Average Cmax Research Articles

Pharmacokinetic Study of a Capsule-based Chronomodulated Drug Delivery System of Salbutamol Sulphate in Rabbits

Purpose: To develop and determine the in vivo performance of a capsule-based pulsatile drug delivery system containing salbutamol sulphate Methods: A controlled pulsatile release of drug after a programmed 4 h lag period was achieved from cross-linked gelatin capsule shells containing salbutamol pellets, and sealed with a suitable mixture of sodium alginate and ethyl cellulose as plug. In order to confirm the utility of developed system for the management of nocturnal asthma, a crossover study was conducted. six male rabbits were fasted overnight and divided into two groups comprised of 3 rabbits each. The individual rabbits were administered the developed pulsatile capsule and immediate release salbutamol capsule as reference, separately. Blood samples were collected from the ear vein of the animals into heparinized tubes and used to determine pharmacokinetic parameters, namely, maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), and area under the plasma concentration - time curve (AUC0-∞) using a validated HPLC method. Results: It was observed that drug release from the optimized time-controlled capsule stopped for a period of approximately 4.25 h with an average Cmax and Tmax of 271.54 ± 58.95 ng/ml and 6.00 ± 0.25 h. The AUC0-∞ of salbutamol after administration of the time-controlled pulsatile system was 2494.73 ± 525.95 ng h/ml while that of the immediate-release formulation was 2352.77 ± 432.51 ng h/ml. Using ANOVA at a significant difference of p < 0.05 (CI 95%), there was no significant difference for the AUC0∞ between immediate release and the pulsatile capsule developed. Conclusion: The developed system is capable of releasing salbutamol after a 4 h lag period and can be considered as promising delivery system for time-controlled (pulsatile) delivery of the medication for the management of nocturnal asthma.

Pharmacokinetic Study of a Capsule-based Chronomodulated Drug Delivery System of Salbutamol Sulphate in Rabbits

Purpose: To develop and determine the in vivo performance of a capsule-based pulsatile drug delivery system containing salbutamol sulphate Methods: A controlled pulsatile release of drug after a programmed 4 h lag period was achieved from cross-linked gelatin capsule shells containing salbutamol pellets, and sealed with a suitable mixture of sodium alginate and ethyl cellulose as plug. In order to confirm the utility of developed system for the management of nocturnal asthma, a crossover study was conducted. six male rabbits were fasted overnight and divided into two groups comprised of 3 rabbits each. The individual rabbits were administered the developed pulsatile capsule and immediate release salbutamol capsule as reference,seeparately. Blood samples were collected from the ear vein of the animals into heparinized tubes and used to determine pharmacokinetic parameters, namely, maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), and area under the plasma concentration - time curve (AUC0-‡) using a validated HPLC method.Results: It was observed that drug release from the optimized time-controlled capsule stopped for a period of approximately 4.25 h with an average Cmax and Tmax of 271.54 } 58.95 ng/ml and 6.00 } 0.25h. The AUC0-‡ of salbutamol after administration of the time-controlled pulsatile system was 2494.73 } 525.95 ng h/ml while that of the immediate-release formulation was 2352.77 } 432.51 ng h/ml. UsingANOVA at a significant difference of p &lt; 0.05 (CI 95%), there was no significant difference for the AUC0-‡ between immediate release and the pulsatile capsule developed.Conclusion: The developed system is capable of releasing salbutamol after a 4 h lag period and can be considered as promising delivery system for time-controlled (pulsatile) delivery of the medication for the management of nocturnal asthma.Keywords: pH-controlled release, Lag time, Pulsatile release, Hydrocolloid plug, Nocturnal asthma.

Abstract C62: Phase I trial of ABC294640, a first-in-class sphingosine kinase-2 inhibitor.

Abstract Sphingosine kinases (SK1 and SK2) are new potential targets for anticancer drugs because SK inhibitors elevate ceramide levels thereby promoting apoptosis of tumor cells, and concomitantly reduce sphingosine 1-phosphate (S1P) levels thereby attenuating tumor cell proliferation and migration, as well as reducing host angiogenesis and inflammation. ABC294640 is a first-in-class orally-available inhibitor of SK2 that has activity both as a single-agent and in drug combinations in models of liver, kidney, pancreas, breast, ovary, colon and lung cancer, as well as leukemia and multiple myeloma. ABC294640 is currently in Phase I testing in patients with advanced solid tumors. The primary objectives are to identify the MTD, to determine the dose limiting toxicities (DLTs) and to evaluate the safety of ABC294640. Secondary objectives are to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of ABC294640, and to assess its antitumor activity. The study employs a standard 3+3 dose-escalation design. To date, this Phase I trial has enrolled 16 patients at the following dose levels: 250 mg po qd (6 patients), 250 mg po bid (4 patients), 500 mg po bid (4 patients) and 750 mg po bid (2 patients). In general, the drug has been well tolerated, with the most common side effects being low-grade fatigue and nausea. One pancreatic cancer patient at 250 mg po qd developed grade 4 DLT of hyperglycemia as disease progressed, which was possibly related to drug. Additionally, a patient at 750 mg po bid with a malignant neoplasm of the ovary experienced a grade 3 DLT of nausea and vomiting that was possibly drug-related. After 2 cycles of treatment (8 weeks), tumor imaging demonstrated that 6 of 10 patients had stable disease. Notably 2 patients have had prolonged stabilization of disease: 1 patient with metastatic cholangiocarcinoma (16 months), and 1 patient with metastatic/recurrent bladder cancer (11 months). The MTD has not yet been reached, and dose escalation is continuing. The t1/2 for ABC294640 was approximately 4 hours, and through at least the first 3 cohorts, PK parameters (Cmax and AUC) were proportional to the dose of ABC294640 received. Importantly, the average Cmax for patients receiving 500 mg ABC294640 (16.4 μM) is sufficient for anticancer efficacy in mouse models. This study includes the first-ever analysis of plasma S1P levels as a potential PD biomarker for activity of a sphingolipid-targeted drug, and will establish the degree of intra-and inter-patient variability needed for assessment of this PD marker in future clinical trials. Overall, this first-in-human study provides key information about the safety, toxicities, PK and PD of ABC294640 that are needed to support future Phase II and III clinical trials. (Supported by: P30 CA138313 from the National Cancer Institute to MUSC; R01 FD004102 from the Food and Drug Administration to Apogee; and SAP#4100061668 from the Pennsylvania Department of Health to Apogee.) Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C62. Citation Format: Melanie B. Thomas, Carolyn D. Britten, Elizabeth Garrett-Mayer, Steve H. Chin, Tricia A. Bentz, Alan Brisendine, Terri L. Matson, Susan Cusack, Lynn W. Maines, Yan Zhuang, Charles D. Smith. Phase I trial of ABC294640, a first-in-class sphingosine kinase-2 inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C62.

Coagulation Factor Concentrates Restore Alterations in Hemostasis Induced by a High Dose of Apixaban: Studies in Vitro with Circulating Human Blood.

AbstractAbstract 2263 Background:Newly developed oral anticoagulants require less frequent controls, have fewer interactions with other medications and effects are more reliable. Despite these advantages, bleeding is still a frequent complication for patients on treatment with oral anticoagulants and reversal of their effects remains an unsolved issue for the newer agents. Apixaban is a new oral anticoagulant with inhibitory action on FXa. It has showed a very good efficacy/safety profile in studies in prophylaxis of thrombotic complications after mayor orthopaedic surgery and in atrial fibrillation (AF). Aims:To explore the effects of concentrations of apixaban in excess of those achieved after standard approved dosage, on platelet and coagulation mediated mechanisms of hemostasis. To evaluate the effectiveness of different factor concentrates at reversing the alterations of hemostatic mechanism induced by apixaban. Methods:Apixaban was added in vitro to blood alliquots from healthy donors. Concentrations of apixaban tested (200 ng/ml) doubled the average Cmax reached at steady state with standard approved treatment for AF. Modifications in platelet reactivity towards surfaces were measured at elevated shear rates in a cone and plate analyzer (Impact R®). Effects on thrombin generation (TG) and on thromboelastometry parameters (TEM) were also assessed. Changes in platelet adhesive, aggregating and procoagulant activities were additionally evaluated in perfusion studies through vascular surfaces in a system producing results that correlate with clinical situations (Transfus Med Rev 15:144, 2001). The potential action of prothrombin complex concentrates (PCCs) (50 IU/kg), activated PCCs (aPCCs) at 75 IU/kg, or rFVIIa at 270 μg/kg reversing the anticoagulant actions of apixaban were evaluated. Results:Apixaban did not affect the reactivity of platelets to surfaces in the Impact R®. Apixaban caused a moderate reduction in TG as confirmed by delayed lag phase, prolonged time to peak and reduced velocity index. Thrombin peak and velocity indexes in TG were improved by concentrates with the following order of efficacy PCC≥aPCC>rFVIIa. Apixaban prolonged clotting time (CT) and reduced maximal clot firmness (MCF) in TEM studies using tissue factor as activator. Alterations in these parameters were corrected by the different concentrates according to the following order of efficacy rFVIIa≥aPCC>PCC. Apixaban quantitatively reduced fibrin and platelet interactions with damaged vascular surfaces (p<0.05) in perfusion studies. These alterations were counteracted by the different concentrates with efficacies following this order rFVIIa>PCC>aPCC. Conclusions:Apixaban at 200 ng/ml did not show a direct antiplatelet effect in studies in the cone plate analyzer, but demonstrated evident alterations in hemostasis related to its recognized anticoagulant action. These alterations were variably compensated or even reversed by the different factor concentrates. Effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG and rFVIIa being more effective on TEM and perfusion tests. Studies with flowing blood that reproduce conditions closer to the bleeding situation indicate that current coagulation factor concentrates can effectively restore the impairement in fibrin formation on damaged vascular surfaces resulting from apixaban overdose. Disclosures:Escolar:BMS: Honoraria, Research Funding; Bayer: Honoraria; Boehringer Ingelheim: Honoraria.

Effect of administration route on the pharmacokinetics of cobalamin in elderly

ntroduction.– The standard treatment for cobalamin deficiency s supplementation by intramuscular injection. These injections, owever, are painful and inconvenient. It is thought that cobalmin can also be administered intranasally. Previous studies do ot provide insight in the pharmacokinetics in deficient elderly or in comparison with cobalamin injection. Here we aimed at uantifying the pharmacokinetics of intranasal and intramuscular dministered cobalamin in elderly cobalamin deficient patients. ethods.– Ten subjects were recruited and randomly divided nto two groups. A single dose of 1mg cobalamin was adminisered either by way of intranasal spray or intramuscular injection. nclusion criteria were written informed consent >65 years and obalamin serum concentration<200pmol/l. Total cobalamin erum concentrations were determined at ten different time interals. The average Tmax, Cmax, and AUC0–48 hours per administration oute were statistically compared with ANOVA. esults.– After intranasal cobalamin administration, the average max was 42minutes versus 342minutes for intramuscular adminstration. The average Cmax was 1040pmol/l versus 38486pmol/l, espectively. Due to the significant differences in Tmax andCmax, the UC0-48 hours also differed significantly between these two adminstration routes. iscussion and conclusion.– The pharmacokinetics of cobalamin fter intranasal and intramuscular administration differ signifiantly. Oral administration has been shown to be effective in the reatment of cobalamin deficiency. A Cmax comparable to the Cmax ound in this study after intranasal administration is reached after single oral dose of 1mg cobalamin. Therefore, further research n the safety, pharmacokinetics and efficacy of repeated intranasal obalamin administration is warranted. isclosure.– No significant relationships.

Pharmacokinetic and dynamic study of levofloxacin and rifampicin in bone and joint infections

ObjectiveWe studied the pharmacokinetic and pharmacodynamic parameters of levofloxacin and rifampicin in bone and joint infections. The optimal dose regimen of these two antibiotics has not been documented yet. Patients and methodWe performed plasma dosage for each antibiotic in patients with a bone and joint infection requiring treatment with a levofloxacin and rifampicin combination. We then computed the 6hours post dose area under the concentration-time curve (AUC0-6h), the peak plasma concentration (Cmax), the area under the inhibitory concentration curve (AUIC), and the peak-to-minimum-inhibitory-concentration ratio (Cmax/MIC). The pharmacodynamic results were then compared to the published thresholds of effectiveness. The doses used were levofloxacin 500mg bid and rifampicin 20mg/kg per day. ResultsThe plasma of 17 patients was dosed. The average AUC0-6h for levofloxacin was 46.59mg.h/l, the average Cmax 10.7mg/l, the average AUIC 932, and the average Cmax/MIC 107.5. The averages for rifampicin were 42.2mg.h/l, 11.8mg/l, 11,125 and 1514. Given that bone concentration of levofloxacin is 30% that of the plasma concentration, that concentration was divided by three to estimate bone concentration. ConclusionThe optimal thresholds of pharmacodynamic effectiveness were obtained for most patients with levofloxacin at 500mg bid. Additional studies are still required to determine the optimal rifampicin dose.

First human study in treatment of unresectable liver metastases from colorectal cancer with irinotecan-loaded beads (DEBIRI)

The objective of this pilot clinical study was to assess the safety, technical feasibility, pharmacokinetic (PK) profile and tumour response of DC Bead™ with irinotecan (DEBIRI™) delivered by intra-arterial embolisation for the treatment of metastatic colorectal cancer. Eleven patients with unresectable liver metastases from CRC, tumour burden <30% of liver volume, adequate haematological, liver and renal function, performance status of <2 were included in this study. Patients received up to 4 sessions of TACE with DEBIRI at 3-week intervals. Feasibility of the procedure, safety and tumour response were assessed after each cycle. PK was measured after the first cycle. Patients were followed up to 24 weeks. Only mild to moderate adverse events were observed. DEBIRI is a technically feasibile procedure; no technical complications were observed. Average Cmax for irinotecan and SN-38 was 194 ng/ml and 16.7 ng/ml, respectively, with average t½ of 4.6 h and 12.4 h following administration of DEBIRI. Best overall response during the study showed disease control in 9 patients (2 patients with partial response and 7 with stable disease, overall response rate of 18%). Our study shows that transarterial chemoembolisation with irinotecan-loaded DC beads (DEBIRI) is safe, technically feasible and effective with a good PK profile.

Clinical Pharmacology Basis of Deriving Dosing Recommendations for Dabigatran in Patients With Severe Renal Impairment

The objective of this work was to derive a dosing regimen for dabigatran in patients with severe renal impairment by modeling and simulation. Data from a dedicated renal impairment study were used to model the pharmacokinetics of dabigatran in normal and renal-impaired subjects. Model parameters were used to simulate the average concentration time-course of dabigatran following various dosing regimens. Pharmacokinetics of dabigatran in normal and renal-impaired subjects were best described by a 2-compartment open model with first-order absorption and elimination. Simulations were performed to select an appropriate regimen that reasonably matched the exposures on an average with those observed in subjects with moderate renal impairment who did not require a dose adjustment because of a favorable benefit-risk. Dabigatran 150 mg given once daily resulted in 35% higher average C(max, ss), whereas a 75 mg once daily regimen resulted in 42% lower average Cτ, relative to that observed with 150 mg administered twice daily in subjects with moderate renal impairment. A twice daily regimen of dabigatran 75 mg resulted in a reasonable matching of exposures and was selected as an appropriate dosing regimen in patients with severe renal impairment. This recommendation was incorporated in the dosing and recommendation section of dabigatran product insert.

P1-12-07: Pharmacokinetics (PK) of Trastuzumab Emtansine and Paclitaxel or Docetaxel in Patients with HER2−Positive MBC Previously Treated with a Trastuzumab-Containing Regimen.

Abstract Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab, DM1 (a potent cytotoxic tubulin polymerization inhibitor), and the stable MCC linker. Based on in vitro and preclinical data suggesting synergy in tumor cell cytotoxicity with T-DM1 + taxanes, these combinations are being tested in phase Ib studies. The assessment of risk for PK-based drug interaction (PK-DI) with these combinations is important. T-DM1 is expected to undergo proteolytic degradation with no significant involvement of cytochrome P450 isoenzymes (CYPs), and DM1 is metabolized mainly by CYP3A4 (and to a lesser extent by CYP3A5). Paclitaxel (P) and docetaxel (D) are metabolized primarily by CYP2C8 and CYP3A4, respectively. None of these drugs inhibits or induces CYPs at clinically relevant concentrations. Since DM1 and D are both metabolized by CYP3A4, PK-DI may occur. This is less likely with DM1 and P since they are primarily metabolized by different CYPs. Methods: The tolerability, PK, and dose-limiting toxicities of T-DM1 + P or D were investigated in 2 studies (TDM4652g and BP22572) of patients with HER2−positive MBC previously treated with a trastuzumab-containing regimen. For PK-DI analysis, both studies used a staggered dosing design in the first cycle, with same-day dosing in subsequent cycles. Study BP22572 was later amended to give both drugs on the same day in all cycles. Either P (65 mg/m2, n=11; 80 mg/m2, n=6) or D (60 mg/m2, n=12; 75 mg/m2, n=6) was combined with T-DM1 at various doses (2 mg/kg or 2.4 mg/kg q3w or 1.2 mg/kg qw for TDM4652g; 2.4 mg/kg or 3.6 mg/kg q3w for BP22572). PK of T-DM1, total trastuzumab (conjugated + unconjugated trastuzumab), DM1, P, and D were evaluated and compared with historical singleagent data and across cycles within the study, using population analysis and/or noncompartmental analysis (NCA), as data allowed. Preliminary safety and efficacy data for the historical T-DM1 singleagent studies were reported previously (Krop JCO 2010; Burris JCO 2010; Krop ESMO 2010). Results: The PK of P and D were similar from cycle 1 to cycle 2 for maximum concentration (Cmax), area under the concentration-time curve, halflife, clearance (CL) and steady-state volume of distribution, and were also similar to historical single-agent data. The Cmax of DM1 was &amp;lt;8 ng/mL in both studies, and the average Cmax values were similar to historical single-agent data. T-DM1 PK parameters for the combination studies are within the range of historical single-agent data (Table). Data from additional patients and doses in the combination studies will be presented. Conclusion: The risk of clinically relevant PK-DI between T-DM1 and P or D appears to be low. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-07.

Phase 1 Study of UCN-01 in Combination with Perifosine in Patients with Relapsed and Refractory Acute Leukemias and High Risk Myelodysplastic Syndromes (MDS)

Abstract 1557 Introduction:The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway controls key cellular processes and is frequently activated in both acute and chronic myeloid leukemia (AML, CML) as well as high-risk MDS, thus representing an attractive therapeutic target. UCN-01 inhibits a number of serine-threonine kinases, including phosphatidylinositide-dependent kinase 1, which phosphorylates and activates Akt. Perifosine, an alkylphospholipid, targets the pleckstrin homology domain of Akt, thereby inhibiting its plasma membrane translocation and activation. Synergistic inhibition of Akt by UCN-01 and perifosine has been demonstrated in prostate and lung cancer cell lines (Clin Cancer Res 10: 5242, 2004). Methods:We conducted a Phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose of UCN-01 and perifosine, using a standard 3+3 dose escalation design. Patients (pts) >18 years with poor-risk, or relapsed/ refractory AML or acute lymphoblastic leukemia (ALL), CML in accelerated/blastic phase or MDS failing standard therapy, and peripheral blast count <30×109/l were eligible. Perifosine was administered on day (d)1 at 150 mg orally every 6 hours, then 100 mg daily from d2 continuously. UCN-01 was given as a 3-hour infusion on d4 at one of 3 dose levels (DL) (DL1 40/DL2 65/DL3 90 mg/m2). 28-day cycles were repeated depending on response/tolerability, with UCN-01 given at 50% dose. Antiemetic prophylaxis (perifosine) and hydration (UCN-01) were required. Results:Thirteen pts with AML (11), ALL (1), and MDS (1) were treated (DL1, n=6; DL2, n=4; DL3, n=3). Median age was 69 years (range, 20–85), 77% pts were male, and median number of prior treatments was 3 (range, 1–6). Nine of 11 AML patients had secondary (7)/therapy-related (2) disease, 4 had adverse and 5 intermediate karyotypes, and all were either primary refractory (4) or had first remission duration < 12 months (7). Pts received median 1 (range, 1–3) cycle of therapy. Five pts did not complete 1st cycle due to disease progression (n=3; DL1), cholecystitis/sepsis (n=1; DL3), or drug-related toxicity (n=1; DL3), and 4 received hydroxyurea temporarily to control increasing blast counts. The most frequent drug-related toxicities (NCI CTC v3) were grade (gr) 1/2 nausea and diarrhea (62% each), vomiting (54%), fatigue and hyperglycemia (31% each) anorexia, hypocalcemia and constipation (23% each), increased AST/ALT (15%), hypokalemia and hypotension (8% each). Few ≥gr 3 toxicities were seen, all at DL3: fatigue (gr 3), hyperglycemia (gr 4), hypokalemia (gr 3), pericarditis/tamponade/hypotension (gr 4) and respiratory distress (gr 4). MTD was therefore defined as 65 mg/m2 based on 2 pts with dose limiting toxicities at DL3. One AML pt (DL1) had disease stabilization for 3 cycles and one MDS pt (DL2) had improvement in neutrophil count. Given lack of sufficient evidence of clinical efficacy, the DL2 cohort was not expanded to 6 pts as planned. However, no gr 3/4 drug-related toxicities were observed in 10 pts treated at DL1/2. Pharmacodynamics:Western blot analysis did not consistently demonstrate appreciable direct Akt inhibition in ficolled blood/marrow mononuclear cells from 5 pts (DL1/2) on d4 (perifosine alone) or d21-28, however, a 38–74% reduction in phosphorylated ribosomal protein S6 in leukemic blasts from 3 pts on d4 was noted by intracellular flow cytometry, consistent with inhibition of signaling through the Akt downstream target p70S6 kinase. Pharmacokinetics:The average steady state concentration (Css) of perifosine was 4.75±2.53 μg/mL, consistent with published data (Eur J Cancer 38: 1615, 2002), with 1 pt having an unusually high Css of 9.25 μg/mL. The end-of-infusion concentration for UCN-01 was also consistent with published data (Clin Cancer Res 13: 2667, 2007), with average Cmax 13.2±0.424 μg/mL and 20.7±3.08 μg/mL at doses of 40 and 65 mg/m2, respectively. Conclusion:UCN-01 (40 or 65 mg/m2)/perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo and/or need to inhibit more than one signaling pathway to produce clinical response. Future studies with more potent Akt inhibitors should examine the validity of this approach in conjunction with pharmacodynamic monitoring. Disclosures:Carroll:Glaxo Smith Kline, Inc.: Research Funding; Sanofi Aventis Corporation: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding. Gojo:Keryx Inc.: Research Funding. Off Label Use: Neither UCN-01 nor perifosine have an approved indication.

Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs

Pharmacokinetics of cefpodoxime in plasma (total concentration) and subcutaneous fluid (free concentration using microdialysis) was investigated in dogs following single oral administration of prodrug cefpodoxime proxetil (equivalent to 5 and 10 mg/kg of cefpodoxime). In a cross over study design, six dogs per dose were utilized after a 1 week washout period. Plasma, microdialysate, and urine samples were collected upto 24 h and analyzed using high performance liquid chromatography. The average maximum concentration (C(max) ) of cefpodoxime in plasma was 13.66 (±6.30) and 27.14 (±4.56) μg/mL with elimination half-life (t(1/2) ) of 3.01 (±0.49) and 4.72 (±1.46) h following 5 and 10 mg/kg dose, respectively. The respective average area under the curve (AUC(0-∞) ) was 82.94 (±30.17) and 107.71 (±30.79) μg·h/mL. Cefpodoxime was readily distributed to skin and average free C(max) in subcutaneous fluid was 1.70 (±0.55) and 3.06 (±0.93) μg/mL at the two doses. Urinary excretion (unchanged cefpodoxime) was the major elimination route. Comparison of subcutaneous fluid concentrations using pharmacokinetic/pharmacodynamic indices of fT(>MIC) indicated that at 10 mg/kg dose; cefpodoxime would yield good therapeutic outcome in skin infections for bacteria with MIC(50) upto 0.5 μg/mL while higher doses (or more frequent dosing) may be needed for bacteria with higher MICs. High urine concentrations suggested cefpodoxime use for urinary infections in dogs.

Evaluation of bioequivalence of two oral formulations of olanzapine.

Olanzapine is an atypical antipsychotic drug, used for the management of schizophrenia and for the treatment of moderate to severe mania associated with bipolar disorder. The objective of the present randomised, crossover study was to compare the bioavailability of olanzapine 10 mg/5 ml powder for oral suspension with olanzapine 10 mg orally disintegrating tablet. Eighteen healthy male volunteers were randomly assigned to crossover, single-dose treatment regimens. Serial blood samples were collected, and plasma concentrations of olanzapine were analysed using the LC-MS/MS technique. Pharmacokinetic parameters and bioequivalence limits were calculated using non-compartmental methods. Average Cmax following administration of the single 10 mg disintegrating tablet formulation and 10 mg/5 ml suspension were 14.47±4.25 ng/ml and 13.56±3.99 ng/ml respectively. Corresponding median Tmax were 5.0 h and 6.0 h, respectively. The average AUC0–t values and AUC0–inf values were similar following each of the olanzapine preparations. Overall, the 90% Confidence Interval for the intra-individual ratios of the log-transformed Cmax and AUC values of the two formulations were within the bioequivalence interval of 80–125%. The study has demonstrated the bioequivalence of the 10 mg tablet and the 10 mg/5 ml oral suspension of olanzapine.

Prodrug, Laninamivir Octanoate, a Long-Acting NeuraminidaseInhibitor, Using an Easy-to-Use Inhaler in Healthy Volunteers

Pharmacokinetic profiles of laninamivir after a single inhalation of laninamivir octanoate (LO), a prodrug of laninamivir, using a newly developed easy-to-use inhaler were evaluated in healthy volunteers. LO appeared rapidly in plasma after an inhaled administration in healthy volunteers with a median value of tmax of 0.25 hr, and the plasma concentrations decreased below the detection limit after 24 hr of inhalation. The median tmax of laninamivir was 4.0 hr and laninamivir slowly declined after Cmax with a mean t1/2 of 66.6 and 74.4 hr at a dose of 20 mg and 40 mg, respectively. The average AUC0-inf and Cmax for LO and laninamivir almost increased proportionally with the dose. The mean cumulative excretion amounts of LO in urine for 144 hr after inhaling 20 mg or 40 mg dose of LO were 4.7 and 5.5% of the dose, respectively, and those of laninamivir were 19.2 and 23.3%, respectively. No clinical or laboratory adverse experiences were reported and no subject discontinued because of an adverse experience. As plasma concentrations of both LO and laninamivir revealed a similar pattern between using the prototype and this new inhaler, LO exhibited potential for long lasting anti-influenza activity using this easy-to-use inhaler.

SGI-110, a Novel Second Generation Potent DNA Methylation Inhibitor, In Development for the Treatment of MDS and AML. Preclinical Safety, Pharmacokinetics, and DNA Methylation Results of a Low Volume Subcutaneous (SC) Formulation

AbstractAbstract 1872SGI-110, is a novel second generation DNA methylation inhibitor that is currently in Phase I/II clinical study for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). SGI-110 is a dinucleotide of decitabine and guanosine developed to be more biologically stable than decitabine by making it less prone to deamination by cytidine deaminase, thus offering a promising alternative to current hypomethylating agents approved in MDS. SGI-110 demonstrated potent activity in vivo using different routes of administration (Chuang JC, et al, Mol Cancer Ther, 2010; 9:1443-50).We report here the results of a novel SGI-110 non-aqueous formulation intended for clinical use. The clinical formulation can be administered in small volumes subcutaneously (SC) up to a concentration of 100 mg/mL. We evaluated 2 regimens: daily SC × 5 days (in rats, and rabbits); and weekly SC (once weekly in rabbits, and cynomolgus monkeys; and twice weekly in rats). Both regimens are intended for 28-day cycles.The 5-day regimen was well tolerated up to a dose of 1.5 mg/kg/day × 5 in the most sensitive species (rabbit) which is equivalent to 18 mg/m2/day × 5 in humans. The weekly regimen was also well tolerated up to 1.5 mg/kg weekly × 3 in rabbits, and up to 3 mg/kg weekly × 3 in monkeys (equivalent to 36 mg/m2 weekly × 3 in humans). Rats tolerated much higher doses (30 mg/kg/day × 5; and 20 mg/kg twice weekly × 4 weeks). The main toxicity was myelosuppression in all species. The relative bioavailability of SGI-110 dosed SC is close to 100%. In vivo, SGI-110 rapidly converts to decitabine in rats, and rabbits, with much slower conversion in monkeys compared to other species, possibly sustaining efficacy for longer duration. Dose proportional pharmacokinetics and no significant accumulation of both SGI-110 and decitabine levels were evident after SC treatment in both the 5-day and the weekly regimens. We studied changes in LINE-1 DNA methylation in rats and monkeys after SGI-110 SC administration. Changes in LINE-1 DNA methylation after SGI-110 SC weekly × 4 in rats at tolerated doses of 12.5, 25 and 30 mg/kg/week were evident during the first recovery week (Day 31) and were dose-dependent. Maximum methylation reduction was observed with 30 mg/kg/week of SGI-110. These data in rats suggest a delayed pharmacodynamic effect.In monkeys, SGI-110 was administered at 3 mg/kg/week SC for 3 weeks (Days 1, 8 and 15). Reduction in LINE-1 DNA methylation became evident by Day 8, reached a maximum reduction of 10–15% by Day 15–22, and was maintained until Day 29.LINE-1 methylation levels were significantly reduced from baseline levels (p< 0.05) from Days 8–29. On Day 1, an average Cmax of 33.4 ng/mL at a Tmax of 1 hr and AUC of 120 ng*hr/mL were achieved for decitabine compared to Cmax of 184 ng/mL at a Tmax of 1 hr and AUC of 381 ng*hr/mL for SGI-110. On Day 15, an increase in the average SGI-110 AUC to 592 ng*hr/mL was observed suggesting some accumulation. All other pharmacokinetic parameters for decitabine and SGI-110 were similar to those on Day 1. Compared to other animal species tested, levels of SGI-110 were consistently and substantially higher in monkey plasma across studies. SGI-110 was well tolerated in monkeys at this dose with only mild reversible myelosuppresion and no deaths.In conclusion, based on the non-human primate monkey data, this uniquely developed low volume non-aqueous SC formulation of SGI-110 may allow sustained efficacy with less frequent weekly dosing offering a new alternative to MDS and AML patients. SGI-110 is being studied in a first-in-human study. This study is a randomized Phase I/II, dose escalation, multicenter study of two subcutaneous regimens (daily on Days 1–5, and weekly × 3 on Days 1, 8, 15, both given in a 28-day cycle) in relapsed or refractory MDS, and relapsed, refractory, or elderly AML patients. Disclosures:Scholl:SuperGen: Employment. Joshi-Hangal:SuperGen: Employment. Inloes:SuperGen: Employment. Shi:SuperGen: Employment. Taverna:SuperGen, Inc.: Employment. Choy:SuperGen, Inc.: Employment. Redkar:SuperGen: Employment. Azab:SuperGen: Employment.

Population pharmacokinetic (PK) and exposure-response analysis of nilotinib in newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: Results from ENESTnd.

6556 Background: Results from ENESTnd at 12 months (mo) demonstrated superior efficacy of nilotinib at both 300 mg BID and 400 mg BID doses over imatinib 400 mg QD. Methods: Full PK profiles of nilotinib were obtained at steady state from a subgroup of 34 pts, and sparse (pre-dose/Cmin and 3 hr post-dose/Cmax) concentration data were obtained over 12 mo from 542/563 treated pts. Results: Nilotinib concentrations were stable over 12 mo in both arms (Cmin: 1,158 ± 568 ng/mL [median 1,097 ng/mL] for 300 mg BID; 1,340 ± 621 ng/mL [median 1,217 ng/mL] for 400 mg BID). The average nilotinib Cmin and Cmax were 15.7% and 14.8% higher in the 400 mg BID arm than the 300 mg BID arm. Estimated relative bioavailability ratio was 0.84 for nilotinib 400 mg BID to 300 mg BID. Gender was a statistically significant covariate for nilotinib bioavailability: male pts had 10% lower bioavailability and systemic exposure than females, although this difference is not clinically meaningful. Age, body weight, ethnicity, and racial group did not significantly affect nilotinib PK. Total bilirubin elevation was higher in pts with higher nilotinib concentrations. For example, pts with nilotinib Cmin in quartiles Q1 (< 829 ng/mL, n = 113), Q2/3 (≥ 829 and ≤ 1,569 ng/mL, n = 229) and Q4 (> 1,569 ng/mL, n = 113), 0.9%, 4.8% and 7.1%, respectively, had grade 3/4 bilirubin elevation. Logistic regression confirmed a significant correlation between nilotinib daily AUC and total bilirubin. There was little evidence for a correlation between nilotinib exposure and elevation in AST or lipase. On average, an increase of 1000 ng/mL in nilotinib serum concentrations was associated with minimal increase in QTcF (4.2 to 6.9 msec). Although no relationship was observed for MMR at 12 mo with average nilotinib Cmin, there was a positive correlation with BCR-ABL transcript level reductions at 12 mo with nilotinib Cmin. Conclusions: There is a less than proportional dose-exposure relationship between nilotinib 300 mg BID and 400 mg BID. Exposure was stable over the 12 mo treatment course at both doses. Demographics were not a clinically important factor affecting nilotinib PK. The study is ongoing and additional PK data will be available. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Merck, Novartis Novartis Bristol-Myers Squibb, Merck, Novartis Bristol-Myers Squibb, Genzyme, Novartis The Royal Collage of Pathologists

Enhanced Bioavailability of Ambroxol by Transdermal Administration of the EVA Matrix Containing Penetration Enhancer in Rats

The pharmacokinetics and bioavailability of ambroxol, an expectoration improver and mucolytic agent, were studied to determine the feasibility of enhanced transdermal delivery of ambroxol from the ethylene-vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether as an enhancer in rats. The ambroxol-010 matrix system (15 mg/kg) was applied to abdominal skin of rats. Blood samples were collected via the femoral artery for 28 hrs and the plasma concentrations of ambroxol were determined by HPLC. Pharmacokinetic parameters were calculated using Lagran method computer program. The area under the curve (AUC) was significantly higher in the enhancer group (1,678 ± 1,413.3 ng/ml·hr) than that in the control group 1,112 ± 279 ng/mlㆍhr), that is treated transdermally without enhancer, showing about 151% increased bioavailability (p<0.05). The average Cmax was increased in the enhancer group (86.0 ± 21.5 ng/ml) compared with the control group (59.0 ± 14.8 ng/ml). The absolute bioavailability was 13.9% in the transdermal control group, 21.1% in the transdermal enhancer group and 18.1% in the oral administration group compared with the IV group. The Tmax, Ka, MRT and t1/2 of ambroxol in transdermal enhancer group were increased significantly (p<0.01) compared to those of oral administration. As the ambroxol-EVA matrix containing polyoxyethylene-2-oleyl ether and tributyl citrate was administered to rats via the transdermal routes, the relative bioavailability increased about 1.51-fold compared to the control group, showing a relatively constant, sustained blood concentration. The results of this study show that ambroxol-EVA matrix could be developed as a transdermal delivery system providing sustained plasma concentration.

An open-label, dose-escalating study of Maxy-G34, a novel potent, long-acting Pegylated G-CSF, compared with pegfilgrastim (PF) for the treatment of chemotherapy induced neutropenia (CIN)

e14500 Background: rhG-CSF reduces the incidence and duration of CIN in patients (pts) receiving myelosuppressive chemotherapy. Maxy-G34 is a recombinant, modified human G-CSF, containing three 5 kD PEG groups. These modifications alter both renal and receptor mediated clearance, leading to a longer half-life and the potential for enhanced activity. Phase I studies demonstrated safety of Maxy-G34 in normal volunteers with a dose dependent rapidly reversible increase in the absolute neutrophil count (ANC). The effect of Maxy-G34 on CIN was evaluated in an open-label, active-comparator controlled, dose-ranging study. Methods: The primary efficacy endpoint was duration of severe, Grade 4 neutropenia (G4N) in treatment cycle 1. Adults with high-risk Stage I-IIIa breast cancer eligible for TAC chemotherapy received Maxy-G34 at 10, 30, 45, 60 or 100 μg/kg or the active control PF 6 mg, given sub- cutaneously 24-hours after each dose of TAC for 6 cycles. Blood samples were collected daily and analyzed at a central laboratory throughout each of the 21-day chemotherapy cycles to determine ANC and evaluate PK profile of Maxy-G34. Results: All dose groups of Maxy-G34 enrolled 6 pts each, except the 100 μg/kg group (3 pts), and the PF group (8 pts). The mean durations of G4N in cycle 1 were 2.2 days for 10 μg/kg, 1.8 days for 30 μg/kg, 0.8 days for 45 μg/kg, 2.2 days for 60 μg/kg, and 1.7 days for 100 μg/kg Maxy-G34 groups vs. 2.0 days for PF. The rate of FN was 2.6% across all Maxy-G34 doses vs. 4.2% for PF. CD34+ cell counts increased across Maxy-G34 groups following recovery from nadir with maximum concentration in treatment cycle 1 ranging from 25.8 to 133.3 cells/mL versus 49.6 cells/mL for PF. The average half-life and Cmax obtained after Maxy-G34 were approximately 2-fold higher than PF. Adverse events were consistent with those reported for G-CSF and TAC with no serious unexpected adverse events. Grade 3/4 AEs for Maxy-G34 was 9.5% vs. 8.5% for PF. No neutralizing antibodies related to Maxy-G34 were observed. Conclusion: Once-per-cycle Maxy-G34 appears to be effective in reducing CIN with no new safety signals. Further Phase II studies are planned. [Table: see text]

Effect of Biomass Pre-Treatment and Solvent Extraction on β-Carotene and Lycopene Recovery from Blakeslea trispora Cells

The production of carotenoids from Blakeslea trispora cells in a synthetic medium has been reported, with the main products being β-carotene, lycopene, and γ-carotene. The effect of biomass pretreatment and solvent extraction on their selective recovery is reported here. Eight solvents of class II and III of the International Conference of Harmonization: ethanol, methanol, acetone, 2-propanol, pentane, hexane, ethyl acetate, and ethyl ether, and HPLC analysis were used for the evaluation of their selectivities towards the three main carotenoids with regard to different biomass pre-treatment. The average Cmax values (maximum concentration of caronoids in a specific solvent) were estimated to 16 mg/L with the five out of eight solvents investigated, whereas methanol, pentane, and hexane gave lower values of 10, 11, and 9 mg/L, respectively. The highest carotenoid yield was obtained in the case of wet biomass, where 44–56% is recovered with one solvent and three extractions and the rest is recovered only after subsequent treatment with acetone; thus, four extractions of 2.5 h are needed. Two extractions of 54 min are enough to recover carotenoids from dehydrated biomass, with the disadvantage of a high degree of degradation. Our results showed that, for maximum carotenoid recovery, ethyl ether, 2-propanol, and ethanol could be successfully used with biomass without prior treatment, whereas fractions enriched in β-carotene or lycopene can be obtained by extraction with the proper solvent, thus avoiding degradation due to time-consuming processes.

Phase I study of NPI-2358 (a novel vascular disrupting agent) in patients with solid tumors and lymphomas

3525 Background: NPI-2358 is a novel vascular disrupting agent (VDA) acting on tubulin dimerization that destabilizes tumor vascular endothelial cells and has cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in murine tumor models and potentiates other oncology agents. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity. Methods: Dose escalation of NPI-2358 was conducted in a phase I trial enrolling patients with advanced solid tumors and lymphomas. Patients were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. The study utilized a dynamic accelerated dose titration (DADT) design in which the dose of NPI-2358 would be escalated in cohorts from 2 mg/m2 to a recommended phase II Dose (RP2D). Any cohort could consist of 1 patient provided no ≥ Grade 2 adverse event (AE) is reported in the prior cohort. If a ≥ Grade 2 AE is reported in the prior cohort, the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO and PK were obtained on D1 & D15. DCE-MRI were utilized to assess changes in tumor blood flow. Results: 25 subjects were enrolled. 30 mg/m2 was selected as the RP2D (predicted minimum efficacious dose = 7.5 mg/m2), based on toxicities of nausea, vomiting, fatigue, fever, tumor pain and transient elevations in blood pressure. DCE-MRI demonstrated decreases in Ktrans beginning at 13.5 mg/m2, and a 16–54% decrease in patients evaluated at 30 mg/m2. Five patients had stable disease for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles), anal squamous cell carcinoma (3 cycles), adrenalcortical carcinoma (2 cycles) and melanoma (2 cycles). Average Cmax and AUClast have increased from 34 to 468 ng/ml, and from 101 to 1518 ng/ml*hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.3 ±2.8 h, CL was 37.3±28 L/h and Vss was 214±63 L. Conclusions: NPI-2358 generally produced modest toxicity at the RP2D, which was significantly above the predicted efficacious dose and elicited decreases in tumor blood flow by DCE-MRI. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently entering Phase 1b/2 trials in solid tumor malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nereus Nereus Nereus Nereus

Abstract LB-202: Phase 1 dose escalation trial of the novel vascular disrupting agent NPI-2358

Abstract Background: NPI-2358 is a novel vascular disrupting agent that inhibits tubulin polymerization leading to tumor vascular endothelial destabilization. NPI-2358 selectively induces tumor vascular collapse resulting in tumor regression and potentiates other oncology agents in preclinical tumor models. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity. Methods: In this study the dose of NPI-2358 was escalated from 2 to 30 mg/m2 in patients with advanced solid tumors and lymphomas. Patients were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. The study utilized a dynamic accelerated dose titration (DADT) design in which the dose of NPI-2358 was escalated in cohorts, in which any cohort could consist of 1 patient provided no ≥Grade 2 adverse event is reported in the prior cohort, otherwise the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO, and PK were obtained on day 1 and day 15. DCE-MRI were performed at baseline, day 2 then every other cycle and end of study as feasible, to assess changes in tumor blood flow and vascular permeability as reflected in the volume transfer constant (Ktrans). An improved two-compartment model is utilized which incorporates motion correction and an automated arterial input function. This is expected to improve the accuracy and reproducibility in the estimation of Ktrans by eliminating variability associated with subject motion, contrast injection, and cardiac output. Results: Twenty-five subjects were enrolled in the dose escalation phase. We selected 30 mg/m2 as the RP2D, based on adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient elevations in blood pressure. DCE-MRI demonstrated decreases in Ktrans beginning at 13.5 mg/m2, and a 16-82% decrease in patients evaluated at 30 mg/m2. Decreasing Ktrans over multiple treatment cycles was seen in the two patients that underwent repeat DCE-MRI imaging. Five patients had stable disease for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles), anal squamous cell carcinoma (3 cycles), adrenalcortical carcinoma (2 cycles), and melanoma (2 cycles). Average Cmax and AUCtotal have increased from 34 to 610 ng/ml, and from 101 to 3998 ng/ml/hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.8 ±3.2 h, CL was 34.1 ±26 L/h, and Vss was 211±61 L.Conclusions: At the RP2D NPI-2358 produced tolerable toxicities, while eliciting decreases in tumor blood flow by DCE-MRI. Maximum effect on Ktrans appeared to increase with increasing dose and time on treatment. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently proceeding into Phase Ib/II trials in solid tumor malignancies.