Epirubicin pharmacokinetics

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

Gurney HP, Ackland S, Gebski V, Farrell G. Factors affecting epirubicin pharmacokinetics and toxicity evidence against using body-surface area for dose calculation. J Clin Oncol 1998 16 2299-2304. 

Paclitaxel also may be given concurrently with doxorubicin or epirubicin as a combination regimen. Pharmacokinetic interactions make these regimens more difficult to give. 

Coukell, AJ. and Faulds, D. 1997. Epirubicin An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer. Drugs. 53 453. 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

Camaggi CM, Comparsi R, Strocchi E, Testoni F, Angelelli B, Pannuti F. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study. Cancer Chemother Pharmacol 1988 21(3) 221-8. 

Plosker GL, Faulds D. Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs 1993 45(5) 788-856. 

Twelves CJ, Dobbs NA, Michael Y, Summers LA, Gregory W, Harper PG, Rubens RD, Richards MA. Clinical pharmacokinetics of epirubicin the importance of liver biochemistry tests. Br J Cancer 1992 66(4) 765-9. 

FAC may also be given with bolus doxorubicin administration, and the fluorouracil dose is then given on days 1 and 8. Paclitaxel may also be given concurrently with doxorubicin or epirubicin as a combination regimen. Pharmacokinetic interactions make these regimens more difficult to give. 

When applied to real-life problems, however, there is little experience reported using the frequentist prior approach in the literature. Gastonguay et al. (1999) used prior information from adults to estimate the model parameters in a PopPK analysis in children. Simonsen et al. (2000) used prior information to estimate the pharmacokinetics and pharmacodynamics of epirubicin in rats. So, while it appears that using prior information may be useful in certain circumstances, but caveat emp-tor applies at the present time—let the buyer beware. Gisleskog, Karlsson, and Beal conclude that considerable care must be taken with the use of a frequentist prior. That would seem good advice. 

Verapamil can increase the efficacy of doxorubicin in tissue culture systems and increase doxorubicin levels in patients. D-vera-pamil can alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects. 

Mross K, Hamm K, Hossfeld DK. Effects of verapamil on tiie pharmacokinetics and metabolism of epirubicin. Cancer Chemo er Pharmacol (1993) 31,369-75. 

Eggert J, Scheulen ME, Schiitte J, Budach W, Annweiler HM, Mengelkolch B, Skorzec M, Wiefelspiitz J, Sack H, Seeber S. Influence of cyclosporin A on the pharmacokinetics and pharmacodynamics of doxorubicin and epirubicin, Am Hematol (1994) 68, A26. 

Toxicity associated with combinations of paclitaxel with doxorubicin or epirubicin depends on the order of administration. Some modest pharmacokinetic changes may occur when paclitaxel and epirubicin are given together. The combination of doxorubicin and pacUtaxel is more cardiotoxic than doxorubicin alone paclitaxel increases doxorubicin levels but doxorubicin does not alter pacUtaxel levels. Docetaxel may modestly affect the pharmacokinetics of epirubicin and doxorubicin. 

Conversely, a study of the combination of docetaxel and epirubicin did not find that the sequence of drug administration affected the pharmacokinetics of epirubicin, nor was there any difference in toxicity. In another study, 16 patients with breast cancer had a transient but significant increase in epirubicin plasma levels during the subsequent infusion (after an interval of 1 hour) of docetaxel 75 mg/m, which was not seen if the docetaxel was given within 10 minutes of epiruhicin. ... 

Bergaglio M, Del Mastro L, Rosso R Comparative effects of paclitaxel and docetaxel cn tile metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Chn Oncol (1999) 17, 1132-40. 

Venturini M, Lunardi G, Del Mastro L, Vannozzi MO, Tolino G, Numico G, Viale M, Pas-trone I, Angiolini C, BertelU G, Straneo M, Rosso R, Eposito M. Sequence effect of epirubicin and pacUtocel treatment on pharmacokinetics and toxicity. J Clin Oncol (2000) 18, 2116-25. 

Danesi R, Irmocenti F, FogU S, Gennari A, Baldini E, Di Paolo A, Salvador B, Bocci G, Conte PF, Del Tacca M Pharmacokinetics and pharmacodynamics of combination chemotherapy witii paclitaxel and epirubicin in breast cancer patients. BrJ Clin Pharmacol (2002) 53,508-18. 

Lunardi G, Venturini M, Vannozzi MO, Tolino G, Del Mastro L, Bighin C, Schettini G, Esposito M Influence of alternate sequences of epirubicin and docetaxel on the pharmacokinetic behaviour of botii drugs in advanced breast cancer. Ann Oncol (2002) 13, 280-5. 

Ceruti M, Tagini V, Recalenda V, Arpicco S, Cartel L, Airoldi M, Bumma C. Docetocel in combination witii epirubicin in metastatic breast cancer pharmacokinetic interactions. Far-maco (1999) 54, 733-9. 

Murray LS, Jodrell DI, Morrison JG, Cook A, Kerr DJ, Whiting B, Kaye SB, Cassidy J. The effect of cimetidine on die pharmacokinetics of epirubicin in patients widi advanced breast cancer preliminary evidence of a potentially common drug interaction. Clin Oncol( 99Z) 10,... 

Some evidence su ests ondansetron may modestly affect the pharmacokinetics of cyclophosphamide and cisplatin but it does not appear to affect those of carmustine. Ondansetron did not affect the in vitro activity of epirubicin, bleomycin, cisplatin or es-tramustine. Cisplatin and fluorouracil do not affect the pharmacokinetics of ondansetron. In in vitro studies granisetron potentiated the cytotoxic effects of epirubicin, had an additive effect on bleomycin and estramustine activity and appeared not to affect the metabolism of docetaxel and paclitaxel. 

The concurrent use of gemcitabine and doxorubicin or epirubicin does not appear to affect the pharmacokinetics of either drug. An in vitro study found that the efficacy of the combination of gemcitabine and epirubicin may be schedule-dependent. 

The pharmacokinetics of gemcitabine and doxorubicin did not differ when they were given on the same day, when compared with when they were given alone in patients with breast cancer. Similarly, gemcitabine pharmacokinetics were unchanged by the concurrent use of epirubicin and paclitaxel in patients with breast cancer, and gemcitabine did not alter the interaction between epirubicin and paclitaxel (see Anthracyclines -i-Taxanes , p.612). 

Fogli S, Danesi R, Gennari A, Donati S, Conte PF, Del Tacca M. Gemeitabine, epirubicin and paclitaxel pharmacokinetic and pharmacodynamic interactions in advanced breast cancer. Ann Oncol 2002) 13, 919-27. 

In a randomised study, amifostine did not alter the response to, or the phar-maeokineties of, paclitaxel, neither did it protect against paclitaxel-relat-ed neurotoxicity or myelotoxicity. Another study in 8 patients has confirmed that amifostine (750 mg/m as a 15-minute infusion 30 minutes beforehand) had no effect on the pharmacokinetics of paclitaxel 135 to 200 mg/m. Six of the patients were also taking epirubicin and cisplatin. Although the preliminary findings of an earlier study had suggested that pre-treatment with amifostine reduced the AUC of paclitaxel by 29%, the full report of this study concluded that amifostine had no clinically relevant effect on paclitaxel pharmacokinetics. In a study in which patients were given amifostine 500 mg as an infusion over 15 minutes just before low-dose paclitaxel 80 mg/m7 as a one-hour infusion, amifostine reduced maximum plasma levels by about 20%. However, the AUC of paclitaxel was not affected, but the paclitaxel plasma circulation time was prolonged. ... 

Mayhew, E. G., Lasic, D., Babbar, S. and Martin, F. J., Pharmacokinetics and antitumor activity of epirubicin encapsulated in long-circulating liposomes incorporating a polyethylene glycol-derivatized phospholipid, Int. J. Cancer, 51, 302-309 (1992). 

Pannuti F, Camaggi CM, Strocchi E, Comparsi R, Rossi AP, Angelli B, Franchini A. 1986. Intrahepatic aterial administration of 4 -epidoxorubicin (epirubicin) in advanced cancer patients A pharmacokinetic study. Eur J Cancer Clin Oncol 22 1309-1314. 

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