Etoposide pharmacokinetics

Lum BL, Kaubisch S, Yahanda AM, et al. Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 1992 10(10) 1635-1642. 

Lum B, Kaubisch S, Yahanda A, Adler K, Jew L, Ehsan M, Brophy N, Halsey J, Gosland M, Sikic B. Alteration of etoposide pharmacokinetics and pharmacod5mamics by... 

Rodman JH, Murry DJ, Madden T, Santana VM. Altered etoposide pharmacokinetics and time to engraflment in pediatric patients undergoing autologous bene marrow transplantation. J Clin... 

Newell DR, Eeles RA, Gumbrell LA, Boxall FE, Horwich A, Calvert AH. Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma. Cancer Chemoiher Pharmacol 9Z9) 23, 376-72,... 

Relling MV, McLeod HL, Bowman LC, Santana VM. Etoposide pharmacokinetics and pharmacodynamics after acute and chronic exposure to cisplatin. Clin Pharmacol Ther ( 994) 56, 503-11. 

Similarly, no changes in etoposide pharmacokinetics were seen when oral etoposide 100 mg was given immediately after oral cyclophosphamide 100 mg/m and methotrexate 12.5 mg/m in 8 patients with SCLC. In addition, no changes were seen when the same dose of oral etoposide... 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

P-gp is responsible for transport of the carboxylate form of irinotecan (64). The homozygous mutant 8 polymorphism has been associated with significantly increased exposure to irinotecan and its active metabolite SN-38 (65). Furthermore, significantly decreased docetaxel clearance was found in patients homozygous mutant for P-gp 8 (66), although Goh et al. (67) did not find a significant effect of this polymorphism on docetaxel pharmacokinetics. Also, a trend to an increased AUC of tipifamib in patients with the homozygous mutant allele compared to patients with only one or no mutant alleles of 8 was found in a study by Sparreboom et al. (68). In a study by Kishi et al. (40), the mutant allele for 6 was also correlated with a lower clearance of etoposide in children with ALL. 

Reddy, PR. and Venkateswarlu, V. (2005) Pharmacokinetics and tissue distribution of etoposide delivered in long circulating parenteral emulsioih.Drug Target, 13 543-553. 

Pharmacokinetic studies in dogs demonstrated a 3.5-fold increase in oral bioavailability of phenytoin when administered as the disodium phosphate prodrug versus sodium phenytoin [54]. A few additional examples of investigations with this strategy include the steroids betamethasone [55] and hydrocortisone [56], HIV protease inhibitors [57], and the anticancer drug etoposide [58,59]. Comprehensive reviews of this strategy are also available [52,60,61]. 

Sessa, C., et al. 1995. Phase I clinical and pharmacokinetic study of oral etoposide phosphate. J Clin Oncol 13 200. 

Cyclosporin A readily inhibits CYP3A metabolism and may lead to significant pharmacokinetic interactions (288). Several studies have been performed using cyclosporin A as a P-gp modulator in combination with etoposide, doxorubicin, and paclitaxel as described below. 

The effects of cyclosporin A on the pharmacokinetics of etoposide have been determined and were shown to be dose dependent. A variable range of cyclosporin A concentrations was obtained (297-5073 ng/mL), and it was observed that patients with higher cyclosporin A concentrations also had larger increases in etoposide AUC (290). Results from studies using clinically relevant plasma concentrations of cyclosporin A (1000-5000 ng/mL) as a P-gp inhibitor resulted in mean 48%, 52%, and 52% decreases in the systemic, renal, and nonrenal clearances of intravenously administered etoposide (232,290). Similar decreases in the systemic, renal, and nonrenal clearances of doxorubicin were observed with administration of cyclosporin A (232,291). 

In 66 patients who received busulfan in combination with cyclophosphamide, etoposide, and/or cytarabine in preparation for bone marrow transplantation, there was a higher incidence of veno-occlusive disease of the liver (sinusoidal obstruction syndrome) in those who received busulfan + cyclophosphamide (four of 10) than in those who received busulfan + cyclophosphamide + cytarabine (one of 18) or busulfan + cyclophosphamide + etoposide (seven of 38) (24). The risk of veno-occlusive disease was higher in those whose busulfan AUC was over 1500 minute.pmol/l (relative risk = 11). Other pharmacokinetic parameters, age, sex, type of bone marrow transplantation, previous therapy, or pretransplant liver function tests were not predictive of veno-occlusive disease. 

Bisogno G, Cowie F, Boddy A, Thomas HD, Dick G, Pinkerton CR. High-dose cyclosporin with etoposide— toxicity and pharmacokinetic interaction in children with solid tumours. Br J Cancer 1998 77(12) 2304-9. 

There is large interindividual variability in etoposide plasma concentrations with conventional dosages, and some authors have suggested that plasma concentration monitoring would reduce the pharmacokinetic variability and optimize outcomes (93,94). 

Dowlati A, Levitan N, Gordon NH, Hoppel CL, Gosky DM, Remick SC, Ingalls ST, Berger SJ, Berger NA. Phase II and pharmacokinetic/pharmaco-dynamic trial of sequential topoisomerase I and II inhibition with topotecan and etoposide in advanced... 

Aita P, Robieux I, Sorio R, Tnmolo S, Corona G, Cannizzaro R, Colnssi AM, Boiocchi M, Toffoh G. Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma. Cancer Chemother Pharmacol 1999 43(4) 287-94. 

Millward MJ, Newell DR, Ynen K, Matthews JP, Balmanno K, Charlton CJ, GnmbreU L, Lind MJ, Chapman F, Proctor M, Simmonds D, Cantwell BMJ, Calvert AH. Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer. Cancer Chemother Pharmacol 1995 37(l-2) 161-7. 

Schacter LP, Igwemezie LN, Seyedsadr M, Morgenthien E, Randolph J, Albert E, Santabarbara P. Clinical and pharmacokinetic overview of parenteral etoposide phosphate. Cancer Chemother Pharmacol 1994 34(Suppl) S58-63. 

Kaul S, Igwemezie LN, Stewart DJ, Fields SZ, Kosty M, Levithan N, Bukowski R, Gandara D, Goss G, O Dwyer P, Schacter LP, Barbhaiya RH. Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors. J Clin Oncol 1995 13(11) 2835-41. 

Kreis W, Budman DR, Vinciguerra V, Hock K, Baer J, Ingram R, Schacter LP, Fields SZ. Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors. Cancer Chemother Pharmacol 1996 38(4) 378-84. 

Nguyen L, Chatelut E, Chevreau C, Tranchand B, Lochon I, Bachaud JM, Pujol A, Houin G, Bugat R, Canal P. Population pharmacokinetics of total and unbound etoposide. Cancer Chemother Pharmacol 1998 41(2) 125-32. 

D Incalci M, Rossi C, Zucchetti M, Urso R, Cavalli F, Mangioni C, Willems Y, Sessa C. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res 1986 46(5) 2566-71. 

Mross K, Bewermeier P, Kruger W, Stockschlader M, Zander A, Hossfeld DK. Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies. J Clin Oncol 1994 12(7) 1468-74. 

Holthuis JJ, Van de Vyver FL, van Oort WJ, Verleun H, Bakaert AB, De Broe ME. Pharmacokinetic evaluation of increasing dosages of etoposide in a chronic hemodialysis patient. Cancer Treat Rep 1985 69(ll) 1279-82. 

Pharmacokinetics Absorption/distribution Topotecan and irinotecan available IV only Etoposide available IV and PO (50% bioavailable)... 

The pharmacokinetics of etoposide fit a two-companmeni model. A terminal half-life of 7 hours is independent of the dose and method of administration. About 4.3% of adaseo recovered in the urine, of which 66% is unchanged drug. The primary metabolites found in plasma ate picnihydmvi acids and picro lactone the major urinary metabolite is 4-dcmethylepipodophyllic acid. Oral bioavailability is alxu 50%. 

Chen CL et al. Bioavailability and pharmacokinetic features of etoposide in childhood acute lymphoblastic leukemia patients. Leukaemia Lymphoma, 2001, 42 317-327. 

Morikawa N, Mori T, Abe T, Kawashima H, Takeyama M, Hori S (1999) Pharmacokinetics of etoposide and carboplatin in cerebrospinal fluid and plasma during hyperosmotic disruption of the blood brain barrier and intraarterial combination chemotherapy. Biol Pharm Bull 22 428-431. 

J. C. Panetta, M. Wrlkinson, C. H. Pui, and M. V. Rolling, Limited and optimal sampling strategies for etoposide and etoposide catechol in children with lenkemia. J Pharmacokinet Pharmacodyn 29(2) 171-188 (2002). 

Pharmacokinetics Etoposide is well absorbed after oral administration and distributes to most body tissues. Elimination of etoposide is mainly via the kidneys, and dose reductions should be made in patients with renal impairment. 

---