Abstract
The bifunctional alkylating agent busulfan (Bu) was solubilized in a cosolvent mixture of anhydrous dimethylacetamide (DMA), polyethylene glycol 400 (PEG400), and water at a ratio of 1:2:2(v/v/v), to achieve a Bu concentration of 3 mg/ml, a preparation that would be suitable for parenteral administration in high-dose chemotherapy preceding bone marrow transplantation. The complete formulation was stable for more than 54 h at room temperature (RT, 22° C). An accelerated stability study of Bu in anhydrous DMA or DMA/PEG400 (1:2) as stock solutions indicated shelf-lives of 191 and 180 days respectively, at RT, and 8.2 and 7.5 years, respectively, at 4°C. Although the complete formulation with Bu was very hypertonic, hemolysis studies indicated that the formulation would be safe for intravenous (i.v.) administration, since it would be rapidly diluted to harmless tonicity levels in the blood. Cytotoxicity studies of the complete formulation in vitro proved that Bu retained its activity when dissolved in the complete vehicle. A preliminary pharmacokinetic study in a rodent model after the i.v. administration of Bu at a dose of 1 mg/kg body weight yielded high plasma concentrations of Bu for at least 5 h after injection.
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References
Witts LJ (1968) Chronic granulocytic leukemia: comparison of radiotherapy and busulphan therapy. Report of the Medical Research Council’s Working Party for Therapeutic Trials in Leukemia. BMJ 1:201–208
Galton DAG (1969) Chemotherapy in chronic myeloid leukemia. Semin Hematol 6:323–343
Canellos GP, Young RC, Nieman PE, DeVita VT (1975) Dibromomannitol in the treatment of chronic granulocytic leukemia: a prospective randomized comparison with busulfan. Blood 45: 197–203
Canellos GP (1985) Chronic leukemias. In: De Vita VT Jr, Hellman S, Rosenberg SA (eds) Cancer: principles and practice of oncology, 2nd Edn. J.B. Lippincott, Philadelphia, pp 1739–1752
Hughes TP, Goldman JM (1991) Chronic myeloid leukemia. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ (eds) Hematology, basic principles and practice. Churchill Livingstone, New York, pp 854–869
Santos GW, Tutschka PJ (1974) Marrow transplantation in the busulfan-treated rat: Preclinical model of aplastic anemia. J Natl Cancer Inst 53:1781–1785
Tutschka PJ, Santos GW (1975) Bone marrow transplantation in the busulfan-treated rat. II. Effect of cyclophosphamide and antithymic serum on the presensitized state. Transplantation 20:101–106
Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM (1983) Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309:1347–1353
Lu C, Braine HG, Kaizer H, Saral R, Tutschka PJ, Santos GW (1984) Preliminary results of high-dose busulfan and cyclophosphamide with syngeneic or autologous bone marrow rescue. Cancer Treat Rep 68:711–717
Tutschka PJ Copelan EA, Klein JP (1987) Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood, 70:1382–1388
Copelan EA, Grever MR, Kapoor N, Tutschka PJ (1989) Marrow transplantation following busulfan and cyclophosphamide for chronic myelogenous leukaemia in accelerated or blastic phase. Br J Haematol 71:487–491
Sheridan WP, Boyd AW, Green MD, Russell DMR, Thomas RJS, McGrath KM, Vaughan SL, Scarlett JD, Griffiths JD, Brodie GN, Januszewicz EH, Fox RM (1989) High-dose chemotherapy with busulphan and cyclophosphamide and bone-marrow transplantation for drug-sensitive malignancies in adults: A preliminary report. Med. J Aust 151:379–386
Geller RB, Saral R, Piantadosi S, Zahurak M, Vogelsang GB, Wingard JR, Ambinder RF, Beschorner WB, Braine HG, Burns WH, Hess AD, Jones RJ, Stratford May W, Rowley SD, Wagner JE, Yeager AM, Santos GW (1989) Allogeneic bone marrow transplantation after high dose busulfan and cyclophosphamide in patients with acute non lymphocytic leukemia. Blood, 73:2209–2218
Yeager AM, Kaizer H, Santos GW, Saral R, Colvin OM, Stuart RK, Braine HG, Burke PJ, Ambinder RF, Burns WH, Fuller DJ, Davis JM, Karp JE, Stratford May W, Rowley SD, Sensenbrenner LL, Vogelsang GB, Wingard JR (1986) Autologous bone marrow transplantation in patients with acute non-lymphoblastic leukemia using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 315:141–147
Peters WP, Henner WD, Grochow LB, Olsen G, Edwards S, Stanbuck H, Stuart A, Gockerman J, Moore J, Bast RC, Seigler HF, Colvin OM (1987) Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res 47:6402–6406
Grochow LB, Jones RJ, Brundrett RB, Braine HG, Chen T-L, Saral R, Santos GW, Colvin OM (1989) Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 25:55–61
Vassal G, Deroussent A, Hartmann O, Challine D, Benhamou E, Valteau-Couanet D, Brugieres L, Kalifa C, Gouyette A, Lemerle J (1990) Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Cancer Res. 50:6203–6207
Henner WD, Furlong EA, Flaherty MD, Shea TC (1987) Measurement of busulfan in plasma by high-performance liquid chromatography. J Chromatogr Biomed Appl 416:426–432
Busulfan. The Merck Chemical Index, 10th edn, 1983. p 208
Vassal G, Gouyette A, Hartmann O, Pico JL, Lennerle J (1989) Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 24:386–390
Hassan M, Öberg G, Békàssy AN, Aschan J, Ehrsson H, Ljungman P, Lönnerholm G, Smedmyr B, Taube A, Wallin I, Simonsson B (1991) Pharmacokinetics of high-dose busulfan in relation to age and chronopharmacology. Cancer Chemother Pharmacol 28:130–134
Hassan M, Ljungman P, Bolme P, Ringdén O, Syrucková Z, Békàssy A, Stary J, Wallin I, Kållberg N (1994) Busulfan bioavailability Blood 84:2144–2150
Hassan M, Ehrsson H (1987) Metabolism of 14C-busulfan in isolated perfused rat liver. Eur J Drug Metab Pharmacokinet 12:71–76
Marchand DH, Remmel RP, Abdel-Monem MM (1987) Biliary excretion of a glutathione conjugate of busulfan and 1,4-diiodobutane in the rat. Drug Metab Dispos 16:85–92
Fitzsimmons WE, Ghalie R, Kaizer H (1990) The effect of hepatic enzyme inducers on busulfan neurotoxicity and myelotoxicity. Cancer Chemother Pharmacol 27:226–228
Beschorner WE, Pino J, Boitnott JK, Tutschka PJ, Santos GW (1980) Pathology of liver with bone marrow transplantation. Effects of busulfan, carmustine, acute graft-vs-host-disease, cytomegalovirus infections. Am J Pathol 99:369–386
Bhagwatwar HP, Andersson BS, Chow DS-L High-performance liquid Chromatographic assay of busulfan in aqueous and plasma samples. J Chromatogr (in press)
Martin A, Swarbrick J, Cammarata A (1993) Physical pharmacy. 4th edn. 1993, Lea and Febiger, Philadelphia, p 313–316
Reed KW, Yalkowsky, SH (1985) Lysis of human red blood cells in the presence of various cosolvents. J Parenteral Sci Technol 39:64–68
Gallagher R, Collins S, Trujillo J, McCredie KB, Ahearn M, Tsai S, Anlakh GS, Ting R, Ruscetti F, Gallo R (1979) Characterization of the continuously differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia. Blood 54:254–268
Beran M, Andersson BS (1987) Development and characterization of a human myelogenous leukemia cell line resistant to 4′-(9-acridinylamino)-3-methanesulfon-m-anisidide. Cancer Res 47:1897–1904
Bhagwatwar HP, Andersson BS, Chow DS-L (1994) Comparative pharmacokinetics of intravenous (i.v.) and oral busulfan (BU) in rats (abstract no 1772). Proceedings of the Annual Meeting of the American Association for Cancer Research, 35. p 298
Vaughn WP, Dennnison JD, Reed EC, Klassen L, McGuire TR, Sanger WG, Kumar PP, Warkentin PI, Gordon BG, Bierman PJ, Coccia PF, Armitage JO (1991) Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy. Bone Marrow Transplant 8:489–496
Linker CA, Ries CA, Damon LE, Rugo HS, Wolf JL (1993) Autologous bone marrow transplantation for advanced myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81:311–318
Chao NJ, Stein AS, Long GD, Negrin RS, Amylon MD, Wong RM, Forman SJ, Blume KG (1993) Busulfan/etoposide — Initial experience with a new preparative regimen for autologous bone marrow transplantation in patients with acute non-lymphoblastic leukemia Blood 81:319–323
Przepiorka D, Nath R, Ippolitti C, Mehra R, Hagemeister F, Diener K, Dimopoulos M, Giralt S, Khouri I, Samuels B, vanBesien K, Andersson B, Deisseroth AB, Luna M, Cabanillas F, Champlin R (1995) A phase I-II study of high-dose thiotepa, busulfan, and cyclophosphamide as a preparative regimen for autologous transplantation for malignant lymphoma. Leuk Lymphoma 17:427–433
Champlin RE, Ho WG, Lenarsky C, Winston D, Mitsuyasu R, Feig SA, Gale RP (1985) Successful second bone marrow transplants for treatment of acute myelogenous leukemia or acute lymphoblastic leukemia. Transplant Proc 17:496–499
Yalkowsky SH, Roseman TJ (1981) Solubilization of drugs by cosolvents. In: Yalkowsky SH (ed) Techniques of solubilization of drugs. Marcel Dekker New York, pp 91–134
Spiegel AJ, Noseworthy MN (1963) Use of nonaqueous solvents in parenteral products. J Pharm Sci 52:917–927
Kim SN (1988) Preclinical toxicology and pharmacology of dimethylacetamide with clinical notes. Drug Metab Rev 19:345–368
Arlin ZA, Sklaroff RB, Gee TS, Kempin SJ, Howard J, Clarkson BD, Young CW (1980) Phase I and II trial of 4’-(-acridinylamino) methanesulfon-m-anisidide in previously treated patients with acute leukemia. Cancer Res 40:3304–3306
Legha SS, Keating MJ, McCredie KB, Bodey GP, Freireich EJ (1982) Evaluation of AMSA in previously treated patients with acute leukemia: results of therapy in 109 adults. Blood 60:484–490
Keating MJ, Gehan EA, Smith TL, Estey EH, Walters RS, Kantarjian HM, McCredie KB, Freireich EJ (1987) A strategy for evaluation of new treatments in untreated patients: Application to a clinical trial of AMSA for acute leukemia. J Clin Oncol 5:710–721
Weiss AJ, Jackson LG, Carabasi RA, Mancall EL, White JC (1962) A Phase I study of dimethylacetamide. Cancer Chemother Rep 16:477
Lockard JS, Levy RH, Congdon WC, DuCharme LL (1979) Efficacy and toxicity of the solvent polyethylene glycol 400 in monkey model. Epilepsia 20:77–84
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Bhagwatwar, H.P., Phadungpojna, S., Chow, D.SL. et al. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharmacol 37, 401–408 (1996). https://doi.org/10.1007/s002800050404
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DOI: https://doi.org/10.1007/s002800050404