Mean AUCinf Research Articles

Bone turnover markers and pharmacokinetics of a new sustained-release formulation of the cathepsin K inhibitor, ONO-5334, in healthy post-menopausal women

A sustained-release tablet (SRT) of ONO-5334 was compared to the immediate-release tablet (IRT) dose, which demonstrated effects on bone mineral density (BMD) comparable to those of therapy with alendronate. The single-dose phase was a randomized, partial single-blind, crossover study where 50-, 100-, and 300-mg SRTs and 300-mg IRTs were administered to nine post-menopausal women. The multiple-dose phase was a randomized, double-blind, placebo-controlled, parallel-group study where 100- and 300-mg SRTs, or placebo were administered to 24 women. After a single administration of a 300-mg SRT, mean C max was 3.3-fold lower, mean AUCinf was 0.83-fold lower and mean C 24h was 5.4-fold higher compared to the 300-mg IRT. Repeated SRT dosing did not significantly affect PK, although C 24h increased slightly. After a single ONO-5334 dose, serum CTX-I was suppressed by ~50% within 1h, reaching maximum suppression 6h post-dose. Greater suppression was maintained longer by the 300-mg SRT vs. the 300-mg IRT. Second morning void and cumulative urine CTX-I showed clear dose-response effects at/over 24h for SRT, with maximum suppression occurring at/over 24h (except 50- and 300-mg cumulative urine). Repeated dosing suggested greater suppression of urine CTX-I. Compared with the IRT, the SRT showed reduced C max, greater C 24h, and slightly reduced AUCinf dose for dose. The SRT showed clear dose-response suppression on bone resorption and greater efficacy dose for dose vs. the IRT.

Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects

The objective of this study was to establish effects of inhaled loxapine on the QTc interval in this randomized, placebo-controlled, double-blind crossover study. Forty-eight healthy volunteers received a single inhaled placebo or 10 mg loxapine. Plasma concentrations of loxapine increased with a median Tmax of 1 minute and a mean Cmax of 312 ng/mL. After an initial rapid distribution phase, plasma concentrations of loxapine declined with a terminal half-life of 8 hours. Exposure to the active metabolite 7-OH-loxapine was 15% of the parent compound based on mean AUCinf and its terminal half-life was 12 hours. Inhaled loxapine did not increase QT intervals, as demonstrated by the upper bound of the 1-sided 95% CIs placed on the point estimate of the placebo-subtracted change of QTcI (ΔΔQTcI) being less than 10 milliseconds at all 11 post-dose times. The maximum ΔΔQTcI occurred at 1 hour post-dose (LSmean 5.42 milliseconds, upper confidence bound 7.75 milliseconds). The study outcome was validated by the demonstrated assay sensitivity using the positive control moxifloxacin maximum ΔΔQTcI occurred at 3 hour post-dose (LSmean 8.36 milliseconds, lower confidence bound 5.82 milliseconds). The analyses of QTc outliers, and the lack of emergent diagnostic findings for QTcI, QTcB, and QTcF; and simple mean placebo-subtracted changes of QTcI and QTcF supported the primary QT analysis conclusion that this is a negative finding and there is no apparent QT prolongation associated with the therapeutic dose of inhaled loxapine.

Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers

Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

Single-dose Pharmacokinetics of the HCV Polymerase Inhibitor Mericitabine in Healthy Caucasian and Japanese Subjects

To investigate the pharmacokinetics of mericitabine in healthy Caucasian and Japanese subjects, healthy Caucasian (n = 32) and Japanese (n = 32) subjects were randomized to receive single 500, 1,000, or 2,000 mg doses of mericitabine or a placebo, after which plasma and urine samples were collected for 72 h. Mericitabine (prodrug), RO4995855 (parent), and RO5012433 (uridine metabolite) concentrations were quantified by tandem mass spectrometry. Pharmacokinetics were estimated by non-compartmental methods, and pharmacokinetic parameters of RO4995855 were normalized by body weight. Exposure to RO4995855 was similar in both populations after administration of mericitabine 500, 1,000, and 2,000 mg. Mean AUCinf of RO4995855 increased in a dose-proportional manner from 28.8 to 52.3, and 113.0 µg·h/mL in Caucasian subjects, and from 32.5 to 57.1 and 119 µg·h/mL in Japanese subjects. A linear relationship was observed between the weight-adjusted dose of mericitabine and Cmax (r(2) = 0.83 and 0.80) and AUC (r(2) = 0.94 and 0.74) for RO4995855 in Caucasian and Japanese subjects, respectively. Mean half-life and renal clearance of RO4995855 were similar and independent of dose in both populations. The results support the use of the same dosing regimens in Caucasian and Asian subjects.

Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design

1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin.2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose).3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition.4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)].5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263.

Bioequivalence Study of Clopidogrel Bisulfate Film-coated Tablets

The aim of the present study was to evaluate the bioequivalence of two clopidogrel (CAS 120202-66-6) formulations. The study was performed according to an open, cross-over design in one study center in 36 healthy male and female volunteers, comparing a new generic product (tablets containing clopidogrel bisulfate, 75 mg) with the originator product (reference). In each of the two study periods (separated by a wash-out of 7 days) a single dose of 150 mg (test or reference) was administered. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of clopidogrel were determined by an LC/MS/MS method. AUC0-inf, AUC0-t, Cmax, Tmax and T(1/2 el) were calculated for both formulations. The mean AUC0-inf, AUC0-t and Cmax were 29.94 ng x h/mL, 29.53 ng x h/mL and 7.386 ng/mL, respectively, for the test formulation and 29.24 ng x h/mL, 28.83 ng x h/mL and 7.921 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1.25 h. The point estimators of the ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 101.17%, 101.13% and 90.96%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf and AUC0-t were narrow and symmetrical around 100%, i.e. from 96.38% to 106.21% for AUC0-inf and from 96.20% to 106.30% for AUC0-t, whereas the confidence interval for Cmax was 84.07% to 98.41%. In can be concluded that the two clopidogrel formulations (test formulation of clopidogrel bisulfate and reference formulation) are bioequivalent in terms of the rate and extent of absorption.

Serotonin Reuptake Inhibitors: Bioequivalence of Sertraline Capsules

The study was designed to evaluate the bioavailability of two sertraline (CAS 79617-96-2) formulations. A bioequivalence study was carried out in 24 healthy male volunteers, who were administered 50 mg capsules of the test formulation (Seralin) and the originator product (reference) as a single dose. The trial was performed according to an open, randomized, cross-over design with a washout period of 14-20 days in one study center. Blood samples were taken up to 96 h post dose, the plasma was separated and the concentrations of sertraline were determined by HPLC-MS-MS. The mean Cmax were 9.01 +/- 2.26 ng/mL and 8.24 +/- 2.14 ng/mL, while the mean AUC0-t were 259.09 +/- 105.36 ng x h/mL and 234.36 +/- 95.18 ng x h/mL for the test and reference formulations, respectively. The mean AUC0-inf were 292.66 +/- 128.09 ng x h/mL (test) and 267.23 +/- 116.40 ng x h/ mL (reference). The mean tmax was 5.88 +/- 1.03 h for the test capsules and 6.17 +/- 1.66 h for the reference formula. The mean t1/2el was 26.49 +/- 6.45 h for the test formulation and 26.23 +/- 6.64 h for the reference formulation. Mean MRT values for the test and reference formulations were 28.14 +/- 5.37 h and 27.81 +/- 5.13 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence interval for the primary target parameters, intra-individual ratios of AUC0-t and Cmax of sertraline were between 1.03 and 1.19 (AUC0-t) as well as between 1.02 and 1.17 (Cmax) and thus within the acceptance ranges for bioequivalence trials. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences was between -1.00 and 0.50 h. In the light of the present study it can be concluded that sertraline test capsules are bioequivalent to the reference formulation.

Bio equivalence Study of Atorvastatin Tablets

The study was designed to evaluate the relative bioavailability of two formulations of atorvastatin (CAS 134523-03-8). A bioequivalence study was carried out in 24 healthy male volunteers who received four 10 mg tablets of the test formulation (Kolestor) and the same dose of the originator product. The trial was performed according to an open, crossover design with a wash-out period of 7 days in one study center. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of atorvastatin were determined by HPLC-MS-MS method. The mean Cmax were 16.37 ng/mL and 17.05 ng/mL, while the mean AUC0-t were 103.61 ng x h/mL and 102.55 ng x h/mL for the test and reference formulations, respectively. The mean AUC0-inf were 118.10 ng x h/mL and 117.13 ng x h/mL for the test and reference formulations, respectively. The median tmax was 0.67 h for both the test tablet and the reference product. The mean t(1/2 el) was 11.85 h for the test formulation and 13.28 h for the reference formulation. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence intervals for the primary target parameters, intra-individual ratios of AUC0-t and Cmax of atorvastatin, were between 0.85 and 1.05 (AUC0-t) and between 0.84 and 1.23 (Cmax), respectively, and thus within the acceptance ranges. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences was between -0.17 and 0.17 h. In the light of the present study it can be concluded that the two evaluated atorvastatin formulations, i.e. test formulation of atorvastatin and reference preparation are bioequivalent in terms of the rate and extent of absorption.

In vivo Bioequivalence of Oral Antidiabetic Agents: Pioglitazone Tablets

The study was designed to evaluate the bioequivalence of two pioglitazone (CAS 112529-15-4) formulations. The trial was performed in 26 healthy male volunteers with the aim of comparing a new generic product (tablets containing 30 mg pioglit-azone hydrochloride, test) with the originator product (reference). The trial was performed according to an open, crossover design in one study centre. In each of the two study periods (separated by a wash-out of 14 days) a single oral dose of 30 mg (test or reference) formulation was administered. Blood samples were taken up to 120 h post dose, the plasma was separated and the concentrations of pioglitazone and its principal active metabolite hydroxypioglitazone were determined by LC-MS-MS method. AUC0-inf, AUC0-t, Cmax, and Tmax were calculated for both formulations. The mean Cmax of pioglitazone ranged between 1.01 microg/mL and 1.05 microg/mL, while the mean AUC0-inf and AUC0-t ranged between 10.89 microg x h/mL and 10.98 microg x h/mL as well as between 10.56 microg x h/mL and 10.62 microg x h/mL for the test and reference formulations, respectively. The median Tmax for the test tablets was 1.50 h and for the reference was 1.75 h. The ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 99.70%, 100.13% and 99.17%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf were narrow and symmetrical around 100%, i.e. 90.59% to 109.72%, for AUC0-t, 90.69% to 110.55%, whereas for Cmax they were 87.52% to 112.37%. As in the case of pioglitazone, mean values of the principal bioequivalence parameters of hydroxypioglitazone did not differ significantly after administration of the test and reference formulations. In the light of the present study it can be concluded that the two evaluated pioglitazone formulations, i.e. test formulation of pioglitazone hydrochloride and reference formulation, are bioequivalent in terms of the rate and extent of absorption.

Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects

This study investigated the pharmacokinetics, excretion, and metabolism of pamapimod following a single oral dose in healthy male subjects. Nonradio-labeled pamapimod was supplied as bulk powder, [14C]-labeled pamapimod was supplied as ethanol solution. Pamapimod, metabolic synthetic standards, and the internal standard were supplied by Roche. This was an open-label, singledose mass balance study. Healthy male subjects received a single oral dose of 300 mg [14C]-labeled pamapimod. Quantification of pamapimod and metabolites was determined by a validated liquid chromatography/tandem mass spectrometry method (LC/MS/ MS). Urine, blood, and feces were collected for metabolic profiling and radioactivity analysis. Profiling was done using high performance liquid chromatography (HPLC)/ LC/MS/MS. Radioactivity determination was by liquid scintillation counting. Six subjects completed the study. Mean Cmax was 4,120 ng/ml at tmax of 2.8 h, and mean AUCinf was 19,800 ng·h/ml. The t1/2 of pamapimod was 7.2 h. Mean drug recovery was 100 ± 2% by 120 h, of which 76.5% was recovered in urine and 23.9% in feces. Unchanged pamapimod accounted for 15.3% excreta, indicating metabolism is the major elimination pathway. Five metabolites were identified in plasma, urine, and feces. In urine, 41.1% of the dose was excreted as carboxylate metabolite (RO4498496), 19.2% as lactol metabolite (RO4493992), and 12.5% as pamapimod. In feces, 18.5% was excreted as RO4498496, 2.8% as pamapimod. The majority of dose was renally cleared. Urinary and fecal metabolites accounted for > 80% radioactivity. These results indicate hepatic metabolism followed by renal excretion is the major elimination pathway of pamapimod.

Pharmacokinetics and bioequivalence of single dose and multiple doses of immediate- and extended-release formulations of dexibuprofen in healthy Chinese subjects

To compare the pharmacokinetic (PK) profiles and bioequivalence of the extended-release (ER) and immediate-release (IR) formulations of dexibuprofen (DI) in healthy Chinese volunteers after single dose and multiple doses. Zefen® (IR capsule, containing 150 mg DI, Suzhou No.4 Pharmaceutical Factory, Jiangsu, China) and ER capsule (containing 225 mg DI, Tianjin Zhongtian Pharmaceutical Co. Ltd., Tianjin, China). This was an open, randomized, two-period crossover study. Eligible subjects were healthy male Chinese volunteers. 22 subjects were randomly assigned to receive a single 450 mg dose of the test or reference formulation on the first day. During the next 6 days, the test group received a multiple-dose of ER DI capsule (450 mg, b.i.d.) and the reference group took a multiple-dose of IR DI capsule (300 mg, t.i.d.), respectively. Multiple blood samples were collected, and plasma concentrations of DI were analyzed using high performance liquid chromatography (HPLC) system. After a 9-day washout period, the subjects were administered the alternate formulation. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was within accepted limits. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. 21 subjects completed the single dose administration and 20 subjects were evaluable for the multiple doses PK parameters. Single-dose Mean AUC0-t and AUC0-inf for ER formulation were 116.14 ± 21.54 mg·h/l and 117.60 ± 22.27 mg·h/l, and for IR formulation, were 107.25 ± 23.48 mg·h/l and 108.18 ± 23.93 mg·h/l, with the 90% CI within the limits accepted for bioequivalence. Mean Cmax for ER and IR formulations were 22.30 ± 5.17 mg/l and 30.26 ± 13.54 mg/l, respectively. And median tmax for ER and IR formulations were 4.5 h and 2.0 h. The retard quotient (delta R) for ER product was 1.9 ± 0.93, which indicated an intermediate extended release effect. Multiple-dose Mean AUC0-24 for ER formulation was 217.93 ± 41.07 mg·h/l and for IR formulation was 199.33 ± 37.32 mg·h/l. Other PK parameters of ER and IR formulations were as follows: median tmax were 4.8 h and 2.0 h, Css-max were 20.21 ± 2.69 mg/l and 19.71 ± 3.46 mg/l, Css-min were 2.47 ± 0.99 mg/l and 2.48 ± 0.99 mg/l, Cav were 9.08 ± 1.71 mg/l and 8.31 ± 1.56 mg/l, respectively. This study found that in these subjects, the absorption rates of the two DI formulations were not bioequivalent, but at steady state, the daily exposure provided by less frequent DI ER dosing was not significantly different from the same daily dose with DI IR capsules, administered more frequently.

Marqibo® (vincristine sulfate liposomes injection; VSLI) Optimizes the Dosing, Delivery, and Pharmacokinetic (PK) Profile of Vincristine Sulfate (VCR) In Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL)

AbstractAbstract 2142 Background:VCR is an important component of the treatment of ALL, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, and other adult and childhood cancers. In part, because of the cell cycle specific activity of VCR, its anti-cancer activity is believed to be very exposure time and concentration dependent. Standard dosing of conventional VCR (1.4 mg/m2 with a 2 mg cap) is limited because of early onset peripheral neuropathy and fails to achieve sustained VCR delivery. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, prolonged drug delivery and enhanced cancer penetration and concentration. Methods:In a pivotal, Phase 2, multi-national study (RALLY Trial), 65 adults with Philadelphia chromosome negative ALL who were either in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent intravenous VSLI 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. First-dose PK was investigated in a representative subset of 13 study subjects. Blood for analysis was collected at 8 time points ranging from 5 minutes to 48 hours following infusion. Total VCR plasma levels were determined by HPLC-MS/MS. PK parameters were calculated with Phoenix WinNonlin. Results:The PK subject subset had a median body surface area (BSA) of 1.92 m2 (range 1.47 to 2.45 m2) and received a median VSLI dose (VCR component) of 4.32 mg (range 3.3 to 5.51 mg). Based on BSA and the 2 mg dose cap, all subjects in this study group would have been dosed with 2.0 mg of conventional VCR. The median cumulative induction dose of VSLI (VCR component) that was administered in this study was 18.8 mg (range 3.5 to 70.1 mg). Total VCR plasma concentration decreased rapidly from Cmax after the VSLI infusion in 5 subjects (38%); 8 subjects (62%) exhibited a delay of 4 to 10 hours before the total VCR plasma concentration began to decrease. The calculated Tmax was 1.3 ± 0.4 hours (range 1.1 to 2.0 hours). The Cmax was 1214 ± 233 ng/mL (range 919 to 1720 ng/mL). The apparent mean half-life was 7.1 ± 3.2 hours. The mean AUCinf was 13,993 ± 6,588 ng hr/mL with a range from 7,167 to 27,233 ng hr/mL. The mean clearance (CL) was 6.4 ± 2.6 mL/min. The mean volume of distribution (Vd) was 0.051 ± 0.018 L/Kg. There were no significant differences in the PK parameters between the male and female subjects participating in this study. The table below presents VSLI PK parameters in addition to historical PK parameters for conventional VCR dosed at 2 mg. Conclusions:VSLI clearly provides dose intensification and prolonged VCR delivery compared to conventional, non-encapsulated VCR. VSLI, as dosed in this adult ALL clinical trial, delivered individual and cumulative amounts of VCR that exceed those achievable with standard and approved dosing of conventional VCR. This translated into a median dose intensification of 116% (range 65 to 176 percent) calculated as the percent change in VSLI dose from a standard VCR dose. This dose intensification is believed to have contributed to the 35% overall response rate including 20% complete responses (with or without full blood count recovery) reported in this heavily pre-treated, multiply-relapsed/refractory population without apparent enhanced toxicity [J Clin Oncol 28:15s, 2010 (suppl; abst 6507)]. VSLI has a distinctly different PK profile than conventional VCR. The larger VSLI Cmax and AUCinf reflect the dose intensification afforded by a larger mg/m2 dose and lack of dose capping. Even in the absence of dose capping, the 2.25 mg/m2 VSLI dose represents a 61% dose escalation above conventional VCR. While Cmax and AUCinf are dose-dependent PK parameters, the observed differences between VSLI and VCR control cannot be explained by dose alone. The larger AUCinf also reflects prolonged circulation afforded by the sphingomyelin:cholesterol liposome encapsulation. The modest VSLI mean CL and small Vd reflect the retention of encapsulated VCR within the plasma compartment for an extended period of time so that VCR can better penetrate and accumulate in sites of cancer through fenestrated vasculature. The enhanced delivery of encapsulated VCR contributes to maintenance of VCR concentrations above the effective concentration. Disclosures:Silverman: Hana Biosciences: Employment. Deitcher: Hana Biosciences: Employment.

Evaluation of the Single‐ and Multiple‐Dose Pharmacokinetics of Fentanyl Buccal Soluble Film in Normal Healthy Volunteers

Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid-tolerant patients with cancer. This open-label, 3-period, sequential dose study evaluated the dose-to-dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600- or 1800-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg doses administered at 1-hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48-hour period after each single dose of FBSF and 72 hours after the 3-dose regimen. Peak plasma concentrations (mean C(max) = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC(0-12) = 6.3 and 6.2 h.ng/mL; mean AUC(inf) = 9.14 and 9.60 h.ng/mL) were nearly identical after the 2 single doses (P >or= .1, all comparisons). C(max) and overall fentanyl exposure (AUC(inf)) increased approximately 3-fold with the 3-dose regimen compared with the single-dose periods. Fentanyl plasma concentrations following single doses of FBSF were reproducible, and 3 doses administered 1 hour apart produced a tripling in exposure and maximal concentration compared with a single dose.

A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors.

2541 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral pan-inhibitor of the class I PI3K, which demonstrates broad activity in breast, ovarian, lung, and prostate cancer in in vitro and in vivo (xenograft) models. Methods: A phase I dose-escalation study using a 3+3 design was initiated in patients (pts) with solid tumors to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety characteristics of GDC-0941. GDC-0941 was given on day 1, followed by a 1-week (wk) washout to study single-dose PK and PD markers. GDC-0941 was then dosed QD on a 3-wks on, 1-wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with BID dosing was initiated after the third QD cohort. Results: Thirty-six pts have been enrolled in 9 successive dose-escalation cohorts in the QD arm, with dose levels up to 245 mg daily. Twenty-three pts have been enrolled in 8 cohorts in the BID arm at total daily doses (TDD) up to 180 mg daily. Day 1 and day 15 PK data suggest GDC-0941 is rapidly absorbed and displays dose-proportional increases in mean Cmax and AUC0-inf, with a mean apparent half-life that supports either QD or BID dosing regimens. The most frequently reported drug-related adverse events were grade (Gr) 1–2 nausea, fatigue, diarrhea, and dysgeusia. Three dose-limiting toxicities have been reported: Gr 3 headache at 80 mg QD, Gr 3 pleural effusion at 80 mg TDD, and Gr 3 decreased DLCO at 180 mg TDD . A partial response has been observed in one breast cancer pt (130 mg QD) by RECIST. Other signs of anti-tumor activity have also been observed in 3 ovarian pts: one (30 mg BID) was on-study >450 days with a best response of 23% decrease in measured disease and 2.8-fold decrease in CA-125, the second (60 mg QD) was on-study >170 days with stable disease (SD) and the third (130 mg TDD) was on study for >230 days with SD. Analysis of archival tissue for PI3K pathway alterations is ongoing. Conclusions: GDC-0941 is generally well tolerated, with signs of antitumor activity. Preliminary PK data suggest dose-proportional increases in exposure across the dose levels evaluated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche Genentech

A Comparative Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of Azacitidine Following Subcutaneous (SC) and Oral Administration in Subjects with Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML), Results From a Phase 1 Study.

Abstract 1772Poster Board I-798 BackgroundParenteral azacitidine significantly improves overall survival in patients with higher-risk MDS and WHO AML (20-30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009;10:223). An oral azacitidine formulation is in development. A Phase 1, “3+3”, dose-escalation study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, PK and PD profiles of SC and increasing doses of orally-administered azacitidine in subjects with MDS or AML (not candidates for other therapies) by WHO criteria. In this study, each subject served as their own control and received SC azacitidine in Cycle 1 followed by oral azacitidine in subsequent cycles (Cycle 2+). PK and PD were evaluated in blood, following SC and oral administration. DNA methylation patterns in blood pre- and post-treatment (SC and oral) were explored to build an understanding of how DNA methylation may relate to azacitidine PK parameters. MethodsAzacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. PK parameters were derived from azacitidine concentrations in plasma and urine collected after the first and last dose. Samples collected in Cycles 1 and 2 were assayed for DNA methylation using Illumina's Infinium Human Methylation27 BeadArrays, which provide methylation levels for >27,000 CpG loci. A linear models for microarray analysis (LIMMA) was performed to identify loci that were differentially methylated from baseline versus (vs.) each post-treatment timepoint across subjects. To identify loci whose methylation levels were modulated in relation to azacitidine PK parameters, Spearman's correlation coefficients were computed for azacitidine exposure (AUCinf) or peak plasma concentration (Cmax) vs. the fold change in methylation at Day 15 for each locus across subjects. ResultsTo date, PK data have been generated for 31 of 45 enrolled subjects. Oral doses evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. Following SC and oral administrations, azacitidine was rapidly absorbed and reached Cmax within 0.5 hr (0.2, 1.1) and 1.0 hr (0.5, 2.5) post-dose (median [min, max]), respectively. The concentration vs. time profiles declined in a pseudo bi-phasic manner, with a mean elimination half-life of 1.8 ± 1.1 hr and 0.74 ± 0.28 hr for SC and oral, respectively. For SC azacitidine, mean AUCinf = 1090 ± 470 hr*ng/mL, mean apparent total clearance (CL/F) = 170 ± 130 L/hr, and mean apparent volume of distribution (Vd/F) = 445 ± 450 L. Following either SC or oral treatments, azacitidine recovery in urine was very small relative to dose (<2%). The median (min, max) relative oral bioavailability was 13% (5%, 35%) and the median (min, max) exposure (AUCinf) of oral azacitidine compared to SC was 31% (14%, 74%) (except for 1 subject whose oral exposure was 167% SC). CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism; Vd/F was 9- to 11-fold greater than total body water suggesting extensive tissue distribution. To date, PD data have been generated for 8 and 3 subjects during SC and oral treatment, respectively. The numbers of significantly (p<0.010) hypomethylated loci peaked at Day 15 of Cycle 1 (SC) with over 4000 loci hypomethylated and at Day 15 of Cycle 2 (oral) with less than 300 loci hypomethylated vs. either baseline or Day 1 of Cycle 2. Approximately 260 hypomethylated loci are common to both groups. Spearman correlation analyses showed that DNA hypomethylation for 252 and 98 loci were correlated (r>0.8) with Day 1 SC and oral azacitidine AUCinf and Cmax, respectively. ConclusionFollowing oral administration, azacitidine demonstrated increased exposure with increasing dose. At dose levels tested to date, oral exposures are lower than SC. Non-renal clearance (hepatic and extra-hepatic) is the major elimination pathway with renal elimination playing a minor role. Changes in DNA methylation were observed in the blood of MDS/AML subjects following SC and oral azacitidine treatment, and a set of CpG loci was identified for which these changes were associated with AUCinf and/or Cmax. PK/PD correlations identified in these initial subjects will be further explored. The lower exposures and PD effects observed with oral vs. SC azacitidine on a 7-day schedule provide rationale for testing extended schedules and BID dosing in future trials. DisclosuresMacBeth:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ning:Celgene: Employment, Equity Ownership. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Skikne:Celgene: Employment. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Ward:Celgene: Employment, Equity Ownership.

Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity

The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUC(inf)) was 4.28 +/- 0.536 microgxh/mL, and mean elimination half-life (t(1/2)) was 44.9 +/- 4.67 h, with a large volume of distribution (V(ss)) of 24.9 +/- 2.99 L/kg and a high clearance rate (Cl(obs)) of 712 +/- 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUC(inf) values were 4.55 +/- 0.690, 9.42 +/- 1.11 and 12.2 +/- 1.13 microgxh/mL, respectively, and the mean elimination half-lives (t(1/2)) were 51.2 +/- 6.10, 50.8 +/- 3.80 and 58.5 +/- 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6-112%) after s.c. administration. No statistically significant (alpha = 0.05) gender differences in the AUC(Inf) or elimination half-life values were observed. Dose proportionality was established based on AUC(Inf) over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day ( approximately 24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUC(inf) was 194 times higher than the corresponding plasma AUC(inf). The apparent elimination half-life for gamithromycin in lung was 90.4 h ( approximately 4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 +/- 0.60% bound over a range of 0.1-3.0 microg/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease.

Axitinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors

3559 Background: AG is an oral, potent and selective inhibitor of VEGFRs 1, 2, 3. Anti-VEGF therapies combined with chemotherapy improve survival vs chemotherapy alone in pts with advanced solid tumors, including NSCLC. This phase I trial assessed AG combined with chemotherapy. Methods: Pts with advanced solid tumors without prior treatment with platins or taxanes received paclitaxel/carboplatin (P: 200 mg/m2 / C: AUC 6 mg*min/mL) every 3 weeks + AG at lead-in doses of 1, 3 or 5 mg BID. AG was increased to 5 mg BID post lead-in. Another cohort of pts with any prior chemotherapy for metastatic disease received AG 5 mg BID + gemcitabine/cisplatin (G: 1250 mg/m2 on days 1 and 8 / Cis: 80 mg/m2 on day 1) in 3-week cycles. For all cohorts, cycle 1 consisted of a 3–5-day lead-in period followed by AG for 18 days. On day 19, AG was held and then continued without interruption on day 3, cycle 2. Following determination of the maximum tolerated doses (MTDs) of AG + P/C or G/Cis, pts with squamous NSCLC were enrolled into an expansion cohort (prior anti-VEGF therapy not permitted) and received AG 5 mg BID + P/C. Dose-limiting toxicities (DLTs), adverse events (AEs), objective response rate (ORR), and pharmacokinetics (PK) were evaluated. Results: A total of 47 pts were enrolled; 26 pts were evaluable in the P/C cohort (including 12 pts with squamous NSCLC) and 21 pts in the G/Cis cohort. The MTD for AG in combination with standard doses of P/C and G/Cis was 5 mg BID. DLTs included fatigue, proteinuria and rash (1 each). Treatment-related AEs included hypertension (42%), diarrhea (35%) and fatigue (35%) in the P/C cohort, and headache (29%), hypertension (29%) and fatigue (24%) in the G/Cis cohort. There was no grade ≥3 hemoptysis among 12 pts with squamous NSCLC. The ORR was 29% and 26% for P/C (n = 24) and G/Cis (n = 19) cohorts, respectively. AG, P, C, G and Cis PK parameters and profiles were similar when administered alone and in combination (eg P: mean (%CV) AUCinf 20,822 (21) and 20,596 (21) ng.h/mL, respectively). Conclusions: AG 5 mg BID can be combined with standard P/C and G/Cis regimens with no apparent overlapping toxicities and unaltered PK. Both combinations have antitumor activity. In pts with squamous NSCLC, AG + P/C was well tolerated with no evidence of grade ≥3 hemoptysis. [Table: see text]

Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs

To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation beta1-adrenoceptor-selective blocking agent, with those of carvedilol, a third-generation beta1/beta2 and alpha1-adrenoceptor blocking agent, in dogs. 12 healthy adult Beagles. A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed. After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 microg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 microg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 microg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 microg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol. After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of MAP0004 (orally-inhaled DHE) in adult asthmatics

ABSTRACTBackground: MAP0004 (a proprietary formulation of dihydroergotamine mesylate [DHE]) for inhaled delivery is being developed for acute migraine treatment. Because asthma and migraine often occur as co-morbid conditions, it is considered important to study the safety of MAP0004 in a population of asthmatic adults and to confirm that the pharmacokinetics of DHE, when inhaled by asthmatic subjects, were comparable to a population of healthy volunteers. The safety, tolerability, and pharmacokinetics of orally-inhaled MAP0004 administered by the Tempo inhaler were studied in adult asthmatics.Scope: This was a randomized, double-blind, placebo-controlled study of two doses of inhaled MAP0004. Eligible subjects were randomized in a 2 : 1 ratio to MAP0004 or placebo and observed for 4 h after each dose. Pharmacokinetic parameters were determined pre-dose and up to 36 h post-dose.Findings: Among 19 subjects, geometric mean AUC0–36 was 6754 pg·h/mL and geometric mean AUC0–inf was 7483 pg·h/mL. Geometric mean tmax was 9.6 min, geometric mean Cmax was 3174 pg/mL, and geometric mean t½ was 9.5 h. Overall, 13 of 19 (68%) subjects reported at least one adverse event, most commonly nausea, vomiting, dysgeusia, and headache.Conclusion: MAP0004 results in rapid and efficient systemic absorption in asthmatic subjects. Systemic DHE concentrations were similar to those previously reported in healthy subjects, and no clinically relevant safety issues were observed. While this small study was suitable for pharmacokinetic analysis and conclusions, MAP0004 use in migraineurs with concomitant stable asthma should be supported by larger studies of longer duration to confirm that it does not present additional safety risks compared to non-asthmatic migraineurs.

Axitinib (AG-013736) in combination with FOLFOX and bevacizumab (Bev) in patients (pts) with metastatic solid tumors: A phase I study

4112 Background: Axitinib is an oral, potent and selective inhibitor of VEGF receptors 1, 2, and 3 that is being assessed in a broad range of tumors. This phase I portion of the study evaluated the safety and pharmacokinetics (PK) of axitinib in combination with BV and FOLFOX (oxaliplatin/5-fluorouracil [5-FU]/leucovorin) in pts with previously treated gastrointestinal and solid tumors. Methods: Pts in cohort 1 received BV 1 mg/kg, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 bolus then 2,400 mg/m2 by 46–48 h infusion, and axitinib at a starting dose of 5 mg PO BID. BV and FOLFOX were administered once every 2 weeks. Following demonstration of tolerability to BV 1 mg/kg in cohort 1, BV was escalated to doses of 2 mg/kg and 5 mg/kg in cohorts 2 and 3 respectively. Patients were evaluated for potential PK interactions between BV, FOLFOX, and axitinib. Safety and tumor response were also assessed. Results: Among pts enrolled in cohorts 1, 2, and 3 (n=15), 2 patients (13%) showed a partial response and 9 patients (60%) exhibited stable disease. The most frequently reported, treatment-emergent grade 3–5 adverse events were neutropenia (n=3), hypertension (n=3), and dyspnea (n=2). PK parameters and plasma profiles of BV, oxaliplatin, and 5-FU were similar in the presence or absence of axitinib, with mean (%CV) AUCinf for platinum clearance from ultrafiltrate of 7,155 ng.h/mL (74%) and 7,702 ng.h/mL (72%), respectively (n=14). Axitinib PK profiles were similar in the presence or absence of BV/FOLFOX. Conclusions: PK data indicate no evidence of an interaction between axitinib and BV/FOLFOX. Axitinib 5 mg BID in combination with BV 1 mg/kg or 2 mg/kg and FOLFOX was well tolerated. Tolerability data for combination treatment with the 5 mg BV dose await completion of patient enrollment into cohort 3. A 3-arm, randomized phase II study of axitinib/FOLFOX vs BV/FOLFOX vs axitinib/BV/FOLFOX in pts with metastatic colorectal cancer has been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer