0
selected
-
1.
Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of Benfotiamine in Healthy Subjects.
Sheng, L, Cao, W, Lin, P, Chen, W, Xu, H, Zhong, C, Yuan, F, Chen, H, Li, H, Liu, C, et al
Drug design, development and therapy. 2021;:1101-1110
Abstract
PURPOSE Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials. METHODS Healthy subjects were sequentially enrolled into one of five SAD (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, followed by a single morning dose on day 10. RESULTS In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC. CONCLUSION Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.
-
2.
A phase I trial of intraperitoneal nab-paclitaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity.
Cristea, MC, Frankel, P, Synold, T, Rivkin, S, Lim, D, Chung, V, Chao, J, Wakabayashi, M, Paz, B, Han, E, et al
Cancer chemotherapy and pharmacology. 2019;(3):589-598
-
-
Free full text
-
Abstract
PURPOSE To evaluate intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies that are primarily confined to the peritoneal cavity in a phase I trial. METHODS Using a 3 + 3 dose escalation of IP nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle, we evaluated six dose levels (35-175 mg/m2/dose). Maximum tolerated dose (MTD) and pharmacokinetics (PK) of IP nab-paclitaxel were determined. RESULTS There were no dose-limiting toxicities (DLTs) in cohorts 1-3. There was a DLT in one of six patients in cohort 4 (112.5 mg/m2) (grade 3 neutropenia causing treatment delay > 15 days) and a DLT in one of three patients in cohort 6 (175 mg/m2) (grade 4 neutropenia and grade 3 abdominal pain). A second patient in cohort 6 experienced a serious adverse event (cycle 1, grade 4 ANC ≤ 7 days, cycle 4, grade 2 left ventricular dysfunction). This dose level was determined to be above the MTD. No DLTs were seen in seven patients treated in cohort 5 (140 mg/m2). The MTD of IP nab-paclitaxel was established at 140 mg/m2 on days 1, 8, and 15 of a 28-day cycle. There was a PK advantage for IP nab-paclitaxel, with an IP plasma area under the concentration-time curve (AUC) ratio of 147-fold (range 50-403) and therapeutic range systemic drug levels. Eight of 27 enrolled patients had progression-free survival ≥ 6 months. One patient experienced complete response, and one patient experienced partial response. Six patients had stable disease. CONCLUSIONS Weekly IP nab-paclitaxel has a favorable toxicity profile, a significant pharmacologic advantage, and promising clinical activity. CLINICAL TRIAL REGISTRATION NCT00825201.
-
3.
A phase I pharmacologic and pharmacogenetic trial of sequential 24-hour infusion of irinotecan followed by leucovorin and a 48-hour infusion of fluorouracil in adult patients with solid tumors.
Wright, MA, Morrison, G, Lin, P, Leonard, GD, Nguyen, D, Guo, X, Szabo, E, Hopkins, JL, Leguizamo, JP, Harold, N, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;(11):4144-50
Abstract
PURPOSE In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions. EXPERIMENTAL DESIGN CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours. RESULTS Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with ≥1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype. CONCLUSIONS Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.
-
4.
Fecal bile acid concentrations in a subpopulation of the wheat bran fiber colon polyp trial.
Alberts, DS, Einspahr, JG, Earnest, DL, Krutzsch, MF, Lin, P, Hess, LM, Heddens, DK, Roe, DJ, Martínez, ME, Salen, G, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2003;(3):197-200
Abstract
Factors that affect the concentration of secondary bile acids in the aqueous phase of stool may have a greater impact on colon carcinogenesis than those that only modify the total fecal bile acid concentration. This hypothesis was tested using stool samples of a subset of participants enrolled in a Phase III colorectal adenomatous polyp prevention trial, which documented the inability of a 13.5 g/day wheat bran fiber (WBF) supplement to reduce polyp recurrence. Stool was collected from 68 consecutively consented participants who were enrolled in a Phase III clinical trial of WBF for the prevention of adenomatous polyp recurrence. Nineteen (27.9%) of these fecal bile acid substudy participants were on the low fiber (2.0 g/day) intervention group, whereas 49 (72.7%) were on the high fiber (13.5 g/day) intervention group for approximately 3 years. Sixty-four participants had both the aqueous and solid phases of stool samples analyzed for bile acid content. Bile acid concentrations, measured in microg/ml for fecal water and microg/mg for dry feces, were determined for lithochilic, deoxycholic, chenodeoxycholic, cholic, ursodeoxycholic, isodeoxycholic, isoursodeoxycholic, ursocholic, 7-ketolithocholic, and 12-ketolithocholic acids. There were no significant differences between the low and high fiber groups concerning mean or median aqueous phase concentrations of lithocholic or deoxycholic bile acids. In contrast, the median concentrations of deoxycholic acid and other secondary bile acids (including lithochilic, isodeoxycholic, ursodeoxycholic, isoursodeoxycholic, ursocholic, 7-ketolithocholic, and 12-ketolithocholic acids) were significantly lower for the high fiber group in the solid-phase stool (P < 0.05). These results document that a high WBF intervention, taken for a median of 2.4 years, does not significantly reduce aqueous-phase concentrations of secondary bile acids in stool, although their concentrations in solid-phase stool were suppressed. Thus, the inability of the high WBF intervention to reduce colorectal adenoma recurrence may be a consequence of its lack of effect on fecal aqueous-phase secondary bile acid concentrations.
-
5.
Phase I trial of intraperitoneal docetaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity: dose-limiting toxicity and pharmacokinetics.
Morgan, RJ, Doroshow, JH, Synold, T, Lim, D, Shibata, S, Margolin, K, Schwarz, R, Leong, L, Somlo, G, Twardowski, P, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2003;(16 Pt 1):5896-901
Abstract
PURPOSE The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. EXPERIMENTAL DESIGN Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. RESULTS Tumor types included gastric adenocarcinoma (n=7), ovarian cancer (n=4), other gastrointestinal primaries (n=3), and other cancers (n=7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m2 i.p. docetaxel of 3.14 and 6.33 microM.h (ranges, 1.02-5.88 and 3.97-12.70 microM. h), respectively; the mean peritoneal AUCs were 315 and 1063 microM.h (ranges, 250-373 and 239-2222 microM.h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m2 i.p. docetaxel were 0.46 and 0.66 microM, and the mean peak peritoneal concentrations at those doses were 59 and 81 microM, respectively. The median and mean pharmacological advantage calculations (AUCperitoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 microM (range, 0.2-1.6 microM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 microM was 31.2 h (range, 27-36.5 h). CONCLUSIONS i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.