occurred following the 20 mg/day dosage of diltiazem (26 and 67%). The maxi- ... used (180 mg/day), when the increase was 48 and 177%. .... Jones & Morris.
ORIGINAL RESEARCH ARTICLE
Clin Pharmacokinet 2002; 41 (5): 381-388 0312-5963/02/0005-0381/$25.00/0 © Adis International Limited. All rights reserved.
Pharmacokinetic Interaction Between Tacrolimus and Diltiazem Dose-Response Relationship in Kidney and Liver Transplant Recipients Terry E. Jones1 and Raymond G. Morris2 1 Department of Pharmacy, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia 2 Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
Abstract
Objective: To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and tacrolimus in kidney and liver transplant recipients. Design: Nonrandomised seven-period stepwise pharmacokinetic study. Patients: Stable kidney (n = 2) and liver (n = 2) transplant recipients maintained on oral tacrolimus twice daily but not taking diltiazem. Methods: Patients were treated with seven incremental dosages of diltiazem (0 to 180 mg/day) at ≥ 2-weekly intervals. At the end of each interval, 13 blood samples were taken over a 24-hour period to allow determination of morning (AUC12), evening (AUC12-24) and 24-hour (AUC24) areas under the concentrationtime curve for tacrolimus, as well as AUC24 for diltiazem and three of its metabolites. Results: There was considerable interpatient variability in tacrolimus-sparing effect. In the two kidney transplant recipients, an increase in tacrolimus AUC 24 occurred following the 20 mg/day dosage of diltiazem (26 and 67%). The maximum increase in tacrolimus AUC24 occurred at the maximum diltiazem dosage used (180 mg/day), when the increase was 48 and 177%. In the two liver transplant recipients, an increase in tacrolimus AUC24 did not occur until a higher diltiazem dosage (60 to 120 mg/day) was given. The increase at the maximum diltiazem dosages used (120 mg/day in one and 180 mg/day in the other) was also lower (18 and 22%) than that exhibited by the kidney transplant recipients. The increase in tacrolimus AUC12 was similar to the increase in AUC12-24 when diltiazem was given in the morning only (dosages ≤60 mg/day). Hence, diltiazem affects blood tacrolimus concentrations for longer than would be predicted from the half-life of diltiazem in plasma. Conclusions: The mean tacrolimus-sparing effect of diltiazem was similar in magnitude to the cyclosporin-sparing effect previously reported. Whether the lesser tacrolimus-sparing effect with diltiazem seen in the liver transplant recipients was due to functional differences in the transplanted liver is not known, but it was not due to lower plasma diltiazem concentrations. Diltiazem makes a logical tacrolimus-sparing agent because of the potential financial savings and therapeutic benefits. Because of interpatient variability, the sparing effect should be demonstrated in each patient and not merely assumed.
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Tacrolimus is a potent immunosuppressive drug which, although being structurally unrelated and binding to a different intracellular receptor than cyclosporin, has a remarkably similar mode of action and pharmacokinetic properties. In particular, tacrolimus has a poor oral bioavailability, is metabolised by the cytochrome P450 isoenzyme CYP3A4,[1-3] is both a substrate and inhibitor of the P-glycoprotein drug efflux pump, and is also very expensive. Because the oral bioavailability of tacrolimus is less dependent than that of cyclosporin on bile in the gastrointestinal tract,[4,5] it is especially suited to liver transplantation where bile is diverted externally in the immediate postoperative period. When cyclosporin is used in such settings, intravenous administration may be required for prolonged periods because of poor oral absorption.[6-9] Although experience with tacrolimus is more limited than with cyclosporin, a number of interactions have been reported with drugs that also affect the disposition of cyclosporin, either via CYP3A4 or P-glycoprotein. Ketoconazole has been shown to elevate blood tacrolimus concentrations,[10] but evidence in the literature supporting an interaction with diltiazem is conflicting. Diltiazem has been reported not to interact with tacrolimus either in vitro[11] or in vivo (human liver transplant recipients).[12] However, in a retrospective review of 128 kidney transplant recipients, one group of researchers noted that coprescription of diltiazem with tacrolimus in one patient necessitated a 66% reduction in tacrolimus dosage in order to maintain acceptable blood tacrolimus concentrations.[13] In a study where tacrolimus was infused into pigs and subsequently diltiazem was also infused,[14] blood tacrolimus concentrations rose significantly (from 10.0 ± 3.9 to 42.4 ± 10.4 μg/L) and mean tacrolimus clearance fell (5.0 to 1.2 L/h/kg). This short report failed to give details of the timing of samples and, although stating that tacrolimus concentrations were at steady state, it is possible that some of the increase in blood tacrolimus concentration may have been due to failure to reach steady state. Like cyclosporin, tacrolimus causes hyperten© Adis International Limited. All rights reserved.
Jones & Morris
sion[5,15,16] and nephrotoxicity.[13] These were the principal reasons for first investigating the coprescription of diltiazem (a calcium channel antagonist with an approved indication for hypertension) with cyclosporin, and hence a similar argument could be made for coprescribing diltiazem with tacrolimus. Although this has not yet been advocated, given the proven economic and therapeutic benefits afforded by coprescription with cyclosporin,[17,18] and the similarity in adverse effect profile and cost between cyclosporin and tacrolimus, it seems likely that it will. Coprescription of diltiazem with cyclosporin was well established before evidence became available on the dose-response relationship for the interaction.[19] By this time, protocols had become established and prescribers have been reluctant to alter the diltiazem regimens they had become familiar with and on which patients were stabilised (personal communication from T.H. Mathew, The Queen Elizabeth Hospital, Woodville, South Australia, with permission).This study was thus undertaken to provide data on the reliability and magnitude of the interaction before routine coprescribing of diltiazem with tacrolimus becomes established practice. The primary aim of this study was to determine the dose-response relationship of the pharmacokinetic interaction between diltiazem and tacrolimus in organ transplant recipients. A secondary aim was to investigate the potential for difference between kidney and liver transplant recipients given the importance of the liver as a metabolic organ. Patients and Methods Stable kidney transplant (n = 2) and liver transplant (n = 2) recipients maintained on twice-daily tacrolimus (but not on diltiazem) gave written informed consent to take part in this pharmacokinetic study, which was approved by the ethics committees of The Queen Elizabeth Hospital and Flinders Medical Centre (Bedford Park, South Australia). Entry criteria included: • stable blood tacrolimus concentrations on routine monitoring for ≥3 months Clin Pharmacokinet 2002; 41 (5)
Tacrolimus-Diltiazem Interaction
• stable serum creatinine concentrations and liver function tests for ≥3 months and ≤150% of the upper limit of normal. Exclusion criteria included: unstable plasma creatinine concentration, elevated liver function tests, known allergy to diltiazem, sick sinus syndrome, hypotension, severe congestive heart failure, history of acute myocardial infarction and/or pulmonary congestion, the use of any drug known to interfere with tacrolimus (or cyclosporin) metabolism or any drug whose metabolism might have been affected by diltiazem (especially terfenadine). On each 24-hour study day, serial blood samples were taken from an indwelling venous catheter at times 0 (pre-dose) and 1, 2, 3, 4, 6 and 12 hours after both morning and evening tacrolimus doses, making a total of 13 blood samples spanning two tacrolimus administration intervals. Incremental doses of diltiazem were given between study days, which were separated by ≥2 weeks to allow the interaction between tacrolimus and diltiazem to stabilise and steady-state blood tacrolimus concentrations to be achieved. The sequence of diltiazem doses were 0, 10, 20, 30 and 60mg in the morning, followed by 60 and 90mg taken twice daily. Diltiazem doses less than 30mg were taken in the form of a 10mg capsule manufactured from commercially available conventionalrelease tablets (Cardizem®1; ICI Australia) by the hospital’s Pharmacy Department and assayed using a previously reported high-performance liquid chromatography (HPLC) assay.[20] Doses of ≥30mg were taken in the same form of commercially available conventional-release tablets. Each diltiazem dose was taken with the respective morning and/or evening tacrolimus (Prograf®; JanssenCilag Australia) dose and food was not consumed for ≥1 hour before or after tacrolimus administration. Dosage reductions of tacrolimus were planned, if needed, to maintain blood tacrolimus concentrations within the therapeutic range (5 to 1 Use of tradenames is for product identification only and does not imply endorsement. © Adis International Limited. All rights reserved.
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20 μg/L) and, if needed, the resulting pharmacokinetic parameters were to be dose-normalised. Patency of the venous catheter was maintained by instilling 1.5ml of heparinised saline (15 units of heparin) after each 8ml blood sample was withdrawn. To prevent contamination of sample, the first 1.5ml of blood withdrawn was discarded. Blood samples were immediately stored at 0 to 4°C and frozen (–20°C) either as whole blood (for tacrolimus assay) or plasma (for diltiazem assay) as soon as practicable (≤8 hours). Whole blood tacrolimus concentrations were measured by microparticulate enzyme immunoassay (Tacrolimus 2, MEIA®) on the IMx analyser (Abbott Diagnostics), which is relatively specific for parent tacrolimus.[21] Plasma concentrations of diltiazem, demethyl-diltiazem, deacetyl-diltiazem and demethyldeacetyl-diltiazem were determined by using the previously reported HPLC method.[20] Areas under the concentration-time curve (AUCs) were calculated by using the log trapezoidal method. Plasma C-reactive protein concentrations from the first blood sample on each study day were assayed by an immunonephelometric method (ARRAY 360CE, Beckman Instruments). Results Because of the limited numbers of subjects and different transplanted organs, data are presented as individual rather than grouped data. Demographics and concurrent drug therapy for the four study participants are shown in table I. Patient 2 was the only patient who required a tacrolimus dosage reduction (4 to 2 mg/day); this was instituted before the diltiazem 180 mg/day study because blood tacrolimus concentrations were approaching the upper limit of the therapeutic range accepted by this hospital (5 to 20 μg/L). Patient 3 (liver transplant recipient) was withdrawn from the study shortly after the diltiazem 120 mg/day study because of the development of bradycardia, an adverse effect considered to be related to the use of diltiazem. Data from 27 × 24Clin Pharmacokinet 2002; 41 (5)
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Jones & Morris
Table I. Patient demographics for the two kidney and two liver transplant recipients Patient
Gender [age (y)]
Organ transplanted [duration (mo)]
Concurrent drugs (excluding tacrolimus)
1
Male (51)
Kidney (45)
Amiodarone, azathioprine, bumetanide, calcitriol, enalapril, prednisolone, temazepam, thyroxine
2
Female (56)
Kidney (39)
Azathioprine, nifedipine, norfloxacin, omeprazole, simvastatin
3
Female (64)
Liver (28)
Enalapril
4
Female (52)
Liver (10)
Amlodipine, azathioprine, thyroxine
hour pharmacokinetic studies were thus available for analysis. The relationship between the daily diltiazem dosage and the changes in tacrolimus 24-hour AUC (AUC24), morning trough tacrolimus concentration (C24) and the mean of the morning and evening (C12) trough concentrations for each of the study participants is presented in table II. Data from the two kidney transplant recipients (patients 1 and 2) show that an increase in tacrolimus AUC24 occurred following the 20 mg/day dosage of diltiazem (26 and 67%) [table II]. The maximum increases in tacrolimus AUC24 (48 and 177%) occurred at the maximum diltiazem dosage used (180 mg/day). The response from the two liver transplant recipients (patients 3 and 4) was different. Tacrolimus AUC24 fell below the baseline value at initial diltiazem dosages and only increased above the baseline value at 60 or 120 mg/day. The increase in tacrolimus AUC24 at the maximum dosages used (120 mg/day in one and 180 mg/day in the other) was 18 and 22%, respectively (table II). The mean changes in tacrolimus exposure after the morning dose (AUC12), evening dose (AUC12-24) and AUC24 for diltiazem dosages ≤60 mg/day are shown in figure 1. These data suggest that both AUC12 and AUC12-24 contributed approximately equally to AUC24. The relationship between daily diltiazem dosage and AUC24 for diltiazem and each of its three metabolites are shown in table III. These data reveal an approximately linear relationship between daily diltiazem dose and AUC24 for diltiazem and each of its three major metabolites over the dosage range administered. This is consistent with our ear© Adis International Limited. All rights reserved.
lier data for the cyclosporin-diltiazem interaction.[22] Patient 3 exhibited a different diltiazem and metabolite profile to the other three patients. In particular, demethyl-diltiazem and demethyldeacetyldiltiazem concentrations were generally lower (table III), while the deacetyl-diltiazem concentrations were higher, especially at the 120 mg/day dosage (the highest reached in this patient). However, these differences were much less marked than those seen in the study with cyclosporin reported earlier.[22] C-reactive protein results were all within the normal range (
