Published online Dec 24, 2015. doi: 10.5500/wjt.v5.i4.338
Peer-review started: July 6, 2015
First decision: July 31, 2015
Revised: August 10, 2015
Accepted: September 16, 2015
Article in press: September 18, 2015
Published online: December 24, 2015
Processing time: 175 Days and 5.9 Hours
AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors (CNI) alone or combined with everolimus.
METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one (n = 59) received everolimus (target blood level, 3-8 ng/mL) and the other (n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl (MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4 (CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/mL in 2 mo, and 50-65 ng/mL thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/mL until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.
RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up (66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group (20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate than the other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses.
CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.
Core tip: Several immunosuppressive (IS) drugs, used in clinical transplantation, are metabolized by the hepatic cytochrome P-450 system as many other drugs. The co-prescription of IS and ketoconazole reshapes the IS pharmacokinetics and appears to confer benefit to patients receiving calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors. We describe the long term follow-up of kidney allograft recipients receiving ketoconazole with a CNI alone or combined with everolimus and report good graft and patient survivals and low rates of acute rejection episodes. These combinations, in low immunological risk kidney transplant recipients are feasible, effective, safe and affordable even in the long term.