Unexpectedly low immunocompetence in transplant patients on ketoconazole

The P450 inhibitor ketoconazole may be used to decrease the dose, and therefore cost, of cyclosporine (CYA) by greatly decreasing the dose necessary to obtain therapeutic levels. However, the degree of immunosuppression produced using this drug regimen is not certain. We studied the immunocompetence of patients that had been started on ketoconazole to reduce the dose of CYA compared with patients treated conventionally. 95 assays were done in 64 patients including 6 assays in patients receiving low dose CYA plus ketoconazole. Immunocompetence was tested by measuring the mixed lymphocyte response using stimulators either non-depleted (ND) or depleted (D) of antigen presenting cells, based on the finding that CYA inhibits the response against D at a lower dose than against ND. Responses to ND/D ranged from +/+ through +/- to -/-. Normal individuals were always +/+. In conventionally treated patients with CYA the incidence of immunocompetence ≤ +/- was 48%, whereas all patients on CYA + ketoconazole had an immunocompetence score ≤ +/- (p = 0.03, χ²). This degree of immunosuppression contrasted strikingly with the chemical levels, which for those on ketoconazole were in the low acceptable area (182.3 ± 77.1 ng/ml range from 67 to 230 ng/ml), Therefore, patients using low-dose CYA plus ketoconazole to inhibit metabolism were more immunosuppressed than those receiving conventional CYA treatment, in spite of comparable CYA blood levels. If confirmed, this unexpectedly depressed immunocompetence in these patients would warrant caution in general regarding interpretation of trough blood levels in patients receiving CYA that are also being treated with agents that alter P450 activity.