Influence of the interval between the administration of doxorubicin and paclitaxel on the pharmacokinetics of these drugs in patients with locally advanced breast cancer

Moreira, A.; Lobato, Rosario; Morais, José; Silva, Sandra; Ribeiro, J.V.; Figueira, Ana Catarina; Vale, Dina; Sousa, Cátia; Araujo, Fatima; Fernandes, Aires; Oliveira, J.; Passos‐Coelho, José Luís

doi:10.1007/s002800100297

Cited by 24 publications

(15 citation statements)

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“…A sophisticated pharmacokinetic study showed that PTX enhances the nonlinearity of DOX pharmacokinetics and significantly decreases the systemic clearance of both DOX and DOX-ol. The DOX/PTX interaction was found to be PTX-dose dependent, DOX concentration-dependent, and may be the result of competition for elimination mechanisms [48]. However, Platel et al [15] showed that the potentiation of DOX-induced cardiotoxicity by PTX is not related to an increase in tissue concentration of DOX or its active metabolite.…”

Section: Discussionmentioning

confidence: 97%

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

Saad

Najjar

Alashari

2004

J Biochem & Molecular Tox

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The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.

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Section: Discussionmentioning

confidence: 97%

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

Saad

Najjar

Alashari

2004

J Biochem & Molecular Tox

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“…The separate application of doxorubicin and paclitaxel at about a 16-h interval decreased the cardiotoxicity of doxorubicin in patients with locally advanced breast cancer. On the other hand, when doxorubicin and paclitaxel were applied at a shorter interval the cardiotoxicity increased (Moreira et al 2001). At present, there are more than 2000 safer and more effective synthetic analogues of doxorubicin, which are potential anti-tumour compounds, but only a small percentage of them have reached the registration or marketing phases (e.g., epirubicin, pirarubicin, idarubicin, valrubicin, Da-125) ( Figure 1) (Kim et al 2001;Grynkiewicz et al 2002).…”

Section: The Characteristics Of Selected Drugs Causing Multidrug Resimentioning

confidence: 99%

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

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It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.

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“…Taken together, these factors support the assumption that paclitaxel clearance did not vary much for any individual over successive cycles of treatment. Finally, while a pharmacokinetic interaction between doxorubicin and paclitaxel is possible, the literature suggests that while paclitaxel can alter doxorubicin pharmacokinetics, doxorubicin does not impact substantially on paclitaxel pharmacokinetics [43, 44].…”

Section: Methodsmentioning

confidence: 99%

Population analysis of a 24‐h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study

Mould

Fleming

Darcy

et al. 2006

Brit J Clinical Pharma

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AimsTo examine determinants of paclitaxel disposition and the association between paclitaxel exposure and toxicity or survival in patients with advanced stage or recurrent endometrial cancer treated with doxorubicin plus paclitaxel. MethodsA limited sampling scheme was used to examine the population pharmacokinetics of paclitaxel in 160 patients from one arm of a randomized Phase III trial of doxorubicin plus paclitaxel or cisplatin. Four plasma samples per patient were collected at approximately 0, 3, 22 and 27 h after the first 24-h infusion of paclitaxel and submitted to the Gynecological Oncology Group (GOG) Pharmacology Core Laboratory. Total paclitaxel concentrations were quantified by LC/MS and paclitaxel disposition was examined using NONMEM. Paclitaxel exposure was evaluated for associations with toxicity or survival. ResultsPatient weight, age and serum glutamic-oxaloacetic transaminase level were determinants of paclitaxel clearance (clearance increased 0.437 l h − 1 kg − 1 ; decreased 0.223 l h − 1 year − 1 and 0.105 l h − 1 IU − 1 ). Bayesian shrinkage was minimal for this parameter. In different measures of paclitaxel exposure, AUC was most predictive of toxicity, with higher AUC associated with granulocytopenia [probability of 1% at AUC = 1 to 22% at AUC = 4 µ g l − 1 h − 1 for performance status (PS) = 0]. PS was more strongly associated with survival than disease stage and higher paclita xel AUC was associated with worse survival irrespective of PS and stage. ConclusionsPaclitaxel AUC is an independent predictor of granulocytopenia and survival in patients with advanced stage or recurrent endometrial cancer. Future studies are needed to validate the latter finding. This study confirms the appropriateness of evaluating pharmacokinetics and pharmacodynamics in multicentre oncolog y trials.

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Influence of the interval between the administration of doxorubicin and paclitaxel on the pharmacokinetics of these drugs in patients with locally advanced breast cancer

Cited by 24 publications

References 0 publications

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Population analysis of a 24‐h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study

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