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Tolerance and Pharmacokinetics of High Doses of Interferon-alpha-2a in a Hemodialysis Patient

Accessible online at: www.karger.com/journals/nef Dear Sir, Kaposi’s sarcoma (KS) is the most common malignant tumor found in patients with an immunodeficiency state such as acquired immunodeficiency syndrome (AIDS) or organ transplant. Interferon-· (IFN-·) has shown antitumor and antiviral efficacy against various tumors and tumor-related viruses: it has been approved by the Food and Drug Administration (FDA) for the treatment of patients with AIDS-related KS as monotherapy. We report on the tolerance and the pharmacokinetics of biologically active IFN-·2a administered at high doses in a patient on maintenance hemodialysis. In October 1998, a 55-year-old man with anuric endstage renal disease (ESRD) treated with hemodialysis for chronic glomerulopathy had received a kidney transplant. Immunosuppression included cyclosporin (Neoral®), azathioprine (Imurel®) and corticosteroids (Cortancyl®). Four months after organ transplantation, the patient developed cutaneous and pulmonary lesions of KS which led to withdrawal of immunosuppressive therapy and transplantectomy. Hemodialysis was started in July 1999. Initial therapy with bleomycin 15 mg every 2 weeks for KS was ineffective and toxic for the lung (pulmonary interstitial fibrosis). Therefore, IFN-·2a (Roferon®) was started in September 1999. Physical examination as well as biological tests (white and red counts, blood, platelets, serum aminoaspartate and glutamine transferase, amylase and lipase) were normal. IFN-·2a was given, starting with 9 million units subcutaneously injected per day during 2 weeks. No side effects were observed. Dose escalation to 18 million units subcutaneously per day was then allowed. Ten days later, the patient presented neuropsychiatric reactions (delirium, agitation, convulsions and then coma); asymptomatic acute pancreatitis (serum amylase and lipase at 1,000 and 12,000 units, respectively) and thrombocytopenia at 80,000/mm3. Studies of the pharmacokinetics of IFN-·2a in plasma (before and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 20 and 24 h after injection) conducted between hemodialysis sessions were performed. Paired arterial and venous blood samples were also performed simultaneously 2 h after the beginning of a 4-hour hemodialysis session. Very high serum concentrations (300– 400 IU/ml, therapeutic threshold at 2 IU/ ml) were observed. Cmax, Cmin, area under the concentration-time curve (AUC) and half-life (T1/2) were 400 IU/ml, 200 IU/ml, Table 1. Pharmacokinetic parameters of IFN-·2a in a hemodialyzed patient and in those with normal renal function