Plasma Concentrations Of Paclitaxel Research Articles

Systemic exposure to cisplatin and paclitaxel after intraperitoneal chemotherapy in ovarian cancer

PurposeTo determine the systemic exposure to cisplatin and paclitaxel after adjuvant intraperitoneal administration in patients with advanced ovarian cancer who underwent primary debulking surgery. This could provide an explanation for the high incidence of systemic adverse events associated with this treatment regimen.MethodsThis is a prospective pharmacokinetic study in patients with newly diagnosed advanced ovarian cancer who were treated with intraperitoneal administered cisplatin and paclitaxel. Plasma and peritoneal fluid samples were obtained during the first treatment cycle. The systemic exposure to cisplatin and paclitaxel was determined and compared to previously published exposure data after intravenous administration. An exploratory analysis was performed to investigate the relation between systemic exposure to cisplatin and the occurrence of adverse events.ResultsPharmacokinetics of ultrafiltered cisplatin were studied in eleven evaluable patients. The geometric mean [range] peak plasma concentration (Cmax) and area under the plasma-concentration time curve (AUC0–24 h) for cisplatin was 2.2 [1.8–2.7] mg/L and 10.1 [9.0–12.6] mg h/L, with a coefficient of variation (CV%) of 14 and 13.0%, respectively. The geometric mean [range] observed plasma concentration of paclitaxel was 0.06 [0.04–0.08] mg/L. No correlation was found between systemic exposure to ultrafiltered cisplatin and adverse events.ConclusionSystemic exposure to ultrafiltered cisplatin after intraperitoneal administration is high. In addition to a local effect, this provides a pharmacological explanation for high incidence of adverse events seen after intraperitoneal administration of high-dose cisplatin. The study was registered at ClinicalTrials.gov under registration number NCT02861872.

The correlation between paclitaxel chemotoxicity and the plasma albumin level in cancer patients.

The aim of this study was to evaluate the pharmacokinetics of paclitaxel in cancer patients with hypoalbuminemia following paclitaxel-containing chemotherapy and to provide a reference for the prevention of adverse events (AEs) after paclitaxel administration. Peripheral blood was collected from cancer patients treated with paclitaxel. The plasma concentration of paclitaxel was determined by ultra-high performance liquid chromatography after 24 ± 8h of chemotherapy, and individual paclitaxel time above a threshold concentration of 0.05 μmol/L (Tc>0.05 ) was calculated using the population pharmacokinetic model. Haematological and non-haematological toxicities were monitored after chemotherapy, and the correlation between different chemotherapy toxicities and Tc>0.05 was evaluated using the Prism software. The enrolled patients were divided into the hypoalbuminemia group and normal albumin level group. The mean Tc>0.05 values in the normal albumin level and hypoalbuminemia groups were 36.89 and 24.93 h, respectively (P < 0.001). The risk of myelosuppression was positively correlated with Tc>0.05 . Due to the lower Tc>0.05 , the incidences of immediate AEs such as gastrointestinal reactions and rashes were higher in the hypoalbuminemia group than in the normal albumin level group, and the incidences of delayed AEs such as myelosuppression and neurotoxicity were lower in the hypoalbuminemia group. Plasma albumin level has a conclusive effect on Tc>0.05 , which can predict the potential clinical toxicity of paclitaxel. The study provides a theoretical basis for administration of paclitaxel.

Evaluation of the use of a novel bioabsorbable polymer drug-eluting microsphere for transarterial embolization of hepatocellular neoplasia in dogs.

In dogs with non-resectable hepatic neoplasia, treatment options are limited. The objectives of this study were to describe the use of a novel drug-eluting embolic microsphere containing paclitaxel for use during transarterial chemoembolization (TACE), to compare results of liver-specific owner questionnaires and tumor volume pre- and post-TACE, and to measure systemic paclitaxel concentration post-TACE. Client-owned dogs with non-resectable hepatic neoplasia were prospectively enrolled. All owners completed questionnaires validated for the assessment of subjective outcomes in dogs with cancer before the TACE procedure and approximately 4 weeks after the TACE procedure. A CT scan was performed before TACE and 1 month after TACE; results were compared. Blood samples were obtained at specified time points post-TACE to determine systemic paclitaxel concentrations. Seven dogs (median weight: 8.9 kg; range, 4.3–31 kg) were enrolled. TACE was successfully performed in all dogs, and no intra-procedural complications were encountered. Questionnaire scores improved significantly post-TACE. Among the 6 dogs for which full data were available, median pre-TACE tumor volume was 390 cc (range 152–1,484; interquartile range 231–1,139) and median post-TACE tumor volume was 203 cc (range 98–889; interquartile range 151–369), which was significantly (P = .028) lower. All 6 dogs had a reduction in volume at the post-TACE measurement. Mean percent change in tumor volume was -45.6% (95%CI -58.6 to -32.6%). The mean plasma paclitaxel concentration in canine blood peaked at 4 days post-TACE procedure and was 25.7 ng/mL (range = 3.09–110 ng/mL) Median survival time was 629 days (95%CI 18 to upper limit not reached). The use of a novel paclitaxel-eluting microsphere in this cohort of dogs successfully decreased tumor volume significantly after TACE and improved clinical signs. Future investigation into the use of TACE and other similar therapies is warranted due to the promising outcomes noted in this cohort.

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies

PurposeOrally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1).MethodsFifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling.ResultsA pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67–1.33) and 0.46 (95%CI: 0.34–0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122–724).ConclusionThe developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.

The influence of a biomimetic pulmonary surfactant modification on the in vivo fate of nanoparticles in the lung

Direct biomimetic modification of nanoparticles (NPs) with endogenous surfactants is helpful to improve the biocompatibility of NPs and avoid damage to the physiological function of the lung. Therefore, the objective of this study is to investigate the influence of biomimetic endogenous pulmonary surfactant phospholipid modification on the in vivo fate of NPs after lung delivery. Here, two neutral phospholipids (dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylamine (DPPE)) and two negatively charged phospholipids (dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS)) were selected to modify paclitaxel (PTX)-loaded PLGA NPs with different molar ratio. DPPC, DPPE, and DPPG improved mucoadhesion, in contrast, DPPS improved the mucus permeability of the NPs. Neutral DPPC and DPPE reduced, but negatively charged DPPS and DPPG increased the uptake by alveolar macrophages, all types of phospholipid increased the uptake by lung epithelial cells and increased PTX retention in the whole lung. Whereas, DPPC, DPPE, and DPPG promoted PTX retention in bronchoalveolar lavage fluid (BALF), while DPPS promoted PTX absorption in the lung tissue. Only DPPS-PLGA (1:1) NPs remarkably increased PTX systemic exposure. A good correlation between PTX percentage in the supernatant of BALF and PTX concentration in plasma was established, implying PTX entered the system circulation mainly in molecular form. Phospholipid modification had no effect on extrapulmonary organ distribution of PTX. Taken together, our study disclosed that different phospholipid modification can endow the NPs mucoadhesive or mucus penetration and cellular uptake properties, with tunable retention in BALF and absorption in the lung tissue, providing the scientific background for translational nanocarrier design for inhalation as required. Statement of significanceInhaled nanomedicines will inevitably interact with pulmonary surfactant and form “surfactant corona”. However, the contribution of individual pulmonary surfactant phospholipid on the in vivo fate of nanomedicines is still unclear. In this regard, the most abundant pulmonary surfactant phospholipid dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylamine, and dipalmitoylphosphatidylglycerol and dipalmitoylphosphatidylserine were selected to modify the paclitaxel loaded PLGA nanoparticles and the effect of these pulmonary surfactant phospholipids on their in vivo fate was investigated. It was demonstrated that different phospholipid modification can endow the nanoparticles mucoadhesive or mucus penetration properties, with tunable retention in bronchoalveolar lavage fluid, alveolar macrophages uptake and absorption in the lung tissue. The present study provided a comprehensive understanding for the role of pulmonary surfactant phospholipid on inhaled nanomedicines.

Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer.

Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance. Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa. Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: −3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0–48 h: r = 0.72; p < 0.01). Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.

Feasibility of pharmacometabolomics to identify potential predictors of paclitaxel pharmacokinetic variability.

Paclitaxel is a commonly used chemotherapy drug with substantial variability in pharmacokinetics (PK) that affects treatment efficacy and toxicity. Pharmacometabolomic signatures that explain PK variability could be used to individualize dosing to improve therapeutic outcomes. The objective of this study was to identify pretreatment metabolites or metabolomic signatures that explain variability in paclitaxel PK. This analysis was conducted using data previously collected on a prospective observational study of 48 patients with breast cancer receiving weekly 80mg/m2 paclitaxel infusions. Paclitaxel plasma concentrations were measured during the first infusion to estimate paclitaxel time above threshold (Tc>0.05) and maximum concentration (Cmax). Metabolites measured in pretreatment whole blood by nuclear magnetic resonance spectrometry were analyzed for an association with Tc>0.05 and Cmax using Pearson correlation followed by stepwise linear regression. Pretreatment creatinine, glucose, and lysine concentrations were positively correlated with Tc>0.05, while pretreatment betaine was negatively correlated and lactate was positively correlated with Cmax (all uncorrected p < 0.05). After stepwise elimination, creatinine was associated with Tc>0.05, while betaine and lactate were associated with Cmax (all p < 0.05). This study identified pretreatment metabolites that may be associated with paclitaxel PK variability demonstrating feasibility of a pharmacometabolomics approach for understanding paclitaxel PK. However, identification of more robust pharmacometabolomic predictors will be required for broad and routine application for the clinical dosing of paclitaxel.

Inhibition of edge stenosis of endografts in swine iliac arteries by a novel endograft with biodegradable coating at both ends

ObjectiveThis study evaluated the effectiveness and safety of a novel endograft with a biodegradable coating at both ends in preventing edge stenosis in swine iliac arteries. The biodegradable coating was composed of polylactide and paclitaxel. MethodsFour types of endograft were implanted in the iliac arteries of healthy swine: an endograft without coating (control group) and endografts with polylactide and paclitaxel coating containing 0.1, 0.3, or 3.6 μg/mm2 of paclitaxel. The edge stenosis of these endografts in swine iliac arteries was assessed using angiographic image data at 30, 90, and 180 days after the operation. After terminal angiography, histologic evaluation of the treated arteries was performed. The treated sections of iliac arteries and blood samples were obtained at 1, 7, 30, 90, and 180 days for pharmacokinetic analysis. ResultsThe results of angiographic and histologic evaluation demonstrated that intimal hyperplasia contributed to edge stenosis and polylactide-paclitaxel coating effectively inhibited edge stenosis. At 30 days, edge stenosis was observed at both the proximal and distal edges of the endograft without coating. At 90 days, edge stenosis was detected for the endograft coated with 0.1 μg/mm2 paclitaxel, and ectasia dilation occurred at the proximal and distal edges of the endograft coated with 3.6 μg/mm2 paclitaxel. No edge stenosis or other adverse effects were observed at 90 and 180 days for the endograft coated with 0.3 μg/mm2 paclitaxel. In addition, for the endograft coated with 0.3 μg/mm2 paclitaxel, a pharmacokinetic analysis showed that the paclitaxel concentration of treated segments decreased from 14 264 ± 1020 ng/g at day 1 to 80 ± 70 ng/g at day 90, and 20 ± 40 ng/g at day 180. The plasma paclitaxel concentration was low at day 1 and no longer detected after 7 days. ConclusionsPolylactide and paclitaxel coating containing 0.3 μg/mm2 paclitaxel at both ends of endografts effectively and safely inhibits edge stenosis in swine iliac arteries.

Abstract C008: Tolerability and antitumor activity of paclitaxel is improved by the addition of nilotinib in patients with refractory solid tumors

Abstract Background: We initiated the systematic NCI-ALMANAC in vitro combination drug screen of FDA-approved anticancer drugs in the NCI-60 tumor cell line panel to explore novel and effective drug combinations (Holbeck et al., Cancer Res 2017). In this screen and in preclinical xenograft models, the BCR-ABL kinase inhibitor nilotinib demonstrated greater-than-additive activity in combination with the anti-tubulin agent paclitaxel. Additionally, recent preclinical findings suggest a reduced incidence of peripheral neuropathy for this combination relative to paclitaxel monotherapy (Leblanc et al., J Clin Invest 2018). We are performing a phase 1 study to establish the safety, tolerability, and maximum tolerated dose (MTD) of this combination in patients (pts) with advanced solid tumors, and to examine the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the combination to better understand the mechanism of synergy. Materials and Methods: Nilotinib was given orally twice-daily (BID), while paclitaxel was administered intravenously on days 1, 8, and 15 of each 28-day cycle. A 1- or 2-day paclitaxel-only run-in during the first cycle enabled comparison of the PK and PD effects of the combination vs. single-agent paclitaxel. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and response was evaluated by CT per RECIST 1.1. Results: Thirty pts have been enrolled to date. The MTD was 300 mg nilotinib BID and 80 mg/m2 paclitaxel given on days 1, 8, and 15; DLTs were grade 4 rash and grade 3 myelosuppression. Only 2 pts (7%) have experienced grade 2 peripheral neuropathy, no grade ≥3 neuropathy events occurred. Of the 24 pts assessable for response to date, there are 4 confirmed partial responses (PRs; 17%, 1 pt with endometrial cancer, 1pt with anal cancer and 2 pts with granulosa cell of the ovary) and 12 pts with a best response of stable disease (SD; 50%), including 6 pts with SD for ≥ 8 cycles. Mean time on study to date is 8.7 months (range: 2 – 41 months). Three of 4 responding pts had undergone prior paclitaxel-based therapy and experienced a best response of only SD (1 pt) or progressive disease (2 pts) to carboplatin/paclitaxel or paclitaxel monotherapy, respectively. PK data demonstrate dose-dependent plasma paclitaxel concentrations (for 60 vs. 80 mg/m2 paclitaxel), and no substantial effects of nilotinib on paclitaxel plasma concentrations. Conclusions: The combination of nilotinib and paclitaxel is well-tolerated. Consistent with recent preclinical findings, no grade ≥ 3 peripheral neuropathy has been observed, as compared to rates of 8-30% in prior studies of 80-100 mg/m2 weekly paclitaxel monotherapy in pts with metastatic breast cancer (Rivera and Cianfrocca, Cancer Chemother Pharmacol 2015). PK data indicate dose-dependent plasma paclitaxel concentrations, with no substantial nilotinib-induced changes in plasma paclitaxel levels. Preliminary response data are promising, especially considering the PRs observed in pts who had previously been unresponsive to paclitaxel therapy. Accrual to the expansion cohort and PD analyses of circulating tumor cells and tumor biopsy specimens are ongoing. Citation Format: Geraldine O'Sullivan Coyne, Shivaani Kummar, Jennifer Zlott, Lamin Juwara, Naoko Takebe, Murielle Hogu, Larry Anderson, Jerry Collins, Richard Piekarz, Howard Streicher, Elad Sharon, Arjun Mittra, Sabrina Khan, Brandon Miller, Tony Navas, Apurva Srivastava, Ralph Parchment, Laurence Rubinstein, James H Doroshow, Alice P Chen. Tolerability and antitumor activity of paclitaxel is improved by the addition of nilotinib in patients with refractory solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C008. doi:10.1158/1535-7163.TARG-19-C008

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane‐induced alopecia

Taxanes are a leading cause of severe and often permanent chemotherapy‐induced alopecia. As the underlying pathobiology of taxane chemotherapy‐induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell‐rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy‐induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy‐induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell‐protective therapy in taxane‐based oncotherapy, and provides preclinical proof‐of‐principle in a healthy human (mini‐) organ that G1 arrest therapy can limit taxane‐induced tissue damage.

Analysis of paclitaxel concentration in rat plasma by Raman spectrums combined with partial least square

Partial least square (PLS) combining with Raman spectroscopy was applied to develop predictive models for plasma paclitaxel concentration detection. In this experiment, 312 samples were scanned by Raman spectroscopy. High performance liquid chromatography (HPLC) was applied to determine the paclitaxel concentration in 312 rat plasma samples. Monte Carlo partial least square (MCPLS) method was successfully performed to identify the outliers and the numbers of calibration set. Based on the values of degree of approach ( D a ), moving window partial least square (MWPLS) was used to choose the suitable preprocessing method, optimum wavelength variables and the number of latent variables. The correlation coefficients between reference values and predictive values in both calibration set ( R c2) and validation set ( R p2) of optimum PLS model were 0.933 1 and 0.926 4, respectively. Furthermore, an independent verification test was performed on the prediction model. The results showed that the correlation error of the 20 validation samples was 9.36%±2.03%, which confirmed the well predictive ability of established PLS quantitative analysis model.

TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. To evaluate the association of pharmacokinetic parameter TC > 0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxel™ kit. The patients' PTX TC > 0.05 (the time during which PTX plasma concentration exceed 0.05µmol/L) were calculated based on pharmacokinetic analysis. The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 µmol/L; (2) the PTX TC > 0.05 ranged from 14 to 38h with a median time of 27h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC > 0.05 between CR+PR and SD+PD; (4) with the increasing value of TC > 0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC > 0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC > 0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC > 0.05 at 26 to 30h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. PTX TC > 0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors.

Paclitaxel Plasma Concentration after the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy.

Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 μmol/L (Tc>0.05), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy.Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16-26 hours after the first infusion to estimate Cmax and Tc>0.05 Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05 Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption.Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (P < 0.05), but neither Tc>0.05 (P = 0.27) nor Cmax (P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; P = 0.0008) and Tc>0.05 (OR = 1.79; 95% CI, 1.06-3.01; P = 0.029) or Cmax (OR = 2.74; 95% CI, 1.45-5.20; P = 0.002) were associated with peripheral neuropathy-induced treatment disruption.Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602-10. ©2018 AACR.

Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic.

Plasma paclitaxel (PTX) concentration 24h or later after PTX administration may predict myelosuppression. Here, we explored predictive markers for neutropenia induced by intravenous administration of PTX in an outpatient clinic. Thirty women suffering from uterine, ovarian or cervical cancer were enrolled in this study. PTX (mean dose: 167mg/m2) was intravenously infused and followed by carboplatin. Plasma samples were obtained 4h after PTX administration. Genotyping was carried out for CYP3A5*3, ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T. There was no significant relationship between genotype and reduced neutrophil count. Neutrophil reduction rate correlated with the patient's height, neutrophil count on the day of administration, and plasma PTX concentration. Multiple regression analysis with those three indices explained 47.7% of the interindividual variability of the neutrophil reduction rate. The model with plasma PTX concentration, patient's height, and plasma 6-α-hydroxy-paclitaxel /PTX concentration ratio also explained 30.0% of the interindividual variability for the neutrophil nadir count after PTX administration. These results indicate that neutrophil reduction after PTX administration can be partially predicted by multiple regression analysis involving plasma concentration data collected at outpatient clinics.

Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies.

Drug-coated balloons (DCBs) are a predominant revascularization therapy for symptomatic femoropopliteal artery disease. Because of the differences in excipients, paclitaxel dose, and coating morphologies, varying clinical outcomes have been observed with different DCBs. We report the results of 2 studies investigating the pharmacokinetic and clinical outcomes of a new DCB to treat femoropopliteal disease. In the ILLUMENATE Pivotal Study (Prospective, Randomized, Single-Blind, U.S. Multi-Center Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With A Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon), 300 symptomatic patients (Rutherford class 2-4) were randomly assigned to DCB (n=200) or standard angioplasty (percutaneous transluminal angioplasty [PTA]) (n=100). The primary safety end point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness end point was primary patency through 12 months. In the ILLUMENATE PK study (Pharmacokinetic Study of the Stellarex Drug-Coated Angioplasty Balloon), paclitaxel plasma concentrations were measured after last DCB deployment and at prespecified times (at 1, 4, 24 hours and at 7 and 14 days postprocedure) until no longer detectable. In the ILLUMENATE Pivotal Study, baseline characteristics were similar between groups: 50% had diabetes mellitus, 41% were women, mean lesion length was 8.3 cm, and 44% were severely calcified. The primary safety end point was met (92.1% for DCB versus 83.2% for PTA, P=0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3% for DCB versus 57.6% for PTA, P=0.003). Primary patency per Kaplan-Meier estimates at day 365 was 82.3% for DCB versus 70.9% for PTA (P=0.002). The rate of clinically driven target lesion revascularization was significantly lower in the DCB cohort (7.9% versus 16.8%, P=0.023). Improvements in ankle-brachial index, Rutherford class, and quality of life were comparable, but the PTA cohort required twice as many revascularizations. Pharmacokinetic outcomes showed that all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4±116.9 ng/mL to 1.4±1.0 ng/mL). The data demonstrate superior safety and effectiveness of the Stellarex DCB in comparison with PTA, and plasma levels of paclitaxel fall to low levels within 1 hour. URL: http://clinicaltrials.gov. Unique identifiers: NCT01858428 and NCT01912937.

Abstract 2049: Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel

Abstract Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL. Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2). Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016). Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK. Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, François Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.

Effects of Jia-Wei-Xiao-Yao-San on the Peripheral and Lymphatic Pharmacokinetics of Paclitaxel in Rats.

Paclitaxel is effective against breast cancer. The herbal medicine, Jia-Wei-Xiao-Yao-San (JWXYS), is the most frequent prescription used to relieve the symptoms of breast cancer treatments. The aim of the study was to investigate the herb-drug interaction effects of a herbal medicine on the distribution of paclitaxel to lymph. A validated ultraperformance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was used to determine the paclitaxel levels in rat plasma and lymph after intravenous infusion of paclitaxel alone with or without 7 days of JWXYS pretreatment. The pharmacokinetic results indicate that paclitaxel concentrations in plasma exceeded those in lymph by approximately 3.6-fold. The biodistribution of paclitaxel from plasma to lymph was 39 ± 5%; however, this increased to 45 ± 4% with JWXYS pretreatment. With JWXYS pretreatment, the AUC and C max of paclitaxel in plasma were significantly reduced by approximately 1.5-fold, compared to paclitaxel alone. Additionally, JWXYS decreased the AUC and C max of paclitaxel in lymph. However, the lymph absorption rate of paclitaxel with or without JWXYS pretreatment was not significantly changed (27 ± 3 and 30 ± 2%, resp.). Our findings demonstrate that when paclitaxel is prescribed concurrently with herbal medicine, monitoring of the blood pharmacokinetics of paclitaxel is recommended.

Correlation between paclitaxel Tc &gt; 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients

Aim: Although paclitaxel (PTX) is a widely used chemotherapeutic agent across many cancer types, the correlation between its concentration and treatment efficacy and toxicity is yet to be clarified. Hence, the study aims to determine the correlation between PTX Tc > 0.05 and its therapeutic efficacy and toxicity. Methods: Using MyPaclitaxel™, we measured the blood concentration of PTX in 96 ovarian cancer (stage IIIB to IV) patients, who were admitted to the Cancer Hospital of Shantou University Medical College in Chaoshan, China. PTX Tc > 0.05, the time during which PTX plasma concentration exceed 0.05 μmol/L, is calculated using nonlinear mixed effect model. Results: (1) The PTX Tc > 0.05 was constant and significantly correlated with treatment response and the range of Tc > 0.05 of PTX was 14-36 h. (2) There was no correlation between relative PTX dose and the PTX Tc > 0.05. (3) There was a statistically significant difference in the PTX Tc > 0.05 between complete remission (CR) + partial remission (PR) and stable disease (SD) + progressive disease (P = 0.00185). The PTX Tc > 0.05 in most patients with CR and PR was in the range of 26-30 h. (4) The PTX Tc > 0.05 significantly correlated with the occurrence of leukopenia (P = 0.0002) and leukopenic fever (P = 0.0211), and higher PTX Tc > 0.05 correlated with increased incidence of severe leukopenia and leukopenic fever. (5) Occurrence and severity of peripheral neuropathy significantly correlated with the level of PTX Tc > 0.05 (P = 0.0003, 0.0118). Conclusion: These results indicated that the PTX Tc > 0.05 correlated with therapeutic efficacy and drug toxicity. Therefore, monitoring the PTX Tc > 0.05 other than blood concentration of PTX is necessary to optimize individual treatment.

Excel-Based Tool for Pharmacokinetically Guided Dose Adjustment of Paclitaxel.

Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 μmol/L (Tc > 0.05 μmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc > 0.05 μmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 μmol/L and give clinicians an easy-to-use tool. Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a posteriori Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 μmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function. There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 μmol/L values. Tc > 0.05 μmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc > 0.05 μmol/L values between both programs was 1%. The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 μmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc > 0.05 μmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.