Multiple Ascending Dose Study Research Articles

The effect of AZD0530, a highly selective, orally available Src/Abl kinase inhibitor, on biomarkers of bone resorption in healthy males

3041 Background: AZD0530 is a highly selective, dual-specific, orally available small molecule inhibitor of Src kinase and Bcr-Abl. Src kinase activity modulates cell proliferation, adhesion, motility and invasion and in animals its inhibition limits invasion of bone metastases and destructive bone resorption. Src kinase activity is elevated in many human tumors Methods: 2 trials in healthy, male volunteers (18–55 y) assessed the effect of AZD0530 on bone resorption, with a primary objective to establish safety and tolerability. Both were randomized, double-blind and placebo-controlled; one single ascending dose (SAD) study and one multiple ascending dose (MAD) study. The SAD study comprised 27 volunteers (cohorts of 9) who received a single 2.5–1000 mg AZD0530 dose (n=6) or placebo (n=3). In the MAD study 5 cohorts of volunteers received a single 60–250 mg dose (n=9) or placebo (n=3) then, 7–10 days later, multiple doses (10–14 d). After overnight fast, serum and second morning void urine were collected before and 24 and 48 h after the single dose (both studies) and before and 24 and 48 h after the final dose (MAD study). Markers of bone resorption measured were serum cross-linked C telopeptide of type I collagen [sCTX] and urinary cross-linked N telopeptide [NTX], expressed as a ratio to urinary creatinine. Results: In the SAD study mean levels of sCTX and uNTX/Cr significantly decreased from baseline with the 1000 mg dose. Provisional PK-PD modeling suggests the relationship between AZD0530 plasma concentrations and CTX suppression is well described by an inhibitory sigmoid E-max model. Conclusions: These findings are highly suggestive of inhibition of osteoclast-mediated bone resorption via suppression of Src kinase activity. AZD0530 may have therapeutic benefit in treating osteoclast-driven metastatic bone disease and osteoporosis as well as its potential role as an anti-invasive treatment in other cancer types. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca

Phase I ascending single and multiple dose studies to assess the safety, tolerability and pharmacokinetics of AZD0530, a highly selective, dual-specific Src-Abl inhibitor

3125 Background: AZD0530 is a highly selective, dual-specific, orally available, small molecule inhibitor of Src kinase and Bcr-Abl. Methods: Two studies were conducted in healthy male volunteers to assess the safety, tolerability and pharmacokinetic (PK) profile. Firstly, in a single ascending dose study, 27 volunteers in cohorts of 9 were randomly assigned to receive AZD0530 or placebo in a rotating manner between dose levels. Subjects received single doses between 2.5 mg and 1000 mg. Results: Dose-limiting toxicities of diarrhea and vomiting occurred at 1000 mg. Adverse events at lower doses were mild and included nausea and diarrhea. In the second study, a multiple ascending dose study 60 volunteers were randomized in cohorts of 12 to receive AZD0530 (n=9) or placebo (n=3) as a single dose (for PK) followed by a washout period and then multiple daily dosing for up to 14 days. Doses up to 250 mg/day were administered in this manner. Adverse events have been generally mild and have included rash, flu-like symptoms, myalgia, arthalgia, headache, loose stools and raised creatinine. Tmax was approximately 6 hours and mean terminal half-life was approximately 40 hours at steady state. Plasma Cmin concentrations remained above the IC50 for Src kinase as predicted from preclinical modeling. Conclusions: In conclusion, AZD0530 is a small molecule inhibitor of Src kinase and Bcr-Abl. The drug is tolerated when administered in single doses up to 500 mg and in multiple, once-daily doses up to 250 mg. The pharmacokinetic profile of AZD0530 is consistent with once-daily oral dosing Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca

CERA (Continuous Erythropoiesis Receptor Activator): Dose-response, pharmacokinetics and tolerability in phase I multiple ascending dose studies

6692 Background: Preclinical trials have shown that the innovative erythropoietic agent CERA stimulates erythropoiesis more potently than epoetin (in terms of magnitude and duration of response) and has a prolonged serum half-life. Its use may thus allow less frequent dosing (every 3 or 4 weeks) and more flexible treatment of anemia associated with cancer or renal disease. In phase I single ascending dose studies, CERA administered intravenously (IV) or subcutaneously (SC) produced potent dose-dependent erythropoietic activity (Reigner et al. Proc Am Soc Clin Oncol 2003; 22: 732). To examine the pharmacodynamic effect and tolerability of CERA with multiple ascending doses, additional phase I studies were performed. Methods: In two open-label, parallel-group, placebo-controlled studies, healthy volunteers were randomized to receive CERA (0.4, 0.8, 1.6, or 3.2 μg/kg) by IV injection on three occasions at 3-weekly intervals (n=61), or by SC injection on four occasions at 2-weekly intervals (n=48). Results: A rapid and dose-dependent erythropoietic response to CERA was observed; peak effects in reticulocyte counts were seen 7 and 10 days after IV and SC administration, respectively, with cumulative hematocrit, hemoglobin, and RBC responses. Mean (± SEM) elimination half-life was 133 ± 9.83 h for IV and 137 ± 21.9 h for SC CERA. Repeated dosing had no apparent clinically relevant effect on pharmacokinetics. Volume of distribution was small with IV CERA (3.0–5.4 L) and clearance was low with both IV and SC CERA (IV 27.6–44.6 mL/h, SC 97–347 mL/h). Accumulation did not occur with 3-weekly IV dosing and was small with 2-weekly SC dosing. Adverse events were generally mild and there were no serious adverse events. No antibodies were detected by ELISA in any subject. Conclusions: CERA administered either IV or SC demonstrated potent, prolonged dose-dependent erythropoietic activity and was generally well tolerated in phase I multiple ascending dose studies. Phase II studies administering CERA at various dosing intervals to cancer patients are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration F. Hoffmann-La Roche

Use of Monte Carlo simulations to select therapeutic doses and provisional breakpoints of BAL9141.

BAL9141, a new antimicrobial agent belonging to the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, is active against most gram-positive microorganisms, including methicillin-resistant variants (methicillin-resistant Staphylococcus aureus [MRSA] and methicillin-resistant Staphylococcus epidermidis [MRSE]), as well as against penicillin-resistant pneumococci (PRP) and many gram-negative microorganisms. BAL9141 is administered as the prodrug BAL5788, which is rapidly converted to BAL9141 by plasma esterases. Pharmacokinetic (PK) data obtained in a previous multiple ascending dose study were used to fit a population PK model to using the NPEM2 program, yielding PK parameter estimates and its covariance matrix for BAL9141. These estimates and matrix were used to perform Monte Carlo simulations (MCSs) and obtain unbiased target attainment rates (TARs) for various time periods during which the concentration remains above the MIC (T(>MIC)). Assuming a T(>MIC) of 40%, TARs of 100% were reached with a dose of 500 mg/liter every 12 h for pathogens with MICs of 2 mg/liter and with a dose of 750 mg/liter every 12 h for pathogens with MICs of 4 mg/liter. Because MICs are </=2 mg/liter for most strains of MRSA, MRSE, and PRP (with some strains showing an MIC of 4 mg/liter), a dosing regimen of 750 mg every 12 h is proposed for clinical studies. The corresponding provisional breakpoint is S (susceptible) </= 4 mg/liter.