Topotecan pharmacokinetics

Mould et al. (2002), instead of using a conditional model to account for missing covariates, used a joint model that modeled the missing covariate simultaneously within the context of the overall pharmacokinetic model. In their analysis of topotecan pharmacokinetics in subjects with solid tumors, weight was known to be an important covariate but was missing in 20% of the database. The function for males... 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

For other efflux transporters such as BCRP (ABCG2), human pharmacokinetic and pharmacodynamic data are currently rare. However, an investigation of the influence of polymorphisms in ABC-transporter genes on the accumulation of nelfinavir in peripheral blood mononuclear cells (PBMCs) revealed no associations between the polymorphisms in the transporters analyzed and the accumulation of nelfinavir in the PBMCs [151], A second study in patients clearly demonstrated an increase in the AUC of the orally and intravenously administered BCRP substrate topotecan when it is given with GF120918, an inhibitor of P-glycoprotein and BCRP [152],... 

Liu JJ, Hong RL, Cheng WF, et al. Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient stability, pharmacokinetic and therapeutic evaluation. Anti-Cancer Drugs 2002 13(7) 709. 

O Dwyer PJ, LaCretaFP, Haas NB, et al. Clinical, pharmacokinetic and biological studies of topotecan. Cancer Chemother Pharmacol 1994 34 Suppl S46-S52. 

Pharmacokinetics Topotecan is given by IV infusion over 30 minutes for five consecutive days. Responses may not be seen for three weeks. Hydrolysis of the lactone ring destroys the drug s activity. About 30 percent of the drug and its metabolites is eliminated in the urine hence, the dose may have to be modified with impaired kidney function. 

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... 

Grochow LB, Rowinsky EK, Johnson R, Ludeman S, Kaufmann SH, McCabe FL, Smith BR, Hurowitz L, DeLisa A, Donehower RC, Noe D. Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metab Dispos 1992 20(5) 706-13. 

Loos WJ, Gelderblom HJ, Verweij J, Brouwer E, de Jonge MJ, Sparreboom A. Gender-dependent pharmacokinetics of topotecan in adult patients. Anticancer Drugs 2000 11(9) 673-80. 

Zamboni WC, Egorin MJ, Van Echo DA, Day RS, Meisenberg BR, Brooks SE, Doyle LA, Nemieboka NN, Dobson JM, Tait NS, Tkaczuk KH. Pharmacokinetic and pharmacodynamic study of the combiuatiou of docetaxel aud topotecan in patients with sohd tumors. J Chn Oncol 2000 18(18) 3288-94. 

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

Mould, D.R., Holford, N.H.G., Schellens, J.H.M., Beijen, J.H., Hutson, P.R., Rosing, H., ten Bokkel Huinink, W.W., Rowinsky, E., Schiller, J.H., Russo, M., and Ross, G. Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clinical Pharmacology and Therapeutics 2002 71 334-348. 

Herben V M, ten Bokkel Huinink W W, Beijnen J H (1996). Clinical pharmacokinetics of topotecan. Clin. Pharmacokinet. 31 85-102. 

The characterization of a mitoxantrone-resistant breast cancer cell line that displayed an efflux-based MDR phenotype without expression of Pgp or MRPl led to the discovery of BCRP. This transporter, also known as mitoxantrone resistance protein (MXR) or placenta-specific ABC transporter (ABCP), is a half-transporter acting as a homo- or heterodimer to form an active transporter [22]. The substrate specificity of BCRP overlaps somewhat with that of Pgp and MRPl, suggesting a similar role in the pharmacokinetic of chemotherapeutic drugs. In fact, the overexpression of BCRP in tumor cells confers resistance to mitoxantrone, topotecan, SN38, flavopiridol, doxorubicin, bisantrene, etoposide, and methotrexate [16]. 

In 10 women with ovarian cancer amifostine (given daily, before topotecan, for 5 days) did not significantly affect the pharmacokinetics of topotecan. ... 

Zackrisson A-L, Malmstrom H, Peterson C. No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients. EurJ Clin Pharmacol (2002) 58, 103-8. 

In 18 patients with solid tumours, the pharmacokinetics of topotecan (given in initial doses of 2.3 mg/m daily for 5 days and repeated every 3 weeks) and its active metabolite, topotecan lactone, were not affected by the previous use of ranitidine 150 mg twice daily for 4 days. No special precautions would seem necessary if ranitidine or other drugs that increase gastric pH are given with oral topotecan. 

Difficulties associated with CPTs administration, toxicity, and pharmacokinetics were a reason for the development of more favorable alternative forms of their dehvery or prodrug systems [35 10]. Delivery of CPT and its derivatives was studied by using hposomes (see also lurtotecan). Examples of such lipid formulations of CPTs in clinical trials include CPX-1 (irinotecan-floxuridine hposome in Phase 1) firom Celator Pharmaceuticals [285] and Brakiva (Topotecan Optisome) liposomal formulation of topotecan from Hana Biosciences [286]. 

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