Paclitaxel pharmacokinetic

Mielke S, Sparreboom A, Steinberg SM et al (2005) Association of paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer. Clin Cancer Res 11 4843M850... 

Smith, N.F., Marsh, S., Scott-Horton, T.J., Hamada, A., Mielke, S., Mross, K., Figg, W.D., Verweij, J., McLeod, H.L. and Sparreboom, A. (2007) Variants in the SLC01B3 gene interethnic distribution and association with paclitaxel pharmacokinetics. Clinical Pharmacology and Therapeutics, 81, 76-82. 

Lagas, J.S., Vlaming, M.L., van Tellirigeri, O., Wagenaar, E., Jansen, R.S., Rosing, H. etol. (2006) Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics. Clinical Cancer Research, 12 (20 Pt 1). 6125-6132. 

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. 

Amifostine had no effect on docetaxel and paclitaxel pharmacokinetics, except in one study which found that amifostine extended paclitaxel plasma circulation time. Amifostine appears not to reduce the toxicity of these taxanes. 

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. ... 

Merz AL, Kerzic PJ. P450 induction alters paclitaxel pharmacokinetics and tissue distribution with multiple dosing. Cancer Chemother Pharmacol 2005 56(3) ... 

Research of the pharmacokinetic parameters of lipid emulsion of paclitaxel 91... 

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

Karlsson, M.O., Molnar, V., Bergh, J., Freijs, A., and Larsson, R., A general model for time-dissociated pharmacokinetic-pharmacodynamic relationships exemplified by paclitaxel myelo-suppression, Clin. Pharmacol. Ther., 63,11-25,1998. 

The extraordinary biological activity of epothilones has spurred interest of scientists around the world. Indeed, several epothilones and many derivatives are currently in different phases of clinical trials for the treatment of various forms of cancer. Also the synthetic community has given a great deal of attention to these remarkable compounds, probably more than to any other compound in the last ten years. This is not very surprising, because in comparison to paclitaxel (which until recently was one of the main success stories of natural products research), the epothilones have a relatively simple structure, which allows easier modification, and they display higher in vitro activity as well as better pharmacokinetic properties. 

Huizing MT, Keung AC, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993 11(11) 2127—2135. 

Straubinger, R. M. 1995. Biopharmaceutics of Paclitaxel (taxol) formulation, activity, and pharmacokinetics. In Taxol Science and Applications, M. Suffness, ed., Boca Raton, FL CRC Press 237-258. 

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. 

Aebi, S., et al. 1999. A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel. Cancer Chemother Pharmacol 44 259. 

P. Ghahramani. 2003. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel./. Clin. Oncol. 21 3965-3971. 

A121a cells were exposed to paclitaxel at concentrations of 0.2, 0.8, 2, and 5 ng/mL. Paclitaxel uptake by cells was able to be quantified at each time point under four treatment conditions. The lowest measured intracellular accumulation was 6.5 pg/106 cells, observed 10 min after the addition of 0.2 ng/mL paclitaxel to cells. The detected concentration in this sample corresponded to approximately 9.6 pg/mL drug in the cell lysate, which is nearly twice the LOQ. Foremost concentrations of paclitaxel, it appeared that the intracellular drug concentrations increased rapidly with exposure time and reached a plateau within 1-3 h. However, for cells exposed to the lowest concentration (0.2 ng/mL), the maximum intracellular drug concentration apparently was not achieved within 6 h, which was longest time interval investigated. In future studies, these data will be expanded to include additional concentrations and exposure times, and analyzed according to cellular pharmacokinetic models such as those published previously [12],... 

Chiorean EG et al (2010) A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 66 441 148... 

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. 

Despite our inability to predict quantitatively the influence P-gp may have on the in vivo transport of substrates in normal tissues with respect to other processes, in vitro experiments remain the best means of demonstrating that a compound is a substrate for polarized efflux. Nearly all experiments designed to study the extent of P-gp efflux of test compounds in vivo require adequate in vitro data to support the hypothesis (48,217,226,454). In vitro studies on P-gp substrates such as vinblastine, paclitaxel, cyclosporin A, talinolol, acebutolol, and digoxin have provided a good indication of the effect of P-gp on the in vivo pharmacokinetic behavior of these compounds. These studies show that results from the in vitro studies provide a qualitative estimate of the influence of P-gp on its in vivo pharmacokinetic behavior. Findings such as these give confidence that results from in vitro experiments can be extrapolated to explain modulation of dmg disposition by P-gp efflux. 

Further, the enhanced transport of the P-gp substrate acyclovir across excised rat intestinal mucosa and Caco-2 monolayers in the presence of thiolated chitosan was found to be due to efflux pump inhibition (Palmberger et al. 2008). Co-administration of paclitaxel and thiolated polycarbophil significantly improved paclitaxel plasma levels and led to a more constant pharmacokinetic profile and reduced tumour growth in mammary cancer-induced rats (Foger et al. 2008). 

A third focus has been directed toward incorporation of conventional PET radionuclides nC or 18F into existing substrates or inhibitors known to interact with Pgp [113-115]. This strategy has been employed to produce various PET agents, including 1 -colchicine, 11C-verapamil, nC-daunomycin, and uC/18F-paclitaxel[115-123]. While promising data have been generated, some of these PET agents suffer from modest radiochemical yields and others from complex pharmacokinetics in vivo mediated, at least in part, by rapid metabolism of the radiolabeled compounds. 

Pharmacokinetics Paclitaxel is infused over 3-4 hours. Hepatic metabolism and biliary excretion are responsible for elimination of paclitaxel. Thus dose modification is not required in patients with renal impairment, but doses should be reduced in patients with hepatic dysfunction. 

Dosio, R Arpicco, S. Brusa, R Stella, B. Cattel, L. Roly(ethylene glycol)-human serum albumin-paclitaxel conjugates preparation, characterization and pharmacokinetics. J. Controlled Release, 2001 76 107-117. 

In many ways, the development of paclitaxel mirrored that of the camptothecin analogs, both being dogged for many years by supply issues, poor pharmacokinetics, and toxicity, but the subsequent uncovering of novel mechanisms of action fueled renewed efforts to develop these leads into important new anticancer agents (75). 

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