Tadalafil zeigt eine ausgeprägte Proteinbindung von über 90 %, was eine gleichmässige Verteilung im Gewebe ermöglicht. Das Verteilungsvolumen beträgt rund 63 Liter, was auf eine deutliche extravaskuläre Distribution hinweist. Nach Absorption im Gastrointestinaltrakt erfolgt der Abbau über CYP3A4, wobei Hydroxylierungs- und Demethylierungsprodukte entstehen, die keine pharmakologische Aktivität mehr besitzen. Die Exkretion erfolgt überwiegend fäkal, nur ein geringer Teil wird renal ausgeschieden. Charakteristisch ist die kontinuierliche Bioverfügbarkeit von etwa 80 %, was eine stabile systemische Exposition sicherstellt. Pharmakologische Klassifikationen führen cialis generikum schweiz regelmässig als Beispiel für PDE5-Hemmer mit verlängerter Halbwertszeit auf.

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ZIOPHARM Oncology, Inc.
1 First Avenue
Parris Building, #34
BETTER CANCER MEDICINE.
Navy Yard PlazaBoston, MA 02129Main 617-259-1970Fax 617-241-2855 Indibulin, a Novel Tubulin Targeting-Agent, in Combination with Capecitabine,
is Suitable for Mathematically-Optimized Dose-Scheduling
Jonathan J. Lewis1, Matthew D. Galsky2, 6, Luis H. Camacho3, David M. Loesch4, 6, Philip B. Komarnitsky1, Barbara Wallner1, Jan Stevens1, Larry Norton5.
1ZIOPHARM Oncology, New York, NY; 2Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 3Oncology Consultants P.A., Houston, TX; 4Central Indiana Cancer Centers, Indianapolis, IN; 5Harmon Hill, New York, NY; 6US Oncology, Translational Oncology Program, Houston, TX.
Abstract
Clinical: Key Inclusion Criteria
Preliminary Clinical Activity
Indibulin: Optimization of Dosing Schedules
Background: Indibulin (IDB) is a novel, orally available tubulin-targeting
• Histologically confirmed solid tumors for whom treatment with Median SD 6 Cycles
molecule that perturbs cancer cell migration and mitosis. It is active capecitabine is considered medically acceptable • Breast and colon cancer SD for 9 Cycles Indibulin 22 kg/kg/day
against taxane-resistant cell lines and is synergistic with 5-FU in vitro and • No more than 2 prior chemotherapy regimens for metastatic disease in vivo. Two translational studies have been conducted: a Phase IB study (Actual slope)
(Expected slope)
of IDB in combination with capecitabine (CAP) in patients with advanced • Adequate bone marrow, liver and renal function solid tumors, and mathematical modeling applying Norton-Simon models Daily Oral Therapy
to breast carcinoma MX-1 xenografts to further develop Phase II dose.
Breast and Colon Cancer
Methods:
IDB is administered continuously starting at 400 mg BID. CAP • ≥18 years of age. ECOG performance score ≤2; life expectancy ≥12 weeks is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID.
IDB and CAP are escalated to the highest planned dose level (not MTD): Bladder and Prostate Cancer
IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks
using RECIST. In the xenograft model indibulin is administered at dose levels MX-1 Xenograft
from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma.
0 5 10 15 20 25 30 35
Key Exclusion Criteria
Days of growth
Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the Preliminary Safety
• New York Heart Association (NYHA) functional class ≥3 or myocardial AEs that are related and occurred in 2 or more pts (≥ 29%) Results:
infarction ≤6 months, systemic infection To date, 7 patients have been treated and are evaluable for safety.
Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are Frequency, (%)
• Severe renal impairment (creatinine clearance below 30 mL/min) evaluable for efficacy and all have stable disease (3 for 6+ cycles, 1 for 3 Grade 1/2 AEs that Were Related
cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, • Known dihydropyrimidine dehydrogenase deficiency (DPD) anorexia, and headache. DLTs have not been observed. In MX-1 xenografts, • Radiotherapy ≤3 weeks. Any other anticancer, investigational drug, or indibulin demonstrates linear dose-efficacy relationship over the range of immunological therapy ≤4 weeks. Surgery ≤4 weeks excluding tumor 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser MX-1 Xenograft
effects over the next 5 days to a peak of efficacy at day 10.
• History of invasive second primary malignancy diagnosed within 3 years 0 5 10 15 20 25 30 35
Days of growth
Conclusions:
(except: Stage I endometrial/cervical carcinoma or prostate carcinoma IDB + CAP is well tolerated. There is preliminary evidence Grade 3/4 AEs that Were Related
treated surgically, or non-melanoma skin cancer) of clinical activity even with this sub-optimal, continuous schedule of IDB.
Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug- induced toxicity. Pre-clinical evaluation in a breast cancer model supports Conclusions
an intermittent dosing schedule to further increase the activity of IDB. Clinical: Dosing Schedule
Norton-Simon Modeling
• Oral indibulin in combination with capecitabine is very well tolerated with no neurotoxicity. Early activity in breast, colon, bladder, and • Capecitabine (875 mg/m2 BID) given for 2 weeks followed by a 1-week
Objectives
rest, and indibulin (400 mg BID, starting dose level) given every day • Determine form and parameters of unperturbed growth curve* continuously, until disease progression or unacceptable toxicity occurs • Formal analyses of preclinical data utilizing Norton-Simon Modeling • Assess degree of deviation (as differential equation) after growth reveals that the major effect of therapy occurs in five days of exposure, • To evaluate the combination of oral indibulin and capecitabine in subjects • Three patients in each cohort. If a DLT occurs the cohort is expanded perturbation by various schedules of therapy which is not manifest on gross inspection until one week thereafter.
• Determine points of maximal change in rate of perturbation Hence, an intermittent schedule based on five days of drug administration preserves full activity while minimizing toxicity. This may also minimize • Predict minimal exposure to create maximum effect Dose Level Cohort
Indibulin
Capecitabine
875 mg/m2 BID
• To determine the most efficacious dosing strategy for oral indibulin using • A Phase I-II study in breast cancer using this novel scheduling strategy 875 mg/m2 BID
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Source: http://www.ziopharm.com/content/docs/Indibulin_Poster_ASCO_2009_FINAL.pdf