Therapeutic Drug Monitoring - Is it Important for Newer Immunosuppressive Agents?

Drug Ther Perspect 17(22):8-12, 2001. © 2001 Adis International Limited

Introduction

Most patients who undergo solid organ transplantation require lifelong immunosuppressive therapy to prevent allograft rejection. But, because many immunosuppressive agents have narrow therapeutic ranges, and are associated with various toxicities and the potential for drug interactions, the use of therapeutic drug monitoring (TDM) in conjunction with clinical assessment of patients may be particularly important. This article reviews the role of, and factors pertinent to, TDM of the newer immunosuppressive agents tacrolimus (FK-506), sirolimus (rapamycin) and mycophenolate mofetil (MMF) [see Differential features table].

Newer Agents Have Interesting Effects

Tacrolimus: a potent immunosuppressant

Tacrolimus is a macrolide antibiotic that was approved by the US Food and Drug Administration (FDA) in 1994 for the prevention of liver allograft rejection[1] and is currently available in a number of countries for various indications.[8] It is up to 100 times more potent than cyclosporin in vitro, and clinically, is associated with a greater reduction in the incidence of tissue rejection.[1,6] Tacrolimus has demonstrated efficacy both as primary immunosuppressive therapy in patients undergoing various transplantation procedures, and as rescue therapy for patients with refractory acute allograft rejection after liver or kidney transplantation.[1,3,8]

Sirolimus: Cyclosporin Sparing?

Sirolimus is, like tacrolimus, a macrolide antibiotic. It was first approved in 1999 by the US FDA for the prevention of allograft rejection after kidney transplantation, and indeed has shown promising results in this respect when used acutely in combination with cyclosporin and corticosteroids.[1]In vitro, sirolimus is up to 100 times more potent than cyclosporin, and clinically, it may exhibit synergism with cyclosporin, perhaps permitting a reduction in cyclosporin dosage.[1]

Mycophenolate Mofetil is a Prodrug

After oral administration, mycophenolate mofetil (MMF) undergoes rapid hydrolysis in the intestine and blood to form its active metabolite mycophenolic acid (MPA).[1,4-6] MMF is widely available and is approved in the US and UK for the prevention of renal, hepatic or cardiac allograft rejection in combination with corticosteroids and cyclosporin.[9,10] The drug has demonstrated superiority over azathioprine in reducing the incidence of acute rejection of renal allografts.[1,3,5] However, after a mean follow-up period of 3 years in one study, no significant benefits were identified for MMF regarding graft and patient survival.[11]

Pharmacokinetic Variability is High

With Tacrolimus...

The pharmacokinetic profile of tacrolimus is variable, probably to some extent because the major route of metabolism is via intestinal and hepatic cytochrome P450 (CYP) 3A4.[1,3] Additional explanations for such variability include the following:[1]

  • poor dissolution and potentially restricted absorption
  • changes in intestinal p-glycoprotein activity
  • strong affinity for erythrocytes - tacrolimus concentrations in whole blood are approximately 10 to 30 times greater than in plasma
  • hepatic impairment - this has been linked with a decrease of about 30% in tacrolimus clearance and an approximately 3-fold increase in tacrolimus half-life.

...Sirolimus...

Like tacrolimus, sirolimus shows marked pharmacokinetic variability, most probably because it also is a substrate for both CYP3A4 and p-glycoprotein.[1] Again like tacrolimus, sirolimus is markedly sequestered within erythrocytes (95%), but unlike oral tacrolimus, which is usually administered twice daily, sirolimus has a long-terminal elimination half-life (62 hours) that permits once daily oral administration.[1] Furthermore, race may considerably alter the pharmacokinetic profile of sirolimus: in a preliminary study, for example, the oral clearance rate and time to peak plasma concentration of sirolimus were approximately doubled in African-American compared with Caucasian patients who had undergone renal transplantation.[12]

...And Mycophenolic Acid

In renal transplant recipients receiving MMF orally, an approximate 10-fold variation in MPA pharmacokinetics is evident, perhaps because of changes in intestinal metabolism, first-pass hepatic metabolism and enterohepatic recycling.[4] In addition, lower dosages of MMF may be required in the late (>/=3 months after transplantation) rather than immediate post-transplant period, possibly, in part, because of increases over time in plasma albumin levels and MPA binding to albumin.[4]

Race may also have an important influence on the pharmacokinetic variability of MPA. For example, African-American renal transplant recipients required a higher dosage of MMF (3 g/day) to achieve acute rejection rates similar to those in their non-African-American counterparts who received 2 g/day.[13] Although further pharmacokinetic studies are needed to clearly define MMF dosage recommendations for paediatric patients, dosage adjustments are unnecessary in patients with renal or hepatic impairment.[1]

Drug Interaction Potential is Also High

Because both cyclosporin and tacrolimus are substrates for CYP3A4 and p-glycoprotein, a judicious approach is to assume that, until proven otherwise, any major drug interactions that occur with cyclosporin could also occur with tacrolimus. After oral administration, tacrolimus is metabolised in the small intestine by CYP3A4, and also actively pumped by p-glycoprotein from inside intestinal cells back into the lumen. The latter mechanism allows further presentation of tacrolimus to intestinal CYP3A4 and further metabolism. Thus, when interactions are anticipated between tacrolimus and concurrently administered treatments, TDM is particularly appropriate to facilitate maintenance of tacrolimus concentrations within the therapeutic range.[1]

The potential for drug interactions with sirolimus is also considerable, and pharmacokinetic interaction and synergism between sirolimus and cyclosporin may permit the use of lower cyclosporin dosages when the two drugs are taken concurrently, but TDM will be important for optimising treatment with both compounds.[1]

When MMF is used in combination with tacrolimus, the degree of immunosuppression attained may be greater than expected. Indeed, tacrolimus has been shown to increase the area under the plasma concentration time curve (AUC) for MPA in renal transplant recipients,[14] thus providing support for TDM of MMF in this setting.[1]

TDM Predicts Tacrolimus Toxicity...

There appears to be more evidence, albeit limited, to support a correlation between tacrolimus trough concentrations and toxicity rather than efficacy (as indicated by tissue rejection). For instance, in various studies of patients who had undergone kidney or livertransplantation, whole blood and plasma trough concentrations of tacrolimus were higher in patients who experienced neurotoxicity or nephrotoxicity than in those who did not.[1] Logistic regression analysis of four multicentre studies also revealed a statistically significant correlation between trough tacrolimus concentrations and toxicity.[15]

...But Apparently Not Efficacy

In several studies of kidney or liver transplant recipients, and in the logistic regression analysis mentioned above, no link was identified between trough tacrolimus concentrations and the incidence of tissue rejection. A significant link was noted in only 1 study of 92 renal transplant recipients included in the regression analysis. Some of the studies that failed to identify an association had design flaws that may have led to ambiguous results. Future, well designed studies are therefore needed to clarify the association, if any, between trough tacrolimus concentrations and the risk of acute allograft rejection.[1]

TDM May Predict Efficacy and Toxicity

For Sirolimus...

Data from a 4-year study of 150 renal transplant recipients reveal an association between trough sirolimus concentrations and clinical events: that is, concentrations <5µg/L were predictive of acute rejection, whereas concentrations >15µg/L were linked with hypertriglyceridaemia, thrombocytopenia and leucopenia.[16] In general, this is supported by preliminary data from animal studies which suggest that whole blood sirolimus concentrations <5 to 10µg/L correlate with tissue rejection, and that concentrations >60µg/L are associated with increased toxicity.[1]

...And Mycophenolic Acid

In current transplantation procedures, plasma concentrations of MPA are not routinely monitored, although interest in TDM and dosage individualisation and optimisation with MMF is increasing.[1] Various preliminary studies suggest that a link may exist between plasma MPA concentrations and the risk of allograft rejection.[1,2,4] For example, in a study evaluating 3 MPA target AUC values (16.1, 32.2 and 60.6 mg h/L) in 154 renal transplant patients, the rejection rate was significantly greater in the low vs intermediate and high target AUC groups (28 vs 15 and 11%, p = 0.043). Overall, logistic regression analysis revealed a significant (p < 0.001) correlation between median natural logarithm of the AUC value for MPA and the occurrence of biopsy-confirmed rejection.[17]

Measurement of concentrations of free rather than total MPA may be more appropriate, since kidney and liver transplant patients often have variable albumin levels, and indeed, preliminary data suggest that free rather than total MPA concentrations may correlate more consistently with the pharmacodynamic actions of MPA.[18] Another viable approach might be to measure inhibition of the target enzyme inosine monophosphate dehydrogenase.[1,4]

What are the Recommendations for TDM?

TDM for tacrolimus, comprising measurement of trough tacrolimus concentrations in whole blood, is recommended in the routine clinical setting. The therapeutic range of tacrolimus has not been clearly defined, but some researchers report a range of 5 to 20µg/L in whole blood,[19] while others suggest that 5 to 15µg/L may be more appropriate.[20] Generally, high tacrolimus concentrations are likely to be required in the initial post-transplant period, but target concentrations can then be reduced over time.[1]

A recent consensus report[21] made some preliminary recommendations about TDM for sirolimus, while noting that further research is required before definitive statements can be made. Thus, TDM is expected to have a major influence on optimisation of sirolimus therapy. Measurement of trough concentrations in whole blood is the recommended method and the most appropriate therapeutic range appears to be 5 to 15µg/L.[1]

TDM has not been widely used to direct MMF therapy, which has usually comprised fixed dosages in the range 1 to 3 g/day. Nevertheless, recent data indicate that TDM may improve outcomes with MMF therapy, although routine TDM for MPA cannot be endorsed until further, prospective results become available.[1,2,4] Meanwhile, TDM for MPA should be used in clinical settings where marked pharmacokinetic variability is anticipated (e.g. in patients with changeable albumin levels, and in paediatric patients), or where fixed-dosage MMF schedules may be inappropriate (e.g. in African-American patients).[1]

Overall, the new immunosuppressive agents tacrolimus, sirolimus and MMF have significant clinical roles in solid organ transplantation, but they have narrow therapeutic ranges and numerous toxicities. Strategies to individualise dosages and optimise treatment with these agents are therefore particularly important. In this respect, TDM can be used, along with clinical monitoring of patients, and together with an awareness of the pharmacokinetic profiles of specific agents, to optimise treatment outcomes.

Differential features

Principal features of relevance to current therapeutic drug monitoring strategies for newer immunosuppressive agents[1-7]

Feature

Tacrolimus (FK-506)

Sirolimus (rapamycin)

Mycophenolate mofetil
(MMF)a

Oral bioavailability

4-93% (mean 25%)

15%

94%

Time to peak plasma concentration

0.5-6h

0.8-3h

6-12hb

Plasma protein binding

88%

92%

97%

Metabolism

Intestinal and hepatic CYP3A4

Intestinal and hepatic CYP3A4

Hepatic glucuronidation to MPAGc

Principal drug interactions

Erythromycin and clarithromycin have increased tacrolimus concentrations 4- to 6-fold.
Ketoconazole has markedly increased tacrolimus AUC. MPA concentrations may be increased by tacrolimus, through inhibition of MPA conversion to MPAG.
Diltiazem and fluconazole are likely to increase tacrolimus concentrations.
Rifampicin (rifampin), phenobarbital (phenobarbitone) and phenytoin are likely to decrease tacrolimus concentrations

Cyclosporin AUC and Cmax may be increased by sirolimus and vice versa.
Ketoconazole has increased plasma sirolimus concentrations by 990%.
Diltiazem has increased plasma sirolimus concentrations by 60%.
Rifampicin has reduced plasma sirolimus concentrations by 82%. Until proven otherwise, all drugs known to interact with cyclosporin or tacrolimus should also be expected to interact with sirolimus

Tacrolimus increases the AUC of MPA.
Magnesium-and aluminium-containing antacids have reduced the AUC of MPA by 15-37%.
Cholestyramine and other bile acid sequestrants can reduce the AUC of MPA and should be avoided during MMF therapy

Correlation identified between trough concentrations and efficacy?

No

Yes

Yes

Correlation identified between trough concentrations and toxicity?

Yes

Yes

Yes

Most common and/or preferred analytical method

MEIA

HPLC-MS and HPLCd

HPLC

Matrix for concentration measurement

Whole blood

Whole blood

Plasma

Therapeutic trough concentration range

5-20 g/L

5-15 g/L

1-3.5 mg/L

Main adverse events

Headache, nausea, vomiting, diarrhoea, pruritus, tremor, abdominal pain, diabetes mellitus, renal impairment

Leucopenia, thrombocytopenia, dyslipidaemias

Diarrhoea or constipation, nausea, vomiting, leucopenia, thrombocytopenia, anaemia, neutropenia, tissue-invasive cytomegalovirus infection

a Parameters shown are for MPA.

b This is a secondary peak, reflecting considerable enterohepatic recirculation that involves deconjugation of MPAG by colonic bacteria.

c MPAG is pharmacologically inactive and >95% is excreted in the urine.

d These are the only methods currently available, but are unlikely to have widespread clinical applicability.

AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; CYP = cytochrome P450; HPLC-MS = high-performance liquid chromatography with mass spectrometry; MEIA = microparticle enzyme immunoassay; MPA = mycophenolic acid; MPAG = mycophenolic acid glucuronide.

References

  1. Tsunoda SM, Aweeka FT. Drug concentration monitoring of immunosuppressive agents. Focus on tacrolimus, mycophenolate mofetil and sirolimus. BioDrugs 2000 Dec; 14 (6): 355-69
  2. Behrend M. Mycophenolate mofetil. Suggested guidelines for use in kidney transplantation. BioDrugs 2001; 15 (1); 37-53
  3. Ciancio G, Burke GW, Roth D, et al. Tacrolimus and mycophenolate mofetil regimens in transplantation. Benefits and pitfalls. BioDrugs 1999 Jun; 11 (6): 395-407
  4. Bullingham RES, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998 Jun; 34 (6): 429-55
  5. Holt CD, Sievers TM, Ghobrial RM, et al. Mycophenolate mofetil. Effects on clinical transplantation. BioDrugs 1998 Nov; 10 (5): 373-84
  6. Armenti VT, Moritz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression. Effects and outcomes. Drug Safety 1998 Sep; 19 (3): 219-32
  7. Fellström B. Risk factors for and management of post-transplantation cardiovascular disease. BioDrugs 2001; 15 (4): 261-78
  8. Plosker GL, Foster RH. Tacrolimus. A further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 2000 Feb; 59 (2): 323-89
  9. British National Formulary No. 41. London: The Pharmaceutical Press, 2001 Mar
  10. Physicians' Desk Reference 2001, 55th ed. Montvale, NJ: Medical Economics Company, Inc., 2001
  11. Mathew TH, the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, long-term, randomized multicentre study of mycophenolate mofetil in cadaveric renal transplantation; results at three years. Transplantation 1998; 65: 1450-4
  12. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997; 37: 405-15
  13. Neylan JF, the US Renal Transplant Mycophenolate Mofetil Study Group. Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. Transplantation 1997; 64: 1277-82
  14. Zucker K, Rosen A, Tsaroucha A, et al. Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and anlogous in vitro findings. Transpl Immunol 1997; 5: 225-32
  15. Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996; 62: 920-6
  16. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplantation 2000; 14: 97-109
  17. van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A randomized, double-blind, multicentre plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999; 68: 261-6
  18. Nowak I, Shaw LM. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 1995; 41: 1011-7
  19. Jusko WJ, Thomson AW, Fung JJ, et al. Consensus document: therapeutic monitoring of tacrolimus (FK506). Ther Drug Monit 1995; 17: 606-14
  20. McMaster P, Mirza DF, Ismail T, et al. Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit 1995; 17: 602-5
  21. Yatscoff RW, Boeckx R, Holt DW, et al. Consensus guidelines for therapeutic drug monitoring of rapamycin: report of the consensus panel. Ther Drug Monit 1995; 17: 676-80