Reports

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MEDICAL FRONTIERS - 23rd International Congress of the Transplantation Society

Vancouver, British Columbia / August 15-19, 2010

According to Prof. Bernhard Krämer, V. Medizinische Klinik, Mannheim University Hospital, Germany, “There is a high rate of non-adherence in transplant patients. Many studies have shown that the frequency of dosage matters.” He noted that the more frequent the dose, the higher the risk of poor compliance, which emphasizes the importance of lowering dosing frequency. Advances in drug therapy that have the potential to improve compliance by reducing dosing frequency, such as a new once-a-day formulation of the oral immunosuppressant tacrolimus, are therefore of considerable interest to clinicians and their patients. However, in order to avoid reductions in efficacy, it is important to monitor blood levels when patients are converted from one form of immunosuppressant to another.

Pharmacokinetics

Pharmacokinetic and clinical studies comparing the tacrolimus once-daily and twice-daily formulations have found that in stable transplant recipients, steady-state exposure is equivalent (Am J Transplant 2009;9(11):2505-13, Transplantation 2007;83:1648-51). However, a retrospective review of 59 renal transplant patients following conversion to the q.d. formulation reported trough decreases of =20% in 30% of patients (Hougardy et al., Abstract P13.31). Of note, the pharmacokinetics of tacrolimus are known to be strongly affected by CYP3A5*1/*3 polymorphism and homozygous CYP3A5*3/*3 patients have lower drug trough levels than those without. In another retrospective analysis of 284 patients by Varenterghem et al., where 38.8% of patients experienced a trough level decrease of =20%, it was reported that most patients with significant decreases carried the CYP3A5*3/*3 allele (Abstract MO10.11). Given the risk of rejection if therapeutic drug levels are not maintained, this finding requires careful consideration.

Dr. Philip Burgwinkel, Charité Universitätsmedizin Berlin, Germany, reported the results of a study of the pharmacokinetics of conversion from b.i.d. to q.d. tacrolimus in homozygous *3/*3 and heterozygote*1/*3 patients. Of 41 patients studied, 27 were *3/*3 carriers. After conversion from b.i.d. to q.d. dosing, a relatively stable mean trough level in heterozygote*1/*3 patients was maintained, with a clinically relevant trough decrease (trough levels below 4 ng/mL or a decline by more than one-third) observed in one patient (7.7%). In the homozygote *3/*3 patients, clinically relevant trough decreases were observed in 9 patients (33%) with significantly lower trough levels (-13.8%, P=0.001). Overall, 24% of patients experienced a clinically relevant decrease in tacrolimus levels.

Dr. Burgwinkel concluded that while the difference may be due to a predominant intestinal absorption site, if patients are kept at the lower range of the therapeutic window or carry the CYP3A5*3/*3 genotype, physicians should be aware of the lower exposure when converting patients to the once-daily formulation.

However, Dr. F. Tinti, Sapienza University of Rome, Italy, drew different conclusions from a prospective comparison study. Of 43 patients treated with b.i.d. tacrolimus for more than 3 months, 23 were switched to q.d. tacrolimus while the remaining 20 patients continued with b.i.d. dosing. While Dr. Tinti also observed a decrease in trough levels in the q.d. arm, he noted that therapeutic levels were maintained and also reported improvements in glomerular filtration rate during the 6-month trial. Blood glucose and triglycerides also improved; Dr. Tinti suggested to delegates that this might be due to reductions in potentially harmful tacrolimus peak levels that occur with b.i.d. dosing.

In another study, Dr. Kazunari Yoshida, Kitasato University and Hospital, Sagamihara, Japan, observed that while maximum concentration was generally achieved in 1-2 hours, lower blood concentrations in 12 patients receiving the q.d. formulation were reported 7-21 days’ post-transplant compared to 10 patients using the b.i.d. formulation.

These findings underscore the importance of monitoring tacrolimus levels following initiation of therapy or change of formulation; the transition requires careful monitoring, and diligent consideration must be given to the clinical significance of changes in trough levels.

Short- and Long-term Clinical Results

To understand the efficacy and safety profile, both in absolute terms and in comparison to the b.i.d. formulation, investigators evaluated the short-term efficacy and safety of q.d. tacrolimus in 30 patients followed for 1 year after kidney transplantation. Results showed that kidney function was satisfactory to 12 months while patient and graft survival were both 100%. No serious adverse events (SAEs) occurred during the trial; however, 44% of patients developed hyperuricemia during the first 3 months, declining to 26% at 6 months and 23.3% at 12 months. Hyperkalemia occurred in 36% of patients during the first 3 months, dropping to 10% at 6 months and to 3% at 12 months. The investigators observed that the higher incidences of these AEs in the first 3 months’ post-transplant were associated with high levels of the immunosuppressant.

A previously reported phase III, randomized, double-blind, double-dummy trial of 341 kidney transplant patients compared tacrolimus b.i.d. to the q.d. formulation. Patients spent a mean of 18 months in the study. In a 2-year extension phase of the study led by principal investigator Prof. Krämer, 191 of these patients were given once-daily tacrolimus of whom 163 completed the follow-up phase (Figure 1). The majority of these patients were on a regimen consisting of tacrolimus q.d. and mycophenolate mofetil (MMF), with or without corticosteroids. The mean age of the patients was 46.9 years (±12.1), 61.3% were male and 82.2% were Caucasian. All but 9 patients were on their first transplant. Nearly 86% of patients were positive for Epstein-Barr, while 72% were positive for cytomegalovirus (CMV).

Figure 1.

The mean daily dose of q.d. tacrolimus was 0.08 mg/kg for the first 12 months of the follow-up study and 0.07 mg/kg for the last 12 months. Trough levels declined from 7.8 to 6.9 ng/mL during the study period, then recover
e 2).

Figure 2.

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Creatinine clearance increased from 66.1 (±22.0) to 70.0 (±26.3) mL/min. There was 1 death (myocardial infarction unrelated to the study) and 4 other instances of graft loss. Graft survival was 97.4% and patient survival was 99.3% at 2 years’ follow-up; 99.5% of patients were free from acute rejection and biopsy-proven acute rejection (BPAR) at the end of the trial. There were no instances of corticosteroid-resistant acute rejection. Common AEs were hypertension (21.5%) and urinary tract infections (17.3%). Drug-related SAEs were experienced by 15.7% of patients. “The side effects that occur are basically not different between [immediate-release and extended-release tacrolimus],” Prof. Krämer commented. The investigators concluded that q.d. tacrolimus is well tolerated and efficacious in the long term. “I think this represents a stable situation… this study gives the clinician reassurance that, if a patient has been put on extended-release de novo and everything is running smoothly, you don’t need to expect anything unexpected,” Prof. Krämer told delegates.

Five-year Results in Multi-organ Use

Prof. Johannes P. van Hooff, University Hospital Maastricht, The Netherlands, conducted a 5-year, phase III, multicentre, single-arm, open-label, prospective follow-up study of 240 patients who had previously been enrolled in one of 4 phase II pharmacokinetic tacrolimus q.d. trials. Two of the trials were conversion studies from b.i.d. to q.d. dosing and two were in de novo patients. Transplant types were heart (n=79), liver (n=47) and kidney (n=114). Fifty-six patients withdrew before the end of the study, including 18 withdrawals due to AEs, 15 of which were judged to be tacrolimus treatment-related. Of these, 5 were the result of renal impairment/insufficiency/failure. Graft loss occurred in 15 patients, 14 of whom died. Acute rejection was seen in 15 patients, 5 of whom spontaneously resolved, 9 responded to corticosteroids and 2 were corticosteroid-resistant.

Decreases occurred in tacrolimus dose and trough levels during the 5 years. In liver transplant patients, trough levels dropped to 4.3 ng/mL from a baseline of 8.7 ng/mL. Patient survival was 90.9%, 100%, 93.6% and 90.3% in the de novo liver, de novo kidney, conversion kidney and conversion heart cohorts, respectively, while graft survival was 90.9%, 100%, 92.2% and 90.3% (Table 1). Renal function remained good in all patient groups. AEs were similar to those observed with tacrolimus b.i.d. Prof. van Hooff concluded that q.d. tacrolimus is effective and well-tolerated in both conversion (kidney and heart transplant recipients) and de novo (liver and kidney transplant recipients) settings. Furthermore, the safety and ef
.d. was similar to that of the b.i.d. formulation.

Table 1.

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CONCERTO Findings

Therapy with cyclosporine can be problematic due to a safety profile which includes elevated risk of hypertension and hyperlipidemia, as well as disfiguring AEs such as gingival hyperplasia and hypertrichosis, which increase the risk of poor compliance. Previous studies have favourably compared b.i.d. tacrolimus with cyclosporine in terms of both efficacy and safety.

The CONCERTO (Correlation of Neoral C2 Exposure and Renal Transplant Outcome) study was a 24-week international, multicentre, open-label, Phase IIIb conversion study designed to investigate the effects of converting stable renal transplant patients experiencing cyclosporine-related AEs to a regimen of q.d. tacrolimus. The mean time since transplant in the patient population was 98 months and the mean duration of side effects was 67 months for hyperlipidemia (n=49), 87 months for hypertrichosis (n=114), 141 months for arterial hypertension (n=92) and 46 months for gingival hyperplasia (n=84). The primary end point of the CONCERTO study was kidney function change as measured by creatinine clearance. The non-inferiority study design required less than a 10% change in creatinine clearance from baseline to week 24.

Prof. Lionel Rostaing, Department of Nephrology, Toulouse University Hospital, France, presented data from the 301 evaluable patients that demonstrated good maintenance of kidney function, with no significant change in creatinine clearance during the study peri
eriority to cyclosporine was thus demonstrated. Investigators also found no evidence of rejection.

Figure 3.

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The most common drug-related AE following conversion was diarrhea. There were few withdrawals due to AEs and no deaths or graft losses during the study. In addition, rapid and significant improvements in cyclosporine-related AEs were observed. For example, total cholesterol in patients with hyperlipidemia (n=49) decreased by 0.82 mmol/L, while LDL-C declined by 0.43 mmol/L, a decrease of approximately 12%. Triglycerides were reduced by 0.44 mmol/L. In the hypertensive patient subgroup (n=92), mean arterial blood pressure decreased by 8.2 mm Hg. Gingival hyperplasia and hypertrichosis showed a marked improvement in most patients at week 24, according to Prof. Rostaing. “For women patients in particular, it could lead to non-compliance if they get hirsutism, and so in that case, it’s worth converting them from cyclosporine A to tacrolimus,” he told delegates, “or if you get gum hyperplasia, it could also lead to non-compliance to some extent, and so therefore it’s worth converting the patient.” The investigators concluded that conversion from cyclosporine to tacrolimus q.d. is safe and beneficial for maintenance immunosuppression in renal transplant recipients, and may result in reduced cardiovascular risk for those with hypertension or hyperlipidemia.

Summary

There appear to be two major benefits of converting patients to a q.d. tacrolimus formulation: improved compliance and avoidance of high peak levels of tacrolimus, which may be associated with increased toxicity. Both short- and long-term data suggest that efficacy and AE profiles of the q.d. formulation are similar to those of the b.i.d. drug. However, some data suggest that, at least initially in some patients, there may be a clinically significant drop in trough drug levels when patients are converted. Although there are indications that this may be actually beneficial, careful monitoring and interpretation of blood levels should be undertaken during the period following drug conversion. It has been shown that the incidence and degree of trough level depression is greater in patients with the CYP3A5*3/*3 homozygote than in heterozygous patients, although other possible risk factors have been identified. Finally, many patients suffering from a number of metabolic and esthetic AEs associated with cyclosporine activity experience improvement or resolution of these AEs after conversion to tacrolimus q.d. More importantly, no deterioration of renal function was noted in patients following conversion.