A phase I study to assess oral bioavailability of a novel oral soft gelatin capsule formulation of rigosertib (ON 01910.Na) under fasted and fed conditions in patients with myelodysplastic syndromes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3081-3081 ◽  
Author(s):  
Azra Raza ◽  
Rami S. Komrokji ◽  
Roserika Brooks ◽  
Jeffrey E. Lancet ◽  
Alan F. List ◽  
...  
Keyword(s):  
Oral Dose ◽  
Phase I ◽  
Oral Bioavailability ◽  
Phase I Study ◽  
Oral Formulation ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Gelatin Capsule ◽  
Capsule Formulation ◽  
Soft Gelatin Capsule

3081 Background: Rigosertib (ON 01910.Na) is a novel multikinase inhibitor, with selective cytotoxic effects on tumor cells without impact on normal cells. Rigosertib, administered as a 3-day continuous infusion, is now undergoing phase 3 evaluation in higher risk MDS patients refractory to hypomethylating agents. Here, we report the results of the effect of food on the absolute bioavailability of a novel rigosertib oral formulation (soft gelatin capsule) in MDS patients. Methods: This was a single-dose, three-treatment, three-period sequential design for studying the effects of food on the bioavailability of an immediate-release soft gelatin capsule formulation. The following dosing groups were tested in 12 patients: IV Dose 800 mg/m2 over 24 hours and oral dose 560 mg (2 x 280 mg capsules) under fasting and fed conditions. The oral dose was the recommended phase 2 dose, as reported previously (R.S. Komrokji et al., Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results. Blood 2011, 118:Abstract #3797). Plasma samples were collected pre-dose, and over 32 hours (IV dose) or 8 hours (oral dose) after dose initiation. Rigosertib plasma levels were analyzed by a validated LC/MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental analysis (WinNonlinÒ). Results: Rigosertib pharmacokinetic parameters are presented in the table below. The results of the present study demonstrate good oral bioavailability under fasting condition.Oral administration of rigosertib after a meal decreased Cmax and AUC by 77% and 61%, respectively, compared to fasting conditions. Conclusions: The results of this study support the potential for oral delivery of rigosertib, which could become a preferred therapy over a 3-day continuous intravenous infusion. [Table: see text]

scholarly journals Variable Absorption of Clavulanic Acid After an Oral Dose of 25 mg/kg of Clavubactin® and Synulox® in Healthy Cats

2002 ◽  
Vol 2 ◽  
pp. 1369-1378 ◽  
Author(s):  
Tom B. Vree ◽  
Eric Dammers ◽  
Eri van Duuren
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Oral Dose ◽  
Clavulanic Acid ◽  
Phase I Study ◽  
Pharmacokinetic Parameters ◽  
High Efficacy ◽  
Dose Ratio ◽  
Concentration Time ◽  
Crossover Phase

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in cats, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single-dose, open, randomised, two-way crossover phase-I study, each involving 24 female cats treated with two Amoxi-Clav formulations (formulation A was Clavubactin® and formulation was B Synulox® ; 80/20 mg, 24 animals, 48 drug administrations). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin is 1.2 h (t1/2= 1.24 ± 0.28 h, Cmax= 12.8 ± 2.12 μg/ml), and that of clavulanic acid 0.6 h (t1/2= 0.63 ± 0.16 h, Cmax= 4.60 ± 1.68 μg/ml). There is a ninefold variation in the AUCtof clavulanic acid for both formulations, while the AUCtof amoxicillin varies by a factor of two. The highest clavulanic acid AUCtvalues indicate the best absorption; all other data indicate less absorption. Taking into account that the amoxicillin–to–clavulanic acid dose ratio in the two products tested was 4:1, the blood concentration ratios may actually vary much more, apparently without compromising the products’ high efficacy against susceptible microorganisms.

A phase I study of an oral formulation of ixabepilone (ixa) in patients with advanced cancer.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e13090-e13090
Author(s):  
A. R. He ◽  
P. L. Kunz ◽  
M. J. Pishvaian ◽  
A. D. Colevas ◽  
J. J. Hwang ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Cancer ◽  
Phase I Study ◽  
Oral Formulation

Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3797-3797
Author(s):  
Rami S. Komrokji ◽  
Alan F. List ◽  
Francois Wilhelm ◽  
Jeffrey E. Lancet ◽  
Azra Raza
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Oral Formulation ◽  
Refractory Anemia ◽  
Absolute Bioavailability ◽  
History Of ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3797 Background: Rigosertib (ON 01910.Na) is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and myeloblasts, while non-toxic to normal cells. Biological activity of the intravenous formulation has been demonstrated in myelodysplastic syndromes (MDS), including an ongoing randomized clinical trial in patients with refractory anemia and excess blasts failing azanucleosides. We report the preliminary results of a safety and efficacy study of a novel oral formulation of rigosertib. Methods: The trial is a 3 part phase I dose escalation study. The first part addressed bioavailability and tolerability of single oral dosing administered on a weekly basis for 5 weeks, the second included dose escalation, the third represented a dose expansion of the recommended phase 2 dose (RP2D) with absolute biavailability and food/fasting bioavailability studies. Eligibility included any International prognostic Scoring System (IPSS) MDS risk group with at least one cytopenia, failure to respond to at least one prior standard treatment, good performance status (ECOG≤ 2), adequate kidney and liver functions. Key exclusions included hypoplastic MDS (< 10% cellularity), ascites, history of seizures, uncontrolled hypertension, and history of HIV. Dose limiting toxicity (DLT) was defined as grade 3 or greater non-hematological drug related toxicity or delay in blood count recovery for more than 30 days in the absence of response. Rigosertib dose was escalated based on a defined escalation dose schema (70, 140, 280, 560, and 700 mg). The drug was administered orally twice a day for 14 days of a 21 day cycle. Results: Between January 2010 and July 2011, 33 MDS patients were enrolled in an ongoing phase I dose escalating study. Pharmacokinetic dose proportionality was established in the 70–700 mg single dose range in the first 3 patients, and pharmacodynamically active concentrations were reached. A subsequent escalation phase enrolled 15 patients who were treated with 70 to 700 mg doses of rigosertib capsules bid for 2 weeks of a 3 week cycle (70mg: N=3; 140 mg: N=2; 280mg: N=2; 560: N=2; 700mg: N=6). The formulation was well tolerated. One patient experienced DLT at the 700mg dose level during the first 3-week cycle (dysuria and shortness of breath). Another patient at this dose level had grade 3 dysuria during cycle 2. The RP2D was identified as 560 mg bid and 18 patients were enrolled in the expansion cohort (part 3). Up to 12 patients in this cohort are undergoing full pharmacokinetic evaluation (absolute bioavailability vs. the IV formulation and food effect). Encouraging signs of activity have been observed, including two marrow CR responses at the 140 and 560 mg dose levels; erythroid response (reduction of at least 4 units of RBC transfusions over 56 days) in four Low/Int-1 risk transfusion dependent MDS patients (3 at 560mg and 1 at 700 mg dose levels). Full PK results as well as clinical activity and tolerability at the RP2D dose level will be presented. Conclusion: Oral rigosertib is bioavailable and well tolerated. The RP2D was 560 mg bid for 2 weeks of a 3 week with a DLT of dysuria. Early encouraging responses are being confirmed in the expansion phase of the study. Disclosures: Komrokji: Onconova Therapeutics: Research Funding. List:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Lancet:Onconova Therapeutics: Research Funding. Raza:Onconova Therapeutics: Research Funding.

A phase I study to determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy male volunteers

2005 ◽  
Vol 56 (6) ◽  
pp. 557-562 ◽  
Author(s):  
Mireille V. Cantarini ◽  
Merran P. Macpherson ◽  
Anna L. Marshall ◽  
Anna V. Robinson ◽  
Christopher J. Bailey
Keyword(s):  
Oral Dose ◽  
Phase I ◽  
Phase I Study ◽  
Healthy Male ◽  
Healthy Male Volunteers ◽  
Male Volunteers

scholarly journals EPCT-01. PHASE I STUDY OF DAY101 (TAK580) IN CHILDREN AND YOUNG ADULTS WITH RADIOGRAPHICALLY RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii304-iii304
Author(s):  
Karen Wright ◽  
Emily Krzykwa ◽  
Lianne Greenspan ◽  
Susan Chi ◽  
Kee Kiat Yeo ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Phase I Study ◽  
Pediatric Patients ◽  
Mapk Pathway ◽  
Pharmacokinetic Parameters ◽  
Low Grade ◽  
Children And Young Adults ◽  
Dose Levels

Abstract BACKGROUND We report a phase I study examining pharmacokinetics, safety and recommended dosage of the type 2 RAF inhibitor DAY101 in children/young adults with radiographically recurrent/progressive LGGs harboring MAPK pathway alterations. METHODS Applying a 3 + 3 design, patients &lt; 18 years of age with radiographically recurrent/progressive LGG received oral DAY101 weekly for 4-week cycles up to a maximum of 2 years, if deriving clinical benefit. The starting DAY101 dosage was 280 mg/m2. Dose limiting toxicities were determined after one cycle. RESULTS We treated nine eligible patients at 280, 350, and 420 mg/m2. Eight patients had KIAA1549:BRAF fusions. One patient with NF1 did not have a biopsy. There were no DLTs. Weekly administration of DAY101 in children resulted in dose-proportional increases in Cmax and AUC similar to that described in adults. A 2.2-fold mg/kg exposure difference was observed with respect to weight-based dosing and suggested a correlation to best radiographic RANO responses of 2 complete responses, 2 partial responses, 3 stable disease, and 2 progressive disease (independently-reviewed). Median time to response was 10.5 weeks (range: 8–32 weeks). CONCLUSION The phase 1A data provide initial pharmacokinetic parameters to describe oral weekly dosing of DAY101 in pediatric patients with radiographically recurrent/progressive LGG. Plasma exposures of DAY101 achieved in adults can be reached in pediatric patients. Oral weekly DAY101 is well-tolerated and possesses anti-tumor activity. The amended protocol will explore additional dose levels and the potential for differential dosing to achieve similar responses across a variety of BSAs.

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