Clinical Pharmacology of 1-/3-o-Arabinofuranosylcytosine-5'-stearylphosphate, an Orally Administered Long-Acting Derivative of Low-Dose 1-/3-o-Arabinofuranosyicytosinel

1-/]-n-Arahinofuranosylcytosine-5'-stearylphosphate (cytarabine ocfosfate, stearyl-ara-CMP) is a newly synthesized 5'-alkyiphosphate derivative of 1-/]-n-arabinofuranosylcytosine (ara-C), which is lipophUic, resistant to inactivation by deamination, and orally active. Pharmacology of this drug was studied in patients with hematological malignancies. The concentrations of stearyl-ara-CMP, ara-C (its active metabolite), and 1-/]-n-arabinofuranosyluracil (ara-U, its inactive metabolite) were determined by radioimmunoassay. When six patients received a single p.o. dose of the drug (500 mg/m2), stearyl-ara-CMP, ara-C, and ara-U could be detected in the plasma for at least 72 h afterwards. The plasma disappearance curve of stearyl-ara-CMP corresponded to a one-compartment open model with first-order absorption kinetics. The peak plasma level (Cmax) was 322 _+ 218 riM, and the predicted time to reach Crux (Tma,,) was 6.5 -+ 4.5 h, while the elimination half-life (t~/2) was very long (32.0 _+ 8.4 h). The plasma ara-C level increased slowly to a Cmax of 26.3 -+ 12.7 nM (Tmax, 13.3 -+ 4.7 h) after stearyl-ara-CMP administration. This level was quite low compared with that achieved by low-dose s.c. ara-C therapy, but ara-C persisted longer in the plasma in the former case, and the area under the curve was similar for both regimens. For ara-U, the Cmax, Tmax, and t,/2 were 483 _+ 315 riM, 23.6 + 4.0 h, and 19.6 _+ 5.3 h, respectively. No stearyl-ara-CMP was detected in the urine, and only 8.0% of the administered dose was excreted as ara-C and ara-U within 72 h. The stearylara-CMP concentration in the cerebrospinal fluid was below the limit of detection in three patients without meningeal involvement at 6 h. During clinical use of stearyl-ara-CMP, macrocytic anemia was observed, and some patients also developed megaloblastic change of their erythroblasts, suggesting a mild and persistent cytostatic effect. In conclusion, p.o. therapy with stearyl-ara-CMP achieved prolonged maintenance of the plasma drug level. Thus, the drug released a very low dose of ara-C over a long period in plasma and tissues and had a prolonged mild antineoplastic effect in patients with hematological malignancies. I N T R O D U C T I O N ara-C 3 is one of the most effective drugs for the treatment of hematological malignancies including leukemia and lymphoma (1, 2). Recently, low-dose or very low-dose ara-C therapy has been used to treat acute leukemia and myelodysplastic syndrome as a potential type of differentiation induction therapy and has been reported to be effective in some cases (3, 4). One of the problems with this therapy is the troublesome need for daily s.c. or continuous i.v. injection of ara-C, which is especially difficult in patients with thrombocytopenia. Received 12/17/92; accepted 11/1/93. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported in part by a Grant-in-Aid from the Ministry of Health and Welfare, Japan. 2 To whom requests for reprints should be addressed. 3 The abbreviations used are: ara-C, 1-/3-D-arabinofuranosylcytosine; stearyl-ara-CMP, 1-/3-D-arabinofuranosylcytosine-5'-stearylphosphate; ara-U, 1-/3-D-arabinofuranosyluracil; CSF, cerebrospinal fluid; N4-behenoyl-ara-C, Na-behenoyl-1-/3-D-arabinofuranosylcytosine; Na-palmitoyl-ara-C, N4-palmitoyl-1-/3-D-arabinofuranosylcytosine; ara-CTP, 1-/3D-arabinofuranosylcytosine 5'-triphosphate; AUC, area under the plasma concentration curve from time zero to infinity. Thus, for relatively stable patients, such as those with myelodysplastic syndrome and smouldering acute leukemia, an orally active form of ara-C would provide certain clinical advantages. Stearyl-ara-CMP is a 5'-alkylphosphate derivative of ara-C that was synthesized by Saneyoshi e t al. (5) in 1980. As a result of the introduction of a long-chain fatty acyl group at the 5'-position of ara-CMP, the drug shows lipophilicity. Moreover, it is resistant to inactivation by cytidine deaminase, which catalyzes ara-C to its inactive metabolite. These characteristics enabled stearyl-ara-CMP to be orally active and to show a long lasting antitumor effect in tumor-bearing mice (6). Phase I and Phase II clinical studies have since been completed in Japan (7-9). We have already reported some preliminary results of a pharmacokinetic study (10, 11). In addition, the successful treatment of myelodysplastic syndrome with this drug (12) suggested its possible superiority over low-dose ara-C therapy in the Japanese Phase II study. Phase I and Phase II trials are now also under way in Germany. The present study was performed in patients with hematological malignancies with the purpose of clarifying the unique pharmacological characteristics of