Co-administration Of Docetaxel Research Articles

Docetaxel, cyclophosphamide, and epirubicin: application of PBPK modeling to gain new insights for drug-drug interactions.

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71-1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.

Drug-Drug interactions of docetaxel in patients with breast cancer based on insurance claims data.

Despite an increase in the use of targeted anticancer drugs and immunotherapy, cytotoxic anticancer drugs such as docetaxel continue to play a clinically important role. The aim of this study was to evaluate drug-drug interactions between docetaxel and coadministered medicines in patients with breast cancer a claims database. The Health Insurance Review and Assessment Service (HIRA) database (2017 to 2019) was used in this study. We evaluated the risk of neutropenia (defined using receipt of granulocyte colony-stimulating factor (G-CSF) prescriptions) under docetaxel administration or the coadministration of docetaxel and an interacting anticancer drug (predefined based on approval information obtained from the Korean Ministry of Food and Drug Safety and the Lexicomp electronic database). The propensity score matching method was applied to balance covariates in the case (patients with G-CSF prescriptions) and control (patients without G-CSF prescriptions) groups. We identified 947 female patients with breast cancer prescribed with docetaxel and excluded 321 patients based on inclusion criteria. Of the remaining 626 patients, 280 were assigned to the case group and 346 to the control group. Predefined drugs were coadministered to 71 (11.3%) patients during the 7-day period before and after the administration of docetaxel. Adjusted odds ratios (ORs) calculated using the logistic regression model applied to the propensity score matching showed no significant difference between the administration of docetaxel alone and docetaxel coadministration (adjusted OR, 2.010; 95% confidence interval, 0.906, 4.459). In conclusion, we suggest that coadministration of docetaxel and a predefined interacting drug are not associated with G-CSF prescription.

Enhanced chemotherapeutic efficacy of docetaxel in human lung cancer cell line via GLUT1 inhibitor.

The dose-dependent adverse effects of anticancer agents neednew methods with lesser toxicity. The objective of the current research was to evaluate the efficacy of GLUT1 inhibitor, as an inhibitor of glucose consumption in cancer cells, in augmenting the efficiency of docetaxel with respect to cytotoxicity and apoptosis. Cell cytotoxicity was assessed by using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Annexin V/PI double staining was employed to evaluate apoptosis percentage. Quantitative real-time polymerase chain reaction(RT-PCR) analysis was accomplished to detect the expression of genes involved in the apoptosis pathway. The IC50 values for docetaxel and BAY-876 were 3.7 ± 0.81and 34.1 ± 3.4 nM, respectively. The severity of synergistic mutual effects of these agents on each other was calculated by synergy finder application. It showed that the percentage of apoptotic cells following co-administration of docetaxel and BAY-876 increased to 48.1 ± 2.8%. In comparison without GLUT1 co-administration, the combined therapy decreased significantly the transcriptome levels of the Bcl-2 and Ki-67 and a remarkable increase in the level of the Bax as proapoptotic protein(p < 0.05). Co-treatment of BAY-876 and docetaxel depicted a synergistic effect which was calculated using the synergy finder highest single agent(HSA) method (HSA synergy score: 28.055). These findings recommend that the combination of GLUT-1 inhibitor and docetaxel can be considered as a promising therapeutic approach for the treatment of patients with lung cancer.

Co-administration of tariquidar using functionalized nanostructured lipid carriers overcomes resistance to docetaxel in multidrug resistant MCF7/ADR cells

To overcome multidrug resistance (MDR) and to enhance the efficacy of docetaxel (DTX), tariquidar (TRQ) was co-administered with DTX using nanostructured lipid carriers (NLC) functionalized with polyethylene glycol (PEG) and RIPL peptide (P/R). DTX- and TRQ-loaded plain NLC and P/R-NLC (P/R–N) were prepared using the solvent emulsification evaporation technique. All NLC samples showed a homogeneous spherical morphology and nano-sized dispersion (<210 nm) (zeta potential, −19 to −6 mV). DTX or TRQ was successfully encapsulated in NLC formulations (encapsulation efficiency >95%; drug loading 73–90 μg/mg). All NLC formulations were stable for 4 weeks when stored at 4 °C. Drug release was diffusion-controlled. DTX/TRQ combination at a 1:1 w/w ratio showed the highest synergism with a combination index value of 0.285 and was selected as the optimum combination. TRQ-P/R–N significantly enhanced the intracellular accumulation of Rhodamine 123 in MCF7/ADR cells. The co-administration of drug-loaded P/R-Ns led to potent and dose-dependent cytotoxicity and high MDR reversal efficiency. Co-treatment with DTX-P/R–N and TRQ-P/R–N increased apoptosis and enhanced G2/M cell cycle phase distribution in MCF7/ADR cells. These results indicate that the co-administration of DTX and TRQ using P/R-Ns may be a promising strategy to overcome MDR by P-gp inhibition in tumor treatments.

Combination Therapy Against Breast Cancer Cells by Docetaxel With Rosmarinic and Thymoquinone: An Experimental Study

Objectives: Combination therapy with powerful and new components is presented as an effective method in treating breast cancer against conventional approaches. Here, we tried to evaluate the implementation of rosmarinic and thymoquinone on the tumor growth inhibition and apoptotic induction of docetaxel on MDA-MB231 breast cancer cells. Materials and Methods: The drug interaction between rosmarinic acid, thymoquinone, and docetaxel, as the chemotherapeutic drug, was analyzed using the Chou-Talalay method along with CompuSyn. To understand the number of cell proliferation of MDA-MB231 breast cancer, a tetrazolium-based colorimetric assay (MTT assay) was investigated. DAPI and the flowcytometric assay were harnessed to evaluate the morphology and the percentage of apoptosis, respectively. Real-time polymerase chain reaction (PCR) was used to recognize the association between the NF-κB pathway and program cell death signal. Results: The IC50 values for docetaxel, rosmarinic, and Thymoquinone were 2.6 ± 0.62 nM, 15.6 ± 2.4 µM, and 35.5 ± 3.4 μM, respectively. MDA-MB231 breast cancer showed combination index value following three combination recipes; rosmarinic acid + docetaxel, thymoquinone + docetaxel, rosmarinic acid + thymoquinone + docetaxel was 0.26, 0.55, and 0.08, which designated a remarkable synergistic effect. The cultivation of the tumor cells under the exposition of docetaxel and rosmarinic, as well as thymoquinone, discovered a substantial upsurge in the anti-proliferative manner of docetaxel from 60% to 82%, along with a double-fold surge in the number of dead cells. mRNA levels exhibited a noticeable decline in IκB-α as an indicator of NF-κB activation and the decline of survivin and Bcl-2 escorted by a surge in pro-apoptotic Bad mRNA levels (P&lt;0.05). Conclusions: By considering our results, the co-administration of docetaxel, rosmarinic, and thymoquinone can be figured out as a promising adjuvant therapy besides other treatment protocols.

Phase 1b Study of Abiraterone Acetate Plus Prednisone and Docetaxel in Patients with Metastatic Castration-resistant Prostate Cancer

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75mg/m2 + AA 1000mg + P 10mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor–targeted therapy plus taxane in early mCRPC. Patient summaryThe combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: A mechanism study

Here we reported that co-administration of docetaxel and a cell-permeable short-chain ceramide (C6) resulted in a striking increase in growth inhibition and apoptosis in primary and transformed breast cells (MCF-7 and MDA-231), which were associated with mitochondrial permeability transition pore (mPTP) opening, a significant reactive oxygen species (ROS) production and the pro-apoptotic AMP-Protein Kinase (AMPK) as well as c-Jun N-terminal kinases (JNK) activations. Contrarily, the mPTP blocker sanglifehrin A (SfA) or the ROS scavenger N-acetyl-l-cysteine (NAC) largely inhibited co-administration-induced cytotoxicity. Further, cyclosporin A (CsA), the inhibitor of cyclophilin-D (Cyp-D, the key mPTP component), as well as Cyp-D RNA silencing also suppressed breast cancer cell death by the co-treatment, while cells overexpressing Cyp-D showed hypersensitivity to docetaxel. Meanwhile, JNK and AMPK inhibition alleviated cell death induced by the co-administration in cultured breast cancer cells. Significantly, C6 ceramide plus docetaxel caused dramatic human epidermal growth factor receptor (HER)-1/-2 degradation and downstream Akt/Erk inhibition in HER-2 expressing MDA-231 cells. These in vitro findings provide confidence in support of further development of C6 ceramide as an adjunct of docetaxel for the treatment of the metastatic breast cancer.

Severe toxicity related to a pharmacokinetic interaction between docetaxel and ritonavir in HIV‐infected patients

The treatment of AIDS-related malignancies raises specific pharmacological issues in patients receiving highly active antiretroviral therapy (HAART), particularly when the regimen includes a ritonavir-boosted protease inhibitor. Ritonavir potently inhibits CYP3A4, the main enzyme involved in the metabolism of a number of anticancer agents, including docetaxel [1–3]. We have recently treated three patients receiving ritonavir-based HAART, who experienced severe haematological and skin toxicity shortly after the first infusion of docetaxel. We believe that this toxicity was directly triggered by ritonavir. Hence, despite normal baseline liver function and blood cell counts, our patients experienced early febrile neutropenia, grade 3 mucositis, skin rash and hand-foot syndrome (Table 1). None of the patients had other recognized risk factors for docetaxel-induced febrile neutropenia: albuminaemia and C-reactive protein were normal, and baseline lymphocyte count was >700 g l−1[2, 4]. Table 1 Severe toxicity following co-administration of docetaxel and ritonavir-based highly active antiretroviral therapy (HAART) Docetaxel is approved in the treatment of non-AIDS-defining malignancies such as breast, prostate and lung cancers, but also displays clinical activity in Kaposi's sarcoma [5]. In a Phase II study, docetaxel administered weekly was active and well tolerated in Kaposi's sarcoma patients, with moderate haematological toxicity [5]. However, patients included in this study received HAART without ritonavir pharmacoenhancement, and therefore did not experience toxicity in the same range as that observed in our case series. Preclinical reports indicate that ritonavir-induced inhibition of CYP3A4 causes a significant increase in exposure to docetaxel [6]. In a similar way, concomitant administration of docetaxel and ketoconazole, another potent inhibitor of CYP3A4, resulted in a major reduction in plasma clearance of docetaxel [7]. Therefore, we assume that ritonavir-induced inhibition of CYP3A4 may decrease the plasma clearance of docetaxel, and subsequently lead to severe docetaxel-related toxicity (mainly haematological and cutaneous). Another three cases [8, 9] of severe toxicity following co-administration of docetaxel and ritonavir were found in the literature (Table 1). As well, toxicity occurred after the first cycle of treatment, even with moderate doses of docetaxel (25–60 mg m–2). According to the drug interaction probability scale, the event–drug relationship was probable [10]. Among the above-described cases, paclitaxel was substituted for docetaxel in two patients, without recurrence of severe toxicity in the following cycles. However, two cases of severe haematological toxicity (including one fatal outcome) have been reported after the concomitant administration of paclitaxel and ritonavir [11]. Of note, paclitaxel is mainly metabolized by CYP2C8, and to a lesser extent by CYP3A4 [12]. Hence, it remains unclear whether inhibition of CYP3A4 by ritonavir could significantly decrease the plasma clearance of paclitaxel and cause severe haematological toxicity. In conclusion, these cases strongly support our hypothesis of a pharmacokinetic drug–drug interaction between ritonavir and docetaxel, even in patients treated with low doses of docetaxel. Clinicians should be aware that human immunodeficiency virus-infected patients receiving ritonavir-based HAART must receive anticancer drugs that are not metabolized by CYP3A4 instead of docetaxel.

PS1 Late breaking Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75 mg/m2 + AA 1000 mg + P 10 mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor–targeted therapy plus taxane in early mCRPC.The combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER -2/ neu -overexpressing human breast cancer cells to docetaxel (taxotere).

The lipogenic enzyme fatty acid synthase (FAS) is differentially overexpressed and hyperactivated in a biologically aggressive subset of breast carcinomas and minimally in most normal adult tissues, rendering it an interesting target for antineoplastic therapy development. Recently, a molecular connection between the HER -2/ neu (c- erb B-2) oncogene and FAS has been described in human breast cancer cells. Here, we examined the relationship between breast cancer-associated FAS hyperactivity and HER -2/ neu -induced breast cancer chemoresistance to taxanes. Co-administration of docetaxel (Taxotere) and the mycotoxin cerulenin, a potent and non-competitive inhibitor of FAS activity, demonstrated strong synergism in HER -2/ neu -overexpressing and docetaxel-resistant SK-Br3 cells, modest synergism in moderately HER -2/ neu -expressing MCF-7 cells, and it showed additive effects in low HER -2/ neu -expressing and docetaxel-sensitive MDA-MB-231 cells. Sequential exposure to cerulenin followed by docetaxel again yielded strong synergism in SK-Br3 cells, whereas antagonistic and moderate synergistic interactions were observed in MCF-7 and MDA-MB-231 cells, respectively. Importantly, inhibition of FAS activity dramatically decreased the expression of HER -2/ neu oncogene in SK-Br3 breast cancer cells. To the best of our knowledge this is the first study demonstrating that FAS is playing an active role in HER -2/ neu -induced breast cancer chemotherapy resistance.