Paclitaxel interactions

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

Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.60 Vinorelbine was approved by the FDA in 1994 for the treatment of non-small cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer. 

In most studies where a supraadditive interaction was seen, cells were incubated with the drug prior to irradiation (38). In general the use of moderate concentrations (5-100 nmol/L) of paclitaxel in the culture medium for over 24 h lead to maximum sensitization. Most studies used actively proliferating cells in order to conduct their experiments and most investigators reached the conclusion that maximal radiosensitization occurred when cells were arrested in G2 and M, as this part of the cell cycle is the most sensitive to radiation damage. This assumption does, however, presuppose that the majority of the G2/M arrested cells will not die unless they are exposed to ionizing XRT. Plateau phase, i.e., nonproliferating, cells were found to be sensitized to radiation... 

In an excellent review of the literature on the interaction between radiation and the taxanes, especially looking at the effects of paclitaxel, Milas et al.(38) outline how they came to realize that reoxygenation played such a substantial role in the potentiation of tumor radioresponse. It has been well established for years that tumors contain areas of hypoxic cells that are normally 2.5 to 3 times less sensitive to radiation than normal cells (37). Both radiation and chemotherapies can cause reoxygenation through their preferential killing of those oxygenated cells that are located close to blood vessels. Milas et al. summarized observations that showed ... 

Hennequin C, Giocanti N, Favaudon V. Interaction of ionizing radiation with paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. Cancer Res 1996 56(8) 1842-1850. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Trastuzumab (Herceptin) [Antineeplastic/Monoover express the HERlIneu. protein breast CA adjuvant, w/ doxorubicin, cyclophosphamide, and paclitaxel if pt HER2/neu(+) Action MoAb binds human EGF receptor 2 protein HER2) mediates cellular cytotox Dose Per protocol, typical 2 mg/kg/IV/wk Caution [B, ] CV dysfxn, alla-gy/inf Rxns Contra Live vaccines Disp Inj SE Anemia, cardiomyopathy, nephrotic synd, pneumonitis Interactions t Risk of cardiac dysfxn W/ anthracycline, cyclophosphamide, doxorubicin, epirubicin EMS Cardiomyopathy, ventricular dysfxn and pulm tox have been reported monitor for Sxs of reduced cardiac Fxn OD Sxs unknown... 

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. 

Gilmore PM, McCabe N, Quinn JE et al. BRCA 1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3. Cancer Res 2004 64 4148 154. 

Vyas DM and Kadow JF (1995) Paclitaxel a unique tubulin interacting anticancer agent. Prog Med Chem 32, 289-337. 

The possible impact of co-administered chemotherapies and radiation therapy on the PK of cetuximab was furthermore assessed using the population PK approach, as described in Section 14.6. The co-administered chemotherapies included cisplatin, carboplatin, paclitaxel, doxorubicin, irinotecan, and gemcitabine. The results of the analysis indicate that neither the co-administered chemotherapies nor radiation therapy had a significant impact on the PK of cetuximab. This finding suggests that the potential for PK-based drug-drug interactions with cetuximab is low. 

The antiproliferative activity of eleutherobin is based on interaction with tubulin, as is known for epothilone and taxol. These natural products induce depolymerization of microtubules and thereby interrupt the division of cancer cells [2], From experiments with highly purified tubulin, it was possible to show that some eleuthesides as well as epothilone A induce tubulin aggregation comparable to that of paclitaxel, and are also promoted by microtubule-associated proteins or GTP [22], Furthermore, kinetic measurements indicate... 

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. 

It is important to note that P-gp inhibition by a compound for the efflux of any of these ligands does not directly correlate with the ability of P-gp to efflux the compound of interest (177). Such is the case with paclitaxel, which is considered to be an excellent P-gp substrate but a poor inhibitor as determined by the dye-efflux method. The converse is seen with progesterone, which is a good inhibitor of P-gp-mediated efflux and yet is a poor substrate. It is important to note that P-gp inhibition can occur in several ways—competitively, non-competitively, and via inhibition of ATP hydrolysis at the Walker A and B motifs (271). Furthermore, the false negatives due to poor permeability noted for transport assays can also produce false negatives in these interaction assays. 

Jamis-Dow CA, Pearl ML, Watkins PB, et al. Predicting drug interactions in vivo from experiments in vitro human studies with paclitaxel and ketoconazole. Am J Clin Oncol 1997 20 592-599. 

Before these investigations, most of the models of the paclitaxel-tubulin interaction had been directly extrapolated from the conformations of paclitaxel found either in polar [60] or non-polar media [61] and from the single crystal X-ray structure of docetaxel (Fig. 10a) [58],... 

A great step forward was made in 1999 when Nogales and co-workers published the first structure of the complex between paclitaxel and tubulin heterodimer, obtained by EC [46], On this basis, the interactions between the ligand molecule... 

The combination of structural simplicity of epothilones with respect to paclitaxel, together with their very interesting activity profile appealed different research teams, interested to overcome limitations of taxanes (poor solubility, multi drug-resistance - MDR [61-63]). Investigations on epothilones were focused on the interaction between the ligands and the paclitaxel binding site (as well as the possible similar portions between epothilones and taxanes) in order to find common pharmacopores to be used in activity improvement and design of novel molecules. 

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