المؤلفون: Xiaoshu Dai, Michael D. Karol, Matthew Hitron, Marjie L. Hard, John Evan Blanchard, Nicola C. J. E. Eraut, Natalie Rich, Brandon T. Gufford

المصدر: Pharmacology Research & Perspectives, Vol 9, Iss 1, Pp n/a-n/a (2021)

مصطلحات موضوعية: administration, oral, clinical trial, phase I, drugs, investigational, Therapeutics. Pharmacology, RM1-950

الوصف: Abstract This phase 1, open‐label study assessed14C‐napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18–45 years) received a single oral 240‐mg napabucasin dose containing ~100 μCi14C‐napabucasin. Napabucasin was absorbed and metabolized to dihydro‐napabucasin (M1; an active metabolite [12.57‐fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half‐lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per Cmax and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUClast: 0.376; Cmax: 0.525) indicated circulating drug‐related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment‐emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240‐mg dose was generally well tolerated.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2052-1707Test

الوصول الحر: https://doaj.org/article/10ac3b8997ef4b199f99a49697b69367Test

المؤلفون: Matthew Hitron, Michael D. Karol, Marjie L. Hard, Xiaoshu Dai, Colleen F. Mclaughlin, Scott J. Brantley, Matthew T. Goulet

المصدر: Clinical Pharmacology in Drug Development

مصطلحات موضوعية: Male, Organic anion transporter 1, Flurbiprofen, Pharmaceutical Science, Administration, Oral, Pharmacology, 030226 pharmacology & pharmacy, Dextromethorphan, 0302 clinical medicine, phase 1 trial, Cytochrome P-450 Enzyme System, ATP Binding Cassette Transporter, Subfamily G, Member 2, Pharmacology (medical), Drug Interactions, Rosuvastatin Calcium, Omeprazole, biology, Hydroxybupropion, Articles, Repaglinide, Healthy Volunteers, Neoplasm Proteins, 030220 oncology & carcinogenesis, Female, breast cancer resistance protein transporter, medicine.drug, Half-Life, Adult, drug‐drug interactions, cytochrome P450, Midazolam, napabucasin, Original Manuscript, 03 medical and health sciences, Young Adult, Pharmacokinetics, Caffeine, medicine, Humans, Bupropion, Benzofurans, business.industry, Gene Expression Regulation, biology.protein, business, Naphthoquinones

الوصف: Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug‐drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1‐11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug‐drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration–time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%‐141.4%]), intravenous midazolam (118% [94.4%‐147.3%]), repaglinide (127% [104.7%‐153.3%]), and rosuvastatin (213% [42.5%‐1068.3%]) and decreased the area under the plasma concentration–time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%‐108.3%]), bupropion (79% [64.6%‐97.0%]), and hydroxybupropion (45% [15.7%‐129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd249a6a220f2dc5c28a0e4212bd82e9Test
http://europepmc.org/articles/PMC8453567Test

المؤلفون: Michael D. Karol, John Evan Blanchard, Marjie L. Hard, Xiaoshu Dai, Nicola C. J. E. Eraut, Matthew Hitron, Brandon T. Gufford, Natalie Rich

المصدر: Pharmacology Research & Perspectives
Pharmacology Research & Perspectives, Vol 9, Iss 1, Pp n/a-n/a (2021)

مصطلحات موضوعية: Adult, Male, Metabolite, Urinary system, Cmax, Physiology, Administration, Oral, Antineoplastic Agents, Urine, RM1-950, investigational, 030226 pharmacology & pharmacy, administration, drugs, Excretion, 03 medical and health sciences, chemistry.chemical_compound, oral, Feces, Young Adult, 0302 clinical medicine, Pharmacokinetics, Medicine, Humans, Carbon Radioisotopes, General Pharmacology, Toxicology and Pharmaceutics, Active metabolite, Whole blood, Benzofurans, business.industry, clinical trial, Original Articles, phase I, Neurology, chemistry, healthy volunteers, 030220 oncology & carcinogenesis, Original Article, Therapeutics. Pharmacology, business, metabolism, pharmacokinetics, Naphthoquinones

الوصف: This phase 1, open‐label study assessed14C‐napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18–45 years) received a single oral 240‐mg napabucasin dose containing ~100 μCi14C‐napabucasin. Napabucasin was absorbed and metabolized to dihydro‐napabucasin (M1; an active metabolite [12.57‐fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half‐lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per Cmax and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUClast: 0.376; Cmax: 0.525) indicated circulating drug‐related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment‐emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240‐mg dose was generally well tolerated.
Proposed biotransformation pathways of napabucasin in humans. A single 240‐mg oral dose of napabucasin was extensively metabolized to produce 30 metabolites, all of which were found in urine, five in plasma, and one in feces, in healthy male subjects. Based on these results, we propose a biotransformation pathway of napabucasin in humans: reduction of the acetyl side‐chain and/or the naphthalene dione moiety is the exclusive primary biotransformation pathway, with glucuronidation, sulfonation, and, to a lesser extent, transamination as abundant secondary routes of metabolism.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4baa79bca5df8219168c7ac0b9604da9Test
http://europepmc.org/articles/PMC7878185Test

المؤلفون: Michael D. Karol, Bo Xu, Xiaoshu Dai, Yuran Xie, Naoto Noda, Matthew Hitron

المصدر: Journal of Clinical Oncology. 39:477-477

مصطلحات موضوعية: Cancer Research, biology, business.industry, Cellular pathways, Dehydrogenase, Quinone, Oncology, Biochemistry, Phase (matter), biology.protein, Medicine, NAD+ kinase, STAT3, business, Napabucasin

الوصف: 477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1808d4a16c0729152a257bbcff728588Test
https://doi.org/10.1200/jco.2021.39.3_suppl.477Test

المؤلفون: Michael D. Karol, Marjie L. Hard, Scott J. Brantley, Xiaoshu Dai, Matthew T. Goulet, Colleen F. Mclaughlin, Matthew Hitron

المصدر: Journal of Clinical Oncology. 38:142-142

مصطلحات موضوعية: Cancer Research, Oncology, business.industry, Cellular pathways, Drug-drug interaction, Medicine, Pharmacology, Affect (psychology), business, Napabucasin

الوصف: 142 Background: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. This phase 1 open-label study evaluated the DDI potential of napabucasin and its major metabolite (M1) with respect to 7 major human drug cytochrome P450 (CYP) enzymes and the breast cancer resistance protein (BCRP) transporter. Methods: Healthy adult subjects who initially demonstrated they could tolerate administration of 240 or 480 mg twice daily (BID) napabucasin over 2-days (D) received single doses of the CYP and transporter substrates, followed by ≥7-day washout. In the DDI portion, subjects received napabucasin 240 mg BID on D1–11 with the phenotyping cocktail administered on D6 (omeprazole [CYP2C19] 20 mg, caffeine [CYP1A2] 100 mg, flurbiprofen [CYP2C9] 50 mg, bupropion [CYP2B6] 150 mg, dextromethorphan [CYP2D6] 30 mg, and oral midazolam [CYP3A] 2 mg), intravenous (IV) midazolam 2 mg on D7, repaglinide (CYP2C8) 0.25 mg on D8, and rosuvastatin (BRCP transporter) 10 mg on D9. Results: DDI potential was evaluated in 17 subjects. Exposure to omeprazole, flurbiprofen, and oral midazolam with (test) or without (reference) napabucasin 240 mg BID were similar. Napabucasin increased exposure (area under the curve to infinity) to caffeine (124%), IV midazolam (118%), repaglinide (127%), and rosuvastatin (213%); and decreased exposure to bupropion (79%) and dextromethorphan (71%). None of these changes were expected to be clinically meaningful. The exposure of the major metabolites of the probe drugs with or without napabucasin or M1 were similar. Of the 17 subjects, 12 (70.6%) reported adverse events (AEs); 58.8% reported gastrointestinal disorders. One patient had a grade 3 AE (neutrophil count low); no serious AEs were observed. Conclusions: The data suggest minimal in vivo DDI potential for napabucasin with respect to 7 major human drug CYP enzymes and the BCRP transporter. Napabucasin 240 mg BID was generally tolerable in healthy subjects. Co-administration of napabucasin with CYP and transporter substrates was safe and tolerable. Clinical trial information: NCT03411122.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::3fba3583533ad2021968f62cf1ae4f80Test
https://doi.org/10.1200/jco.2020.38.4_suppl.142Test

المؤلفون: Nicola C. J. E. Eraut, Brandon T. Gufford, Marjie L. Hard, Xiaoshu Dai, Natalie Rich, Matthew Hitron, J Evan Blanchard, Michael D Karol

المصدر: Molecular Cancer Therapeutics. 18:A113-A113

مصطلحات موضوعية: Cancer Research, business.industry, Metabolite, Urinary system, Physiology, Urine, Excretion, chemistry.chemical_compound, Oncology, chemistry, Pharmacokinetics, Tolerability, Medicine, business, Feces, Whole blood

الوصف: Introduction: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. The primary objectives of this phase 1, open-label study in healthy male subjects were to characterize the absorption, metabolism, and excretion of 14C-napabucasin and to determine the pharmacokinetics of 14C-napabucasin and relevant metabolites in plasma, urine, and feces. The secondary objective was to assess safety and tolerability of napabucasin. Methods: Healthy male adult (age 18–45 years) subjects were eligible to receive a single oral 240-mg dose of napabucasin containing ~100 μCi of 14C-napabucasin. Blood, urine, and feces were collected up to 264 hours (h; 11 days) postdose. Whole blood, plasma, urine, fecal, and expired air samples were assayed for total radioactivity (TR). Plasma, urine, and fecal samples were assayed for napabucasin and metabolites. Results: Overall, 8 subjects (mean [range] age 29 [23–39] years) were enrolled. The mean TR recovered was 81.1%. In general, elimination of 14C-napabucasin was predominantly via feces (57.2%), to a lesser extent via urine (23.8%), and was negligible in expired air. Most (76.0%) recovery was within 48 h postdose. 14C-napabucasin was rapidly absorbed (median time to peak concentration 2.8 h) and underwent extensive reductive metabolism to yield dihydro-napabucasin (M1), the sole major circulating metabolite. Systemic exposure to 14C-napabucasin was higher than M1, and M1 plasma concentration versus time profiles generally mirrored 14C-napabucasin. Similar arithmetic mean half-lives for 14C-napabuscasin and M1 (7.9 h and 7.1 h, respectively) suggest that the rate of formation of the reduced metabolite is rate limiting. The TR whole blood:plasma ratio of 0.4 indicated that circulating drug-related compounds were essentially confined to plasma. Four minor metabolites were identified but accounted for ≤7.0% of TR in plasma. Consistent with preclinical animal models, no uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites. These data suggest that 14C-napabucasin was mainly cleared by reductive metabolism and, to a lesser extent, by renal elimination. 14C-napabucasin and M1 recovered in urine accounted for 13.2% and 9.6% of the administered dose, respectively. Apparent renal clearance of 14C-napabucasin and M1 were 8.1 L/h and 7.9 L/h, respectively. All subjects experienced treatment-emergent adverse events (TEAEs). All TEAEs were mild (grade 1) and the majority were assessed as related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders and, of these, diarrhea was reported most frequently and generally started within 4.5–5.0 h postdose and resolved without treatment. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Conclusions: 14C-napabucasin is primarily excreted through feces. 14C-napabucasin underwent extensive metabolism to yield M1 as the sole major circulating metabolite. No uniquely human or disproportionate metabolite was quantified. A single oral 240-mg dose of napabucasin was tolerated in healthy male subjects. Citation Format: Xiaoshu Dai, Michael D Karol, Matthew Hitron, Marjie Hard, J Evan Blanchard, Nicola Eraut, Natalie Rich, Brandon Gufford. Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects [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 A113. doi:10.1158/1535-7163.TARG-19-A113

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::eb94f5631ae713d0543ba02684a5610bTest
https://doi.org/10.1158/1535-7163.targ-19-a113Test

المؤلفون: Merrill J. Egorin, Gurkamal Chatta, Lisa L. von Moltke, Suresh Ramalingam, Michael D. Karol, William Riordan, Rachel Neuwirth, Michael R Cooper, Ramesh K. Ramanathan, William L. Trepicchio, Michael Rader, Eric X. Chen, Karthik Venkatakrishnan

المصدر: Clinical Therapeutics. 31:2444-2458

مصطلحات موضوعية: Male, Antifungal Agents, Antineoplastic Agents, Pharmacology, Drug Administration Schedule, Bortezomib, Pharmacokinetics, Neoplasms, hemic and lymphatic diseases, medicine, Humans, Drug Interactions, Pharmacology (medical), Prospective Studies, Cross-Over Studies, Dose-Response Relationship, Drug, business.industry, Middle Aged, Boronic Acids, Crossover study, Ketoconazole, Area Under Curve, Pyrazines, Pharmacodynamics, Concomitant, Proteasome inhibitor, Cytochrome P-450 CYP3A Inhibitors, Drug Therapy, Combination, Female, Median body, business, medicine.drug

الوصف: Background: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies. Objective: The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib. Methods: This was a prospective, multicenter, openlabel, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m2 IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 dosing interval (immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib. Results: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m2) were randomized to treatment. Twelve pa- tients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC0-tlast(AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032–1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%–46%) in the blood proteasome inhibitory effect. Conclusion: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::62e7f3cce84d94a9cedd638354e7eaabTest
https://doi.org/10.1016/j.clinthera.2009.11.012Test

المؤلفون: Charles Locke, Janice S. Griffin, Nancy Lukasik, Fouad Amer, Yi-Lin Chiu, Michael D. Karol, Wei-Jian Pan

المصدر: Clinical Therapeutics. 26:2076-2083

مصطلحات موضوعية: Adult, Male, Adult male, Lansoprazole, Capsules, Bioequivalence, Pharmacology, 2-Pyridinylmethylsulfinylbenzimidazoles, Dosage form, Route of administration, Pharmacokinetics, Humans, Medicine, Pharmacology (medical), Dosage Forms, Cross-Over Studies, business.industry, Capsule, Have Difficulty Swallowing, Anti-Ulcer Agents, Solutions, Therapeutic Equivalency, Area Under Curve, Female, business, Omeprazole, Half-Life, medicine.drug

الوصف: Objective: The pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension were compared with those of corresponding doses of lansoprazole oral capsules. Methods: Healthy adult male and female subjects were randomized (1:1 ratio) into 2 Phase 1, open-label, single-dose, 2-sequence, 2-period complete crossover studies. In the first study, each subject received 1 lansoprazole 15-mg sachet mixed with water and 1 lansoprazole 15-mg oral capsule; in the second study, each subject received 1 lansoprazole 30-mg sachet mixed with water and 1 lansoprazole 30-mg oral capsule. Administration of the 2 formulations was separated by a washout period of ≥7 days. Blood samples were collected before and after each administration to assess the pharmacokinetic parameters of lansoprazole and bioequivalence between suspension and capsule. Results: Thirty-six subjects (19 males, 17 females) with a mean (SD) age of 32.0 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg received lansoprazole 15 mg. Thirty-six subjects (22 males, 14 females) with a mean (SD) age of 38.0 (8.3) years and mean (SD) body weight of 75.1 (9.7) kg received lansoprazole 30 mg. The pharmacokinetic parameters of the 15- and 30-mg lansoprazole sachets for suspension were similar to those of the corresponding doses of the oral capsules. The mean (SD) values for C max and AUC from time 0 to infinity (AUC 0—∞ for the lansoprazole 15-mg sachet (591.9 [242.3] ng/mL and 1614 [2065] ng·h/mL, respectively) did not differ significantly from those for the lansoprazole 15-mg capsules (578.6 [275.2] ng/mL and 1620 [2290] ng·h/mL, respectively). These parameters also did not differ significantly between the lansoprazole 30-mg sachet and 30-mg capsule: mean (SD) C max , 1103 (428.3) and 1077 (465.6) ng/mL, respectively; mean (SD) AUC 0—∞ , 2655 (1338) and 2669 (1311) ng·h/mL, respectively. The 90% Cls for C max and AUC 0—∞ ratios were contained within the 0.80 to 1.25 equivalence range, supporting bioequivalence. Conclusions: These findings suggest that the 15- and 30-mg lansoprazole sachets for suspension are bioequivalent to the corresponding doses of oral capsules. The sachet for suspension may provide an alternative route of administration to patients who have difficulty swallowing solid oral formulations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1b8be4ca4c6343115ece737b1765275Test
https://doi.org/10.1016/j.clinthera.2004.12.008Test

المؤلفون: Michael D. Karol, Thirumazhisai S. Gunasekaran, Roberta Keith, Yi-Lin Chiu, Joseph Fitzgerald, Sandeep Gupta, David A. Gremse, Wei Jian Pan

المصدر: Journal of Pediatric Gastroenterology and Nutrition. 35:S327-S335

مصطلحات موضوعية: Male, medicine.medical_specialty, Adolescent, medicine.drug_class, medicine.medical_treatment, Lansoprazole, Proton-pump inhibitor, Gastroenterology, 2-Pyridinylmethylsulfinylbenzimidazoles, Double-Blind Method, Antacid, Internal medicine, medicine, Humans, Child, Adverse effect, Dose-Response Relationship, Drug, business.industry, Stomach, Heartburn, Hydrogen-Ion Concentration, Anti-Ulcer Agents, medicine.disease, Treatment Outcome, Tolerability, Area Under Curve, Pharmacodynamics, Anesthesia, Pediatrics, Perinatology and Child Health, Gastroesophageal Reflux, GERD, Female, Safety, medicine.symptom, business, Omeprazole, medicine.drug

الوصف: OBJECTIVES To evaluate the pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability of lansoprazole in adolescents between 12 and 17 years of age with gastroesophageal reflux disease (GERD). METHODS Adolescents with symptomatic, endoscopically and/or histologically proven GERD were enrolled in this multicenter, double-blind trial and randomized to lansoprazole 15 mg or 30 mg once daily for 5 days. RESULTS Sixty-three adolescents were enrolled in the study. After lansoprazole administration, T(max) occurred at 1.6 hours in those treated with lansoprazole 15 mg and at 1.7 hours in those treated with lansoprazole 30 mg. Dose-proportional increases in lansoprazole C(max) and AUC were observed in the treatment groups. Age, weight, and gender had no significant effect on T(max), C(max), or AUC. Lansoprazole produced significant increases (P < or = 0.05) in mean 24-hour intragastric pH and the percentages of time intragastric pH was above 3 and 4. The majority of adolescents treated with lansoprazole 15 mg (69%, 22/32) or lansoprazole 30 mg (74%, 23/31) demonstrated improvement in their reflux symptoms after 5 days of treatment. Adolescents in both dosage groups exhibited reductions from baseline in the percentage of days and nights with heartburn (or other predominant symptom of GERD), the severity of heartburn, the percentage of days antacids were used, and the number of antacid tablets used per day. Pharyngitis and headache were the most commonly reported side effects among adolescents treated with lansoprazole 15 mg and 30 mg, respectively. Five patients experienced adverse events considered to be possibly treatment-related. One patient with a history of environmental allergies experienced a mild allergic reaction after 3 days of treatment with lansoprazole 15 mg. Among those treated with lansoprazole 30 mg, 4 patients each reported one occurrence of pain (toothache), diarrhea, dizziness, and rash. CONCLUSION The pharmacokinetic parameters of lansoprazole observed in this study of adolescents are similar to those observed in studies of healthy adults. Lansoprazole 15 mg or 30 mg once daily for 5 days produces significant increases in intragastric pH, effectively relieves symptoms of reflux disease, and is well tolerated in adolescents with GERD.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8927ce2cab31d3462804ee3b12642296Test
https://doi.org/10.1097/00005176-200211004-00005Test

المؤلفون: Eamala Sundaram, Brian M. Wolpin, Thomas A. Abrams, Andrew X. Zhu, Lawrence S. Blaszkowsky, Michael D. Karol, Raymond C. Wadlow, John Chen, Susan Sheehan, Nadine Jackson McCleary, Lipika Goyal

المصدر: Investigational new drugs. 33(1)

مصطلحات موضوعية: Sorafenib, Adult, Male, medicine.medical_specialty, Cirrhosis, Carcinoma, Hepatocellular, Ganetespib, Gastroenterology, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), HSP90 Heat-Shock Proteins, Aged, Pharmacology, Aged, 80 and over, Septic shock, business.industry, Liver Diseases, Liver Neoplasms, Middle Aged, Triazoles, medicine.disease, Surgery, Treatment Outcome, Oncology, Tolerability, Liver, Hepatocellular carcinoma, Toxicity, Female, business, medicine.drug

الوصف: Background Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC. Methods Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2 IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks. Results Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m2. The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m2 dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m2), 0.76 h, and 191 L (100.4 L/m2), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months. Conclusion Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8662805b165d0aa112dc12fe9d56c57aTest
https://pubmed.ncbi.nlm.nih.gov/25248753Test