase I study] postulated that the large interindividual variation in clearance of sirolimus was due mainly to the combined action of the cytochrome P-450 (CUP) 3A4 isozyme responsible for the metabolism of sirolimus and the multidrug efflux pump, p-glycoprotein. Both CYP 3A4 and pglycoprotein are located in the enterocytes of the small intestine.* A study examining small-intestinal biopsy samples from 20 patients found an 1I -fold variation in the intestinal content of CYP 3A4.” Also important is the finding that the activity of both intestinal CYP 3A4 and p-glycoprotein is affected by coadB87
CLINICAL
ministration of other drugs, particularly cyclosporine.3,” This same study’ found a linear relationship between steady-state blood trough concentrations of sirolimus and area under the concentration-time curve (AUC) in the dosage range from 0.5 mg/m2 to 3.5 mg/m* every 12 hours. This finding suggests that monitoring of trough blood concentrations could be used to adjust the dosages of patients within this range. In addition, the ranges of the individual pharmacokinetic parameters were highly overlapped between dose groups, suggesting that pharmacokinetic parameters are not dose dependent. Results of the phase I study’ also suggest that due to the long half-life of sirolimus, a loading dose is necessary to achieve therapeutic steady-state concentrations rapidly. The study demonstrated that a loading dose -3 times greater than the maintenance dose could be administered, to a maximum single dose of 60 mg (based on available data). In such a situation, it may be useful to monitor trough sirolimus concentrations to ensure that a target concentration is achieved after administration of the loading dose. TOXICITY A clinical study in which 20 renal transplant patients were administered various doses of sirolimus found a correlation between adverse events and whole-blood trough sirolimus concentrations 2 I5 ng/mL, as determined by HPLC.S Similar conclusions were drawn from a phase II clinical study conducted in renal transplant patients receiving either cyclosporine (n = 42) or sirolimus (n = 41).” In the latter study, patients were given an initial loading dose of sirolimus I6 to 24 mg/m2 per day, followed by 8 to 12 mg/m* B88
THERAPEUTICS’
per day, adjusted to achieve a target trough level of 30 ng/mL for 8 weeks. Thereafter, daily dosing was reduced to maintain a target trough level of I5 ng/mL, as determined by HPLC. A strong relationship was observed between trough sirolimus concentrations and adverse effects. The abnormalities, primarily thrombocytopenia, leukopenia, hypertriglyceridemia, and cholesterolemia, were noted to improve when trough sirolimus concentrations were in the range from IO to 20 ng/mL. COMPLIANCE TDM is often used to monitor compliance. Because immunosuppression following transplant surgery is chronic therapy and maintenance of trough drug levels is a necessity for the prevention of acute rejection, patients must adhere to the daily drug regimen. However, the literature indicates that not all transplant patients do so, and this lack of adherence can lead to graft loss and possibly death. One study in pediatric heart and heart-lung transplant recipients7 found that one third of individuals examined (n = 53) showed unsatisfactory adherence to the treatment regimen, due in part to family dynamics. A larger multicenter study in 1402 renal transplant recipients” found that 22.4% of patients reported noncompliance. A logistic regression model that included age, occupation, time since transplantation, and medication-related beliefs (ie, efficacy and importance of immunosuppressant therapy) was most predictive of the likelihood of compliance. Donor type and history of diabetes or infection became predictive factors in the multivariate model only when the belief-related variables were excluded.
L.J. ASPESLET
AND R.W. YATSCOFF
DRUG INTERACTIONS Cyclosporine Coadministered cyclosporine and sirolimus are an effective combination for the prophylaxis of rejection. However, the combination of these 2 agents creates a potential for drug interactions. The bioavailability of both relies on intestinal CYP 3A4 isozymes, p-glycoprotein, and membranepermeability, in addition to hepatic first-pass effects.2,y,‘0 Thus, each drug could affect metabolismof the other, leading to increasedlevels of I or both. Such an interaction wasnot immediately apparentin clinical studies.In the phaseI study examining the pharmacokinetic effects of the coadministration of cyclosporineand sirolimus in stable renal transplant patients,’ sirolimus did not produce any significant changesin the AUC of cyclosporine over the 2-week study period. However, patients in this study received cyclosporine -3 hours after sirolimus.Another study involved stablerenal transplant patients who had been receiving a combination of sirolimus, cyclosporine microemulsion formulation, and prednisonefor 23 months.” Dosesof the drugs were kept constantthroughout the study, and only the timing of dosing was varied. This study found that the timing of cyclosporine administration affected sirolimus blood concentrations,whereasthe timing of sirolimus administration did not affect cyclosporine concentrations.AUC and trough concentrations of sirolimuswere significantly higher when the drug was administeredconcomitantly with cyclosporine microemulsion,as opposedto when the drugs were administered 4 hours apart. Conversely, in a study examining sirolimus in liver transplantpatients,12the combination of sirolimus and
cyclosporine appeared to cause a mutual increasein blood concentrations.Theseauthors noted that formal multiple-dosepharmacokinetic studiesare neededto confirm this observation in the hepatic transplant population. There is the possibility that concomitant administrationof the 2 drugsmay produce hyperlipidemic effects. When the drugs are administeredalone, theseeffects are manifested in increasedtriglyceride levels with cyclosporine treatment and increasedcholesterol levels with sirolimustreatment.‘” Prednisolone Prednisolone is often administered in combination with cyclosporine and sirolimus. When a rabbit model was usedto investigate the concomitant administration of sirolimus with prednisolone,“’ it was concluded that at therapeutic concentrations, the 2 drugs do not demonstratea significant pharmacokinetic interaction. Other Drugs Other drugs that are likely to be prescribedconcomitantly with sirolimuswere investigated for possible effects on the pharmacokinetic behavior of sirolimus. Diltiazem and ketoconazole increased sirolimus maximum concentration (CmZlx), T m;,x,and AUC. Rifampin, on the other hand, decreasedsirolimus ClllaTand ALJC. Acyclovir, digoxin, glyburide, nifedipine, and norgestreliethinyl estradiol did not alter sirolimus pharmacokinetics.‘,‘5 DEMOGRAPHIC CHARACTERISTICS Although specific demographic characteristics are not included among the facB89
CLINICAL
tors calling for TDM, they play an important role in the use of sirolimus as an immunosuppressive agent. In the phase 1 study in stable renal transplant patients,’ the pharmacokinetic parameters of sirolimus, as determined by HPLC-MS, were compared in black (n = 9) and nonblack patients (n = 17). Significant differences were noted in terms of T,,,,,, and clearance (Cl). In black patients, T,,,:,, was increased 2000/o, and Cl was increased 45%. These results suggest that there may be a reduced rate and extent of absorption in black patients. However, a recent report that examined the effect of race on the efficacy and safety of sirolimus in a subset of patients enrolled in a phase 111 trial’” did not reach the same conclusions. This study found that at 6 months posttransplantation, there were no significant differences in pharmacokinetic parameters between black and nonblack patients. Experimental details such as the numbers of black and white patients in the study and the analytical method used will be important to interpretation of these data. The phase I study’ also compared the pharmacokinetic parameters of sirolimus in men and women, and found no significant differences.
THERAPELJTICS’
treated de novo with a combination regimen of cyclosporine, sirolimus, and prednisone.‘* Results indicated that the incidence of chronic rejection was inversely proportional to the sirolimus dose and correlated with lower sirolimus absorption. as determined by dose-corrected AUC. A phase II study of sirolimus as base therapy in renal transplant patients6 indicated that trough sirolimus concentrations maintained at 30 ng/mL for the first 8 weeks and then maintained at trough levels of IS ng/mL were sufficient to prevent acute rejection. Statistical analysis of the phase III clinical trial in which sirolimus was administered in combination with cyclosporine emulsion and steroids has revealed a correlation between acute rejection episodes and trough sirolimus concentration.” The emerging data from clinical trials indicate that there is a relationship between sirolimus concentrations and immunosuppressive efficacy, suggesting the usefulness of TDM with this drug. The data support the use of monitoring as a guide to dosage adjustment to achieve maximum immunosuppressive efficacy while minimizing toxicity. CONCLUSIONS
DRUG CONCENTRATIONS VERSUS EFFECT In situations in which TDM is useful, it is necessary to show a correlation between blood drug concentrations and outcomes. To date, few studies have been published that examine the correlation between blood concentrations of sirolimus and efficacy in transplant patients. (This is partly due to the low frequency of acute rejection episodes.“) One single-center study examined 120 renal transplant patients B90
Review of the available literature supports the desirability of TDM for sirolimus based on the drug’s emerging pharmacokinetic and pharmacodynamic characteristics, as follows. A relationship between blood concentrations of sirolimus and toxic events has been observed in transplant patients. Drug interaction studies have demonstrated the ability of cyclosporine to alter the pharmacokinetics of sirolimus when the 2 drugs are coadministered. Finally, recent analyses of the
L.J. ASPESLET
AND R.W. YATSCOFF
phase III clinical trial data suggest that there is a therapeutic window in transplant patients.‘” Routine TDM is not an absolute requirement for the use of sirolimus. However, results have indicated that it may be necessary in some cases. This is similar to the approach for mycophenolate mofetil, but differs from those for both cyclosporine and tacrolimus, in which TDM is considered an essential part of patient management. Based on an informal survey of several transplant centers by the authors (Yatscoff RW, unpublished data, l999), it appears that centers currently using sirolimus are conducting TDM of this drug. Consequently, as automated assays become available, the use of TDM of sirolimus is likely to increase. This, in conjunction with data from ongoing clinical trials, will permit more thorough examination of the variables discussed in this paper.
Address correspondence Aspeslet, PhD, Isotechnika 108th Avenue, Edmonton, T5S lE8.
3. Hebert MF, Roberts JP, Prueksaritanont
T, Benet LZ. Bioavailability of cyclosporin with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. C/i/l Phurmacd Ther. lYY2;52:453+4S7.
4.
Huang JD, Su SF. Effect of quinidine on digoxin absorption in the rat: Interaction on P-glycoprotein in the small intestine. FASEB /. lYY5;Y:A6Yl. Abstract.
5.
Kahan B. Sirolimus: A new agent for clinical renal transplantation. Trmsplnnt Proc. lYY7;29:48-50.
6.
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to: Launa
J. Inc., 17208 AB, Canada
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VI, AZA plus standard immunotherapy in renal transplantation. Presented at: American Society of Transplantation 18th Annual Meeting; May IS- 19, 1999; Chicapo. III. Abstract 924. 17. Kelly PA, Gruber SA. Behbod F. Kahan BD. Sirolimus, a new, potent immtmosuppressive agent. P/rtrrtrrcrt~ot/?rrcrl~~. 1997: 17:114X-I 1.56. IX. Kahan BD, Napoli KL, Mosheim M, et al. Pharmacokinetic and pharmacodynamic correlations of cyclosporine (CSA) and rapamycin (RAPA) in 120 patients treated for at least 2 years at a single center. Presented at: American Society of Transplantation 18th Annual Meeting: May 15-19, 1999; Chicago. III. Abstract 788. 19. MacDonald AS. Scarola J. Zimmerman J. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clitt Thclr. 2000:22(Suppl B):BIOI-Bl2l.