Margaret Schot

Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918

PURPOSE We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate-binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS In cohort A, eight patients received 1.0 mg/m(2) oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m(2) intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 +/- 9.6 microg.h/L without GF120918 to 78.7 +/- 20.6 microg.h/L when GF120918 was coadministered (P =.008). The mean maximum plasma concentration of total topotecan increased from 4.1 +/- 1.5 microg/L without GF120918 to 11.5 +/- 2.4 microg/L with GF120918 (P =.008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P =.008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.

Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel.

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol®) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m2, as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m2, at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

Coadministration of Cyclosporine Strongly Enhances the Oral Bioavailability of Docetaxel

PURPOSE Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2). RESULTS The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m–2 dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m–2, for the other three 15 ml m–2. Prior to paclitaxel administration patients received 15 mg kg–1 oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (Cmax) and area under the concentration–time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m–2, paclitaxel Cmax and AUC values were 0.10 ± 0.06 μM and 1.29 ± 0.99 μM h–1, respectively, whereas these values were 0.31 ± 0.06 μM and 2.61 ± 1.54 μM h–1, respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m–2, paclitaxel excretion in faeces was 38.8 ± 13.0% of the administered dose, whereas this value was 18.3 ±15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel

Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor ciclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m−2 combined with CsA 10 mg kg−1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m−2 week−1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.

Continuous infusion of low-dose topotecan: pharmacokinetics and pharmacodynamics during a phase Ii study in patients with small cell lung cancer

Preclinical schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/day. Plasma levels of topotecan, the sum of topotecan, and its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) in 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (C(ss)) in the first course were 0.46+/-0.17 and 0.47+/-0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (C(ss,tot)) were 1.28+/-0.25 (range 0.93-1.58) and 1.57+/-0.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40+/-14 and 1.2+/-1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, C(ss,tot) was significantly higher (p=0.032, paired t-test), which suggests altered topotecan disposition. A sigmoidal relationship was found between C(ss,tot) and the percent decrease in platelets (r=0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable interpatient and intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics.

An excretion balance and pharmacokinetic study of the novel anticancer agent E7070 in cancer patients.

E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics of the drug. The objective of this study was to quantify the excretion of E7070 and the metabolite 1,4-benzene-sulfonamide (M1) in cancer patients. E7070 (1000 mg) radiolabeled by 14C in the benzene disulfonamide moiety (cohort 1, n =6) or in the indole moiety (cohort 2, n =7) was i.v. infused over 1 h. The levels of radioactivity in plasma, red blood cells, urine and feces were determined by liquid scintillation counting, and the E7070 and M1 concentrations in plasma, urine and feces were determined by coupled liquid chromatography–tandem mass spectrometry (LC/ESI-MS/MS). In plasma, the mean area under the concentration–time curve (AUC) based on radio-activity measurements (32.5 and 28.9 h · mM in cohorts 1 and 2, respectively) was substantially higher than the mean AUC of E7070 (3.8 h · mmol/l) and M1 (0.1 h · mmol/l) in all patients. The excretion of radioactivity (mean±SD) as a percentage of administered radioactivity was higher in urine [63.7±9.8% (cohort 1) and 61.5±5.5% (cohort 2)] than in feces [22.7±2.6% (1) and 21.1±3.1% (2)] during a mean collection period of 11 days. In both cohorts, the contribution of urinary and fecal recovery of E7070 (2.3 and 2.7%, respectively) and M1 (5.3 and 5.1%, respectively) was low. Subsequent HPLC analysis with online radioisotope detection of urine showed that the high radioactivity levels are caused by compounds other than E7070 and M1. The major metabolite is formed by glucuronidation of a hydroxylated metabolite of E7070. In conclusion, the excretion of the benzene sulfonamide and the indole moieties of E7070 was the same with a higher renal than gastrointestinal excretion. E7070 is extensively converted into currently unidentified metabolites. Glucuronidation is a major metabolic pathway.

Phase I and Pharmacokinetic Study of a Daily Times 5 Short Intravenous Infusion Schedule of 9-Aminocamptothecin in a Colloidal Dispersion Formulation in Patients With Advanced Solid Tumors

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.

Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2-positive breast cancer.

To evaluate a nonanthracycline‐containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo‐adjuvant therapy for human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m2, carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node‐positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty‐seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin–paclitaxel–trastuzumab neo‐adjuvant regimen is highly active in HER2‐positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines.

Phase II and pharmacological study of oral docetaxel plus cyclosporin A in anthracycline pre-treated metastatic breast cancer.

INTRODUCTION Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer. MATERIALS AND METHODS Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9. RESULTS Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 - 32). The overall response rate in evaluable patients was 42% (95% CI: 23 - 63) and the median overall survival was 12.2 months (8.4 - 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9. CONCLUSION Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.