Rudy,
My memory on 2103 PK is going back to 2000/2001. It was one report-note (I found it online), but now I can not find even print copy (in 2002 +90% of my bio-files went into garbage). As I know and remember they have eight PI trials. Never saw complete PK data (urine content). For comparison Poly-Glu-Camptothecin urine excretion is 26 + 5%(hydrolized).
Anyway, maybe this PK data will help to understand how drug perform in human. Poly-Glu-P is not active, Glu-glu-P(major metabolite) is under question????
oncolink.com
Bianco note:
<<The chemotherapy passes through tumor blood vessels and the amount of free paclitaxel is 100-fold less than it is for an approved dose of Taxol," James Bianco, chief executive of Cell Therapeutics, told Reuters.>>
Phase I and Pharmacological Study of CT-2103, a Poly(L-glutamic acid)-Paclitaxel Conjugate.
Julieann Sludden, Alan Vincent Boddy, Melanie J. Griffin, Lesley Robson, Radha Todd, James Cassidy, Donald Bissett, Martyn Main, Melvin D. Brannan, Suzie Elliott, Mark Verrill, Hilary Calvert, University of Newcastle, Newcastle upon Tyne, UK; Cancer Research Campaign, London, UK; Aberdeen Royal Infirmary, Aberdeen, UK; Cell Therapeutics, Inc. (cti), Seattle, WA.
Paclitaxel is poorly soluble in aqueous solution and is thus formulated in Cremophor El and ethanol which has a significant effect on the pharmacokinetics of paclitaxel. CT-2103 is a novel poly (L-glutamic acid)-paclitaxel conjugate which has enhanced water solubility as well as preferential tumor distribution and has demonstrated antitumor activity in mice. A Phase I trial of CT-2103 administered intravenously over 30 minutes every 21 days was initiated in patients with histologically diagnosed solid tumors. One patient was entered at each dose level until a drug-related Grade 2 toxicity occurred in cycle 1. The starting dose was 30mg/m2 and doses were escalated by increments of 100%. Plasma levels of CT-2103 and unconjugated paclitaxel were measured by validated LC/MS/MS and HPLC assays respectively. CT-2103 and unconjugated paclitaxel pharmacokinetics were studied for each patient by noncompartmental methods. Seven patients have been entered at dose levels ranging from 30 to 720mg/m2. A total of 24 courses have been administered (range 2-8 per patient). CT-2103 was generally well tolerated, however drug-related Grade 4 neutropenia and Grade 3 leucopenia were seen at 720mg/m2 (266mg/m2 paclitaxel equivalent). CT-2103 was detectable in plasma from all patients. Cmax (6.3µg/ml at 30mg/m2 to 189 µg/ml at 720mg/m2) and AUC (8.1µg/ml.h to 1589 µg/ml.h) for CT-2103 increased with increasing dose. CT-2103 has a long plasma half-life of up to 185hr, consistent with extensive tissue distribution observed preclinically. Peak concentrations of unconjugated paclitaxel in plasma varied from 0.06 to 2.48µM, but were less than the threshold concentration for toxicity of 0.1µM 24 hours after CT-2103 administration at doses up to 480mg/m2. The patient at 720mg/m2 who experienced Grade 4 toxicity had prolonged elevated plasma concentrations of paclitaxel (0.53µM at 24 hr) and remained above 0.1µM for over 48 hours. This Phase I study is continuing to enrol patients to determine the maximum tolerated dose. A potentially dose-limiting toxicity (neutropenia) has been observed, and is consistent with the systemic pharmacology of paclitaxel released from the polymer. Treatment with CT-2103 is well-tolerated and provides a sustained level of active drug in plasma. Further clinical studies to investigate tumor distribution of CT-2103 and unconjugated paclitaxel are ongoing. This work is supported by the Cancer Research Campaign and by Cell Therapeutics Inc, Seattle.
asco.org
Phase 1 pharmacokinetic (PK) study of CT-2103 given Q2 or Q3 weeks in patients with solid tumors Abstract No: 533 Citation: Proc Am Soc Clin Oncol 22: page 133, 2003 (abstr 533) Author(s): M. W. Verrill, A. V. Boddy, R. Todd, M. Verrill, J. Sludden, K. Fishwick, L. Robson, J. Cassidy, D. Bissett, H. Calvert; Univ of Newcastle upon Tyne, Newcastle; University of Newcastle upon Tyne, Newcastle upon Tyne, UK; Newcastle General Hospital, Newcastle upon Tyne, UK; Aberdeen Royal Infirmary, Aberdeen, UK
Abstract: CT-2103 (XYOTAXTM) is a tumor-targeted taxane designed to concentrate selectively in tumors. Conjugation of paclitaxel to poly-L-glutamate enhances aqueous solubility, eliminates the need for Cremophor, and confers desirable PK characteristics such as persistence in the plasma and restricted distribution. A phase 1 dose escalation study evaluating an every 3 week (Q3W) and every 2 week (Q2W) regimen was conducted to determine the maximum tolerated dose (MTD), toxicity, and PK profiles of CT-2103 when given to heavily pretreated taxane-naïve patients (pts) with solid tumors. Serial blood samples were collected during cycles 1 and 2. Plasma was analyzed for conjugated taxanes (CT-2103) by liquid chromatography and tandem mass spectrometry (LC/MS/MS). Unconjugated paclitaxel was determined by HPLC. PK parameters were similar for both schedules. Plasma concentrations of CT-2103 declined rapidly in the first 24 hrs, followed by a slower elimination phase. Both T1/2 (82-120 hr) and clearance (276-429 mL/hr) indicate slow elimination of CT-2103 from plasma The volume of distribution at steady state (Vss) was low (16?6 and 31?21L for 233 and 266 mg/m2 respectively), suggesting a limited tissue distribution. In the Q3W study, the maximum concentration (Cmax) and area under the curve (AUC) were linear across the dosages evaluated (11 to 266 mg/m2). The AUC of unconjugated paclitaxel was < 2% of the AUC of CT-2103. The MTD for Q3W dosing was 233 mg/m2. The MTD for Q2W dosing was 175 mg/m2. The major toxicity was neutropenia. One grade 3 and 2 grade 2 neuropathies were seen at 266 and 233 mg/m2, respectively, in the Q3W schedule. A patient with mesothelioma (177 mg/m2) had partial response and 8 pts had stable disease at Q3W. Q2W is too early to evaluate. CT-2103 has anti-tumor activity and can be safely dosed as a Q2W or Q3W schedule. The human PK data support the putative advantages of polyglutamate technology such as a linear relationship between dose and AUC, stability and persistence of the molecule in the plasma, and restricted tissue distribution over standard taxane therapy. |
