Summary
The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m2 divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m2 cytosine arabinoside (ara-C), 300 mg/m2 carmustine (BCNU), or 1,200 mg/m2 carboplatin. Plasma etoposide concentrations were determined by252Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2β, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629μg min ml−1 (normalized to a dose of 100 mg/m2); volume of distribution at steady state (Vdss), 6.6±1.2l/m2; and clearance (CL), 20.4±2.4 ml min−1 m−2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m2). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 μg/ml, all patients exhibited undelayed hematopoietic reconstitution.
Similar content being viewed by others
References
Blume KG, Forman SJ, O'Donell MR, Doroshow JH, Krance RA, Nademanee AP, Snyder DS, Schmidt GM, Fahey JL, Metter GE, Hill LR, Findley DO, Sniecinski IJ (1987) Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 69:1015
Burnett AK, Watkins R, Maharaj D (1984) Transplantation of unpurged autologous bone marrow in acute myeloid leukemia in first remission. Lancet 11:1068
Cunningham D, Cummings J, Blackie RB, McTaggart L, Banham SW, Kaye SB, Soukop M (1987) The pharmacokinetics of high dose cyclophosphamide and high dose etoposide. Med Oncol Tumor Pharmacother 5:117
Danigel H, Pflüger KH, Jungclas H, Schmidt L, Dellbrügge J (1985) A combined method of liquid chromatography and mass spectrometry. Cancer Chemother Pharmacol 15:121
Douay L, Gorin NC, Mary IY, Lemarie E, Lopez M, Naiman A, Stachowiak I, Giarratana MC, Baillou C, Salmon F (1986) Recovery of CFU-GM from cryopreserved marrow and in vivo evaluation after autologous bone marrow transplantation are predictive of engraftment. Exp Hematol 14:358
Finn GP, Bozek T, Souhami RL, Slevin ML, Thomas DGT (1985) High-dose etoposide in the treatment of relapsed primary brain tumors. Cancer Treat Rep 69:603
Gouyette A, Deniel A, Pico JL, Droz JP, Baume D, Ostronoff M, Le Bail N, Hayat M (1987) Clinical pharmacology of high-dose etoposide associated with cisplatin. Pharmacokinetic and metabolic studies. Eur J Cancer Clin Oncol 23:1627
Green JA, Tarpey AW, Warenius HM (1988) Pharmacokinetic study of high dose etoposide infusion in patients with small cell lung cancer. Acta Oncol 27:819
Hande KR, Wedlund PJ, Noone RM, Wilkinson GR, Greco FA, Wolff SN (1984) Pharmacokinetic of high-dose etoposide (VP16-213) administered to cancer patients. Cancer Res 44:379
Holthuis JJM, Postmus PE, Van Oort PJ, Hulshoff B, Verleun H, Sleijfer DT, Mulder NH (1986) Pharmacokinetics of high dose etoposide (VP16-213). Eur J Cancer Clin Oncol 22:1149
Jungclas H, Pflüger KH, Schmidt L, Hahn M (1989) Quantitative252Cf-PDMS for etoposide. J Phys Coll [C] 50 [Suppl 2]: 41
Köppler H, Pflüger KH, Wolf M, Weide R, Havemann K (1990) High-dose chemotherapy with noncryopreserved autologous bone marrow transplantation for acute myeloid leukemia in first complete remission. In: Büchner T, Schellong G, Hiddemann W, Ritter J (eds) Hematology and blood transfusion, vol 33. Acute leukemias II. Springer, Berlin Heidelberg New York, p 699
Köppler H, Pflüger KH, Havemann H (1991) High-dose chemotherapy with autologous bone marrow rescue: hematopoietic reconstitution by non-cryopreserved bone marrow. Bone Marrow Transplant 7 [Suppl 2]: 143
Loo JCK, Riegelmann S (1970) Assessment of pharmacokinetic constants from postinfusion blood curves obtained after i. v. infusion. J Pharm Sci 59:53
Meloni G, De Fabritiis P, Carella AM (1990) Autologous bone marrow transplantation in patients with AML in first complete remission. Results of two different conditioning regimens after the same induction and consolidation therapy. Bone Marrow Transplant 5:29
Newell DR, Eeles RA, Gumbrell LA, Boxall FE, Horwich A, Calvert AH (1989) Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma. Cancer Chemother Pharmacol 23:267
Newman EM, Doroshow JH, Forman SJ, Blume KG (1988) Pharmacokinetics of high-dose etoposide. Clin Pharmacol Ther 43:561
Pflüger KH, Schmidt L, Merkel M, Jungclas H, Havemann K (1987) Drug monitoring of etoposide (VP16-213). Cancer Chemother Pharmacol 20:59
Postmus PE, De Vries EGE, De Vries-Hospers HG, Vriesendorp R, Van Imhoff GW, Holthuis JJM, Smit Sibinga CT, Sleijfer DT, Mulder NH (1984) Cyclophosphamide and VP16-213 with autologous bone marrow transplantation. A dose escalation study. Eur J Cancer Clin Oncol 20:777
Schmitz N, Gassmann W, Rister M, Johannson W, Suttorp M, Brix F, Holthuis JJM, Heit W, Hertenstein B, Schaub J, Löffler H (1988) Fractionated total body irradiation and high-dose VP16-213 followed by allogeneic bone marrow transplantation in advanced leukemias. Blood 72:1567
Sinkule JA, Hutson P, Hayes FA, Etcubanas E, Evans W (1984) Pharmacokinetics of etoposide (VP16) in children and adolescents with refractory solid tumors. Cancer Res 44:3109
Spinilo JA, Dicke KA, Horwitz LJ (1990) Double intensification with amsacrine/high-dose ara-C and high-dose chemotherapy with autologous bone marrow transplantation produces durable remissions in acute myelogenous leukemia. Bone Marrow Transplant 5:111
Spitzer G, Verma DS, Fisher R, Zander A, Vellekoop L, Litam J, McCredie KB, Dicke KA (1980) The myeloid progenitor cell—its value in predicting hematopoietic recovery after autologous bone marrow transplantation. Blood 55:317
Van Hoogenhuijze J, Lankelma J, Stam J, Pinedo HM (1987) Unchanged pharmacokinetics of VP16-213 (etoposide, NSC 141540) during concomitant administration of doxorubicin and cyclophosphamide. Eur J Cancer Clin Oncol 23:807
Wolff SN, Fer MF, McKay CM, Hande KR, Hainsworth JD, Greco FA (1983) High-dose VP16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study. J Clin Oncol 1:701
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Köhl, P., Köppler, H., Schmidt, L. et al. Pharmacokinetics of high-dose etoposide after short-term infusion. Cancer Chemother. Pharmacol. 29, 316–320 (1992). https://doi.org/10.1007/BF00685951
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00685951