Pharmacokinetics Of Paclitaxel Research Articles

Polycaprolactone – Vitamin E TPGS micelles for delivery of paclitaxel: In vitro and in vivo evaluation

This study aimed to present findings on a paclitaxel (PTX)-loaded polymeric micellar formulation based on polycaprolactone-vitamin E TPGS (PCL-TPGS) and evaluate its in vitro anticancer activity as well as its in vivo pharmacokinetic profile in healthy mice in comparison to a marketed formulation. Micelles were prepared by a co-solvent evaporation method. The micelle's average diameter and polydispersity were determined using dynamic light scattering (DLS) technique. Drug encapsulation efficiency was assessed using an HPLC assay. The in vitro cytotoxicity was performed on human breast cancer cells (MCF-7 and MDA-MB-231) using MTT assay. The in vivo pharmacokinetic profile was characterized following a single intravenous dose of 4 mg/kg to healthy mice. The mean diameters of the prepared micelles were ≤ 100 nm. Moreover, these micelles increased the aqueous solubility of PTX from ∼0.3 μg/mL to reach nearly 1 mg/mL. While the PTX-loaded micelles showed an in vitro cytotoxicity comparable to the marketed formulation (Ebetaxel), drug-free PCL-TPGS micelles did not show any cytotoxic effects on both types of breast cancer cells (∼100% viability). Pharmacokinetics of PTX as part of PCL-TPGS showed a significant increase in its volume of distribution compared to PTX conventional formulation, Ebetaxel, which is in line with what was reported for clinical nano formulations of PTX, i.e., Abraxane, Genexol-PM, or Apealea. The findings of our studies indicate a significant potential for PCL-TPGS micelles to act as an effective system for solubilization and delivery of PTX.

Co-release of paclitaxel and encequidar from amorphous solid dispersions increase oral paclitaxel bioavailability in rats

The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling thesimultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.

Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review.

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN.

Response of Locally Advanced Pancreatic Cancer to Intratumoral Injection of Large Surface Area Microparticle Paclitaxel: Initial Report of Safety and Clinical Outcome.

Large surface area microparticle paclitaxel (LSAM-PTX) provides an intratumoral (IT) chemotherapeutic depot. Safety, tolerability, and tumor response to IT LSAM-PTX delivered by endoscopic ultrasound-fine needle injection were evaluated in subjects with unresectable locally advanced pancreatic cancer (LAPC). Ten subjects treated in a dose escalation phase and 22 additional subjects receiving 2 injections, 4 weeks apart, of 15 mg/mL LSAM-PTX were followed for 12 months. Paclitaxel pharmacokinetics were evaluated, imaging at 3 and 6 months determined tumor response, and multiplex immunofluorescence was conducted to characterize local immune response. Most treatment-emergent adverse events were attributed to LAPC. Plasma paclitaxel levels were negligible. Eight subjects' tumors became resectable after IT LSAM-PTX, and 5 of 6 (83%) were resected with R0. Multiplex immunofluorescence of resected tumors demonstrated increased T cells, natural killer cells, and macrophages and decreased myeloid-derived suppressor cells. Six-month disease control rate was 94%, and median overall survival was 19.7 months in the 2-injection subjects. For nonresected and resected groups, overall survival times were 18.9 and 35.2 months, respectively. Neoadjuvant IT LSAM-PTX, in combination with SOC, was well tolerated and may provide benefits to LAPC patients, evidenced by enhanced immune response, improved disease control rate, restaging leading to surgery, and extended survival.

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.

Pharmacokinetic Herb-Drug Interactions of Xiang-Sha-Liu-Jun-Zi-Tang and Paclitaxel in Male Sprague Dawley Rats and Its Influence on Enzyme Kinetics in Human Liver Microsomes.

Paclitaxel is a prescribed anticancer drug used to treat various cancers. It is a substrate of cytochrome P-450 (CYP-450) enzymes. Despite its efficacy, paclitaxel has severe side effects. Herbal medicines are commonly used to treat the side effects of chemotherapy. They can be administered before, during, and after chemotherapy. Xiang-Sha-Liu-Jun-Zi Tang (XSLJZT) is a herbal formula commonly used in breast cancer patients. The main purpose of this study was to assess the pharmacokinetic (PK) influence of XSLJZT on paclitaxel PK parameters, determine its effect on CYP-450 enzyme expression, and evaluate its effect on enzyme activity. Sprague Dawley rats were classified into pretreatment and co-treatment groups, where XSLJZT was pre-administered for 3, 5, and 7 days and co-administered 2 h before paclitaxel administration. The rat liver tissues and Hep-G2 cells were used to determine the effects of XSLJZT on CYP3A1/2 and CYP3A4 enzymes respectively. Western blot analysis was used to detect changes in the CYP3A1/2 and CYP3A4 enzymes expression. The influence of XSLJZT on enzyme activity was evaluated using human liver microsomes, and a liquid chromatography-tandem mass spectrometric system was developed to monitor paclitaxel levels in rat plasma. Results demonstrated that XSLJZT increased the area under the concentration versus time curve (AUC) for paclitaxel in pretreatment groups by 2-, 3-, and 4-fold after 3, 5, and 7 days, respectively. In contrast, no significant change in the AUC was observed in the co-treatment group. However, the half-life was prolonged in all groups from 17.11 min to a maximum of 37.56 min. XSLJZT inhibited CYP3A1/2 expression in the rat liver tissues and CYP3A4 enzymes in Hep-G2 cells in a time-dependent manner, with the highest inhibition observed after 7 days of pretreatment in rat liver tissues. In the enzyme kinetics study, XSLJZT inhibited enzyme activity in a competitive dose-dependent manner. In conclusion, there is a potential interaction between XSLJZT and paclitaxel at different co-treatment and pretreatment time points.

Effect of turmeric supplementation on the pharmacokinetics of paclitaxel in breast cancer patients: A study with population pharmacokinetics approach.

Turmeric is one of the most used herbal supplements among cancer patients. It reportedly modulates the function of CYP450 enzymes and drug transporters. This study investigates the effect of turmeric on the pharmacokinetics of paclitaxel in breast cancer patients. This is a prospective longitudinal study with 60 breast cancer patients on treatment with single-agent paclitaxel and turmeric. The patients were followed up for two consecutive chemotherapy cycles, and their blood samples were collected, first without turmeric (first cycle) and the next after a 21-day concomitant administration of 2 g/day turmeric (second cycle). Plasma samples were quantified for paclitaxel concentration using High Performance Liquid Chromatograph with UV detector (HPLC-UV) method. The sparse concentration-time data of paclitaxel were subjected to population pharmacokinetic modeling, and then noncompartmental analysis (NCA) was performed on the simulated data to estimate the pharmacokinetic parameters of paclitaxel, before and after turmeric supplementation, for comparisons. The population pharmacokinetic parameters of paclitaxel differed from before to after turmeric supplementation. NCA of simulated concentration-time profiles showed a statistically significant reduction of 7.7% and 12.1% in AUCinf and Cmax, respectively. Given the small magnitude of the changes in pharmacokinetic parameters, the observed changes are not clinically relevant. Thereby, turmeric at the recommended dose can be combined safely with paclitaxel.

Muscle mass affects paclitaxel systemic exposure and may inform personalized paclitaxel dosing.

Patients with low muscle mass have increased risk of paclitaxel-induced peripheral neuropathy, which is dependent on systemic paclitaxel exposure. Dose optimization may be feasible through the secondary use of radiologic data for body composition. The objective of this study was to interrogate morphomic parameters as predictors of paclitaxel pharmacokinetics to identify alternative dosing strategies that may improve treatment outcomes. This was a secondary analysis of female patients with breast cancer scheduled to receive 80 mg/m2 weekly paclitaxel infusions. Paclitaxel was measured at the end of initial infusion to estimate maximum concentration (Cmax ). Computed tomography (CT) scans were used to measure 29 body composition features for inclusion in pharmacokinetic modelling. Monte Carlo simulations were performed to identify infusion durations that limit the probability of exceeding Cmax > 2885 ng/mL, which was selected based on prior work linking this to an unacceptable risk of peripheral neuropathy. Thirty-nine patients were included in the analysis. The optimal model was a two-compartment pharmacokinetic model with T11 skeletal muscle area as a covariate of paclitaxel volume of distribution (Vd). Simulations suggest that extending infusion of the standard paclitaxel dose from 1 hour to 2 and 3 hours in patients who have skeletal muscle area 4907-7080 mm2 and <4907 mm2 , respectively, would limit risk of Cmax > 2885 ng/mL to <50%, consequently reducing neuropathy, while marginally increasing overall systemic paclitaxel exposure. Extending paclitaxel infusion duration in ~25% of patients who have low skeletal muscle area is predicted to reduce peripheral neuropathy while maintaining systemic exposure, suggesting that personalizing paclitaxel dosing based on body composition may improve treatment outcomes.

A phase Ib/II study of regorafenib and paclitaxel in patients with beyond first-line advanced esophagogastric carcinoma (REPEAT).

Purpose:Regorafenib monotherapy, a multikinase inhibitor of angiogenesis, tumor microenvironment, and tumorigenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in patients with advanced esophagogastric cancer (EGC) refractory to first-line treatment, and explore potential biomarkers.Methods:Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on days 1–21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall survival (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second-/third-line systemic treatment. Paclitaxel pharmacokinetics were assessed using samples from day 1 (D1) and day 15 (D15). We performed enzyme-linked immunosorbent assay measurements of galectin-1, RNA sequencing, and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses.Results:In the dose-escalation cohort (n = 14), the MTD of regorafenib was 120 mg. In all, 34 patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ⩾ 3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up: 7.8 months). OS (p = 0.08) and PFS (p = 0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p < 0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p < 0.01). Enrichment of angiogenesis-related gene expression was observed in short survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p = 0.02) and PFS (p = 0.02).Conclusion:Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.Registration:Clinicaltrials.gov, NCT02406170, https://clinicaltrials.gov/ct2/show/NCT02406170

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.

Effect of body mass index on pharmacokinetics of paclitaxel in patients with early breast cancer.

ABSTRACTBackgroundPaclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients.MethodsEarly breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18–24.9 kg/m2 and overweight/obese, ≥25 kg/m2, respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software.ResultsEighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2, mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two‐sample t‐test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2‐sample t‐test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, −0.009; p > 0.05).ConclusionWhen dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under‐dosing of this drug.Trial registrationThis study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.

Population Pharmacokinetics and Exposure-Safety Relationship of Paclitaxel Liposome in Patients With Non-small Cell Lung Cancer.

PurposePaclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure–safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).MethodsData from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.ResultsThe PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m–2, the estimated clearance of total plasma paclitaxel was 21.55 L h–1. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure–safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.ConclusionThis PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure–safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).

Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

The Influence of Body Composition on the Systemic Exposure of Paclitaxel in Esophageal Cancer Patients.

Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m2. Median BSA was 1.98 m2 (range of 1.4 to 2.8 m2). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD.

Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker.

Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol. Carboplatin was administered IV to female mice at 60mg/kg with or without iohexol at 300mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300µg/mL by LC-MS/MS. In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920µg/mL min; kidney 8367 vs 9757µg/g min; bone marrow 12.7 vs 12.7µg/mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4ng/mL/60min; 3-p-OH-paclitaxel 26.2 versus 27.7ng/mL/60min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7µg/mL/30min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes. Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions.

COMPARATIVE STUDY OF HERBAL BIOENHANCER CONTAINING NANO FORMULATION FOR ORAL DELIVERY OF PACLITAXEL: PHARMACOKINETIC AND CYTOTOXICITY ANALYSIS

Objective: The main objective of this study was to develop novel formulation containing herbal bioenhancer to increase the bioavailability of poorly water-soluble anticancer drug. Material and methods: Paclitaxel (PTX) loaded bioenhancer nanoparticle prepared by Emulsification solvent evaporation method by using Eudragit RLPO as a polymer and to evaluate its in-vivo pharmacokinetics (PK) and cytotoxicity studies The result is reduced oral bioavailability, which limits the use of paclitaxel, a crucial anticancer medication, when taken orally. Though multiple formulation approaches have been taken to fight this low absorption profile but consequence of different herbal bioenhancer, happening CYP3A and P-gp inhibitor on augmentation of paclitaxel plasma. Result: The prepared nanoparticles were evaluated for in vitro cell cytotoxicity study by MTT assay on lung cancer cell line and pharmacokinetic profile. The result revealed good in vitro properties with bioenhancer. Conclusion: The goal of the present work is to asses any modification in oral pharmacokinetics of paclitaxel. Therefore, it can be concluded that addition of bioenhancer with antitumor drug can enhance its prolifertive effect. However, further in vivo studies are recommended to establish the fact.

Predicting Paclitaxel Disposition in Humans With Whole-Body Physiologically-Based Pharmacokinetic Modeling.

Paclitaxel is a commonly used drug in the treatment of multiple solid tumors, including cancers of the breast, lung, and ovaries. Despite the established exposure–pharmacodynamic relationships for paclitaxel, treatment is associated with wide interindividual pharmacokinetic variability that leads to unpredictability of the agent's clinical activity and toxicity. We hypothesized that physiologically‐based modeling approaches could be employed to predict the human pharmacokinetics of paclitaxel following administration of the approved Cremophor‐based formulation (Taxol). The model was developed from tissue distribution studies performed in mice and applied to plasma concentration‐time data obtained in adult cancer patients receiving Taxol at the approved dose and schedule (175 mg/m2 by a 3‐hour intravenous infusion), taking into account interspecies differences in physiological parameters. The final model adequately captured the observed concentrations in patients and allowed prediction of paclitaxel distribution profiles in multiple target organs and can be applied to further refine the chemotherapeutic treatment with a clinically important agent.

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

Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?

There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) data was modeled using a non-linear mixed effects approach and a semiphysiological neutropenia model, where systemic paclitaxel exposure was linked to reduced proliferation of neutrophils. The impact of age was evaluated on relevant variables in the model, using a significance threshold of p < 0.005. Paclitaxel PK-PD data was evaluated from 300 patients, with a median age of 65years (range 23-84years), containing 116 patients ≥70years (39%). First cycle neutrophil counts were adequately described by a threshold effect model of paclitaxel on the proliferation rate of neutrophils. Age as a continuous or dichotomous variable (≥70 versus <70years) did not significantly impact sensitivity of the bone marrow to paclitaxel nor the average maturation time of neutrophils (both p > 0.005), causing a decline in the respective interindividual variability of <1%. Results from this large retrospective patient cohort do not suggest elderly patients to be at an increased risk of developing paclitaxel-associated neutropenia during the first treatment cycle. Reflexive dose reductions of paclitaxel in elderly patients are unlikely to improve the risk of severe neutropenia and may be deleterious.