Mean Terminal Phase Half-life Research Articles

A Single- and Multiple-Dose Pharmacokinetic Study of Oral Perampanel in Healthy Chinese Subjects.

Perampanel is a once-daily oral anti-seizure medication indicated for focal-onset seizures and generalized tonic-clonic seizures. This study investigated the single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults. Study 052 (NCT03424564) was a phase I, single-center, open-label, parallel-group study. In the single-dose part of the study, subjects received a single oral dose of perampanel 2, 4, or 8 mg. In the multiple-dose part, subjects received once-daily oral perampanel 2 mg on Days 1-7 and 4 mg on Days 8-21. Pharmacokinetic parameters were determined from perampanel plasma concentrations using non-compartmental analysis. Dose proportionality after single doses of perampanel was assessed. Safety and tolerability were evaluated. In the single-dose part (N=30), median time to reach maximum concentration (tmax) was 0.75-1.0h, mean terminal elimination phase half-life (t½) was 85.6-122h, mean maximum observed concentration (Cmax) was 77.9-276 ng/mL, and mean area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) was 4070-15100 ng·h/mL. Single-dose pharmacokinetics were linear for perampanel 2-8 mg. In the multiple-dose part (N=12), Day 21 steady-state (4 mg/day) parameters were median time at which the highest drug concentration occurs at steady state (tss,max), 1.25h; mean t½, 109h; mean maximum observed concentration at steady state (Css,max), 453ng/mL; and mean area under the concentration-time curve over the dosing interval on multiple dosing (AUC(0- τ)), 7540 ng·h/mL. For single- and multiple-dose perampanel, the most common treatment-emergent adverse events were dizziness and somnolence. Single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults revealed rapid perampanel absorption, slow elimination, and a linear relationship with single perampanel doses of 2-8 mg. Findings were consistent with previous studies of perampanel pharmacokinetics in other ethnic/racial populations of healthy subjects. Single and multiple doses of perampanel were generally safe and well tolerated. NCT03424564; registered February 2018.

Pharmacokinetics and Safety of Vedolizumab Following Administration of a Single Intravenous Dose in Healthy Chinese Subjects.

Vedolizumab is a humanized monoclonal antibody, indicated for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), that specifically binds to the α4β7 integrin. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of vedolizumab following a single intravenous (IV) infusion in healthy adult Chinese subjects. Sixteen participants received a single IV infusion of vedolizumab (300mg). Blood samples were collected to measure vedolizumab serum concentrations. The safety of all subjects was monitored. The pharmacokinetic analysis showed that vedolizumab reached the maximum observed serum concentration (Cmax) at approximately 1.32hours. The mean Cmax and area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC0-t) and to infinity (AUC0-∞) were 137.25µg/mL, 2360days·µg/mL, and 2395days·µg/mL, respectively. The elimination of vedolizumab was relatively slow, with a mean terminal disposition phase half-life elimination (t1/2) of 20.23days. Six subjects were positive for anti-vedolizumab antibodies (AVAs) on day 106 and day 127. Finally, 4 out of 16 subjects (25.0%) had treatment-emergent adverse events (TEAEs), all of which were upper respiratory tract infections. Vedolizumab was well tolerated in healthy Chinese subjects when administered as a single-dose IV 300mg infusion. In this study, the rate of AVA positivity was 37.5%, which occurred near the end of the study; no significant differences in pharmacokinetic profiles were observed between the AVA-positive and AVA-negative groups. http://www.chinadrugtrials.org.cn : CTR20171528.

Abstract P1-18-16: A phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer

Abstract Background: ARX788 is a novel site-specific antibody drug conjugate (ADC) that consists of a human epidermal growth factor receptor 2 (HER2) targeting monoclonal antibody (mAb) linked to the cytotoxic payload AS269, a highly potent tubulin inhibitor. Through a proprietary technology, a non-natural amino acid is precisely incorporated into the pre-determined site on the heavy chain of the mAb, and AS269 is specifically conjugated to the non-natural amino acid. In the first-in-human study in Australia/New Zealand (NCT02512237), delayed drug-induced pneumonitis, which occurred after 4-5 cycles of administration, were observed in participants at dose levels of 1.3 mg/kg Q3W or higher. Here, we present results of a phase I study (CTR20171162) to evaluate safety, pharmacokinetics, and preliminary antitumor effect of ARX788 in Chinese patients with metastatic HER2-positive breast cancer, with special focus on the delayed pneumonitis. Methods: Patients with metastatic HER2-positive breast cancer received intravenous ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, 1.5 mg/kg Q3W or 0.88, 1.1, 1.3 mg/kg Q4W. The DLT assessment period was set to be 21 days in 0.33, 0.66 mg/kg Q3W cohorts, and additional 63 days (total 84 days) in other dose cohorts for the pulmonary toxicity. Dose cohorts were expanded at 1.1 and 1.3 mg/kg Q3W. Safety and tolerability were assessed by monitoring adverse events (AEs) and antitumor effects were evaluated according to the RECIST v1.1 criteria. Pulmonary toxicity of special interest was assessed every 2 cycles of therapy by CT imaging. Serum concentrations of ARX788 ADC, total antibody, and metabolite pAF-AS269 were measured and PK parameters were calculated. Results: As of 3 July 2019, 45 female Chinese participants with age range from 30 to 67 received ARX788, with 31 of whom had been treated for at least 84 days. No dose-limiting toxicities and treatment-related serious adverse events were observed. Serious blood and liver toxicity that are commonly associated with ADCs were rarely observed (only one participant experienced Grade 4 neutrophil count decreased on cycle 18 and none for ≥Grade 3 liver toxicity). Adverse events that required special attentions were ocular and pulmonary toxicity. Ocular events were mostly mild to moderate in severity and were reversible. Three participants experienced Grade 2 drug-related pneumonitis observed on days 130, 172 and 224, all of whom resolved after steroid treatment and re-started ARX788 treatment with dose reduction. ARX788 ADC serum exposure increased with dose increment and the mean terminal phase half-life ranged between 2.3 and 4.9 days. Among 42 evaluated participants, the overall response rate was 31% (13/42) and 42% (5/12) in 1.3 mg/kg Q3W cohort. One participant in 0.88 mg/kg Q3W cohort has undergone the treatment for more than 17 months. Conclusions: ARX788 was well tolerated in heavily-pretreated patients with HER2-positive metastatic breast cancer without evidence of Grade 3 or greater pneumonitis. Encouraging overall response rate was observed in 1.3 mg/kg Q3W cohort. Considering the predicted benefit/risk profile, 1.3 mg/kg Q3W is the recommended dose for further development of ARX788 in HER2-positive breast cancer. Citation Format: Xichun Hu, Jian Zhang, Dongmei Ji, Gang Xia, Yanping Ji, Gaozhun Xiong, Xuejun Liang. A phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-16.

Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling.

Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration–time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2–2.7 m2), sex, age (23–91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0526-4) contains supplementary material, which is available to authorized users.

Absorption and disposition of florfenicol after intravenous, intramuscular and subcutaneous dosing in alpacas

The objectives of this study were to define disposition and systemic availability of florfenicol in alpacas. Administration of 20 mg/kg doses to 8 male alpacas by i.v., i.m. and s.c. routes was performed by randomized, 3-way crossover design. Clearance and steady state volumes (Vdss) after i.v. injection were 5 ml/min/kg and 775 ml/kg respectively. Mean residence time (MRT) and terminal phase half-life (T1/2λz) were 2.8 h and 2 h respectively. Maximum serum concentrations (Cmax) after i.m. were higher than s.c. administration (p = 0.034). After s.c. dosing, T1/2λz and MRT were greater than after i.m. injection (p < 0.001; p = 0.006 respectively). Mean absorption time (MAT) after s.c. dosing was also prolonged (p = 0.006). Fractional absorption of florfenicol after i.m. and s.c. was not different (p > 0.05). Serum florfenicol concentrations remained >1.0 µg/ml for 20 h after i.m. dosing. Differences in rate and extent of florfenicol absorption after extravascular dosing could influence therapeutic outcomes.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans

Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg (14)C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (±3.6), with 80.1% (±3.6) in the urine (28.8% parent), and 13.8% (±1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies.

A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma

This study characterized the multiple-dose pharmacokinetics of vemurafenib 240-960 mg twice daily (bid) in BRAF(V600E) mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets). Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2. Vemurafenib concentration increased with multiple doses to steady state at day 15; C(max), AUC(0-8h), and AUC(0-168h) increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240-960 mg bid. Day 15 mean accumulation ratios (ratio of AUC(0-8h) on day 15/AUC(0-8h) on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration-time profile throughout the bid dosing interval. During dose interruption (days 15-22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5-38.4 h. Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C(max)) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

A Phase I, Open-Label Study of Siltuximab, an Anti–IL-6 Monoclonal Antibody, in Patients with B-cell Non-Hodgkin Lymphoma, Multiple Myeloma, or Castleman Disease

To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.

Duration of Maternal Antibodies against Canine Distemper Virus and Hendra Virus in Pteropid Bats

Old World frugivorous bats have been identified as natural hosts for emerging zoonotic viruses of significant public health concern, including henipaviruses (Nipah and Hendra virus), Ebola virus, and Marburg virus. Epidemiological studies of these viruses in bats often utilize serology to describe viral dynamics, with particular attention paid to juveniles, whose birth increases the overall susceptibility of the population to a viral outbreak once maternal immunity wanes. However, little is understood about bat immunology, including the duration of maternal antibodies in neonates. Understanding duration of maternally derived immunity is critical for characterizing viral dynamics in bat populations, which may help assess the risk of spillover to humans. We conducted two separate studies of pregnant Pteropus bat species and their offspring to measure the half-life and duration of antibodies to 1) canine distemper virus antigen in vaccinated captive Pteropus hypomelanus; and 2) Hendra virus in wild-caught, naturally infected Pteropus alecto. Both of these pteropid bat species are known reservoirs for henipaviruses. We found that in both species, antibodies were transferred from dam to pup. In P. hypomelanus pups, titers against CDV waned over a mean period of 228.6 days (95% CI: 185.4–271.8) and had a mean terminal phase half-life of 96.0 days (CI 95%: 30.7–299.7). In P. alecto pups, antibodies waned over 255.13 days (95% CI: 221.0–289.3) and had a mean terminal phase half-life of 52.24 days (CI 95%: 33.76–80.83). Each species showed a duration of transferred maternal immunity of between 7.5 and 8.5 months, which was longer than has been previously estimated. These data will allow for more accurate interpretation of age-related Henipavirus serological data collected from wild pteropid bats.

Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors

PurposeTo evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)—a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein—in Japanese patients, we conducted a phase 1, dose escalation study.MethodsEligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles.ResultsFrom June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012).ConclusionTrebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.

Pharmacokinetic profile of SKP‐1041, a modified release formulation of zaleplon

Two investigations aimed to define the pharmacokinetic profile of a modified-release preparation of zaleplon (SKP-1041). Protocol SOM001 was a 5-way crossover, double-blind, randomized trial comparing three novel modified-release formulations of zaleplon 15 mg (SKP-1041A, SKP-1041B, SKP-1041C) to placebo and immediate-release zaleplon 10 mg. Protocol SOM002 was a randomized, crossover, open-label trial to compare the pharmacokinetics of SKP-1041B after day and night administration. In SOM001, study drug was administered at 9:00 a.m. (fasted); blood samples were obtained beginning 1 h predose through 12 h postdose. In study SOM002, study drug was administered at 9:00 a.m. or 10:30 p.m.; blood samples were obtained beginning 1 h predose through 12 h postdose. Subjects were 19 (SOM001) and 23 (SOM002) healthy adults between ages 20-46. Dose-normalized total AUCs for modified-release preparations A, B, C and immediate-release zaleplon were not significantly different; peak plasma concentrations were similar for A and B, and both were significantly higher than C. Time to peak plasma concentration for A, B, and C were 4-5 h compared to 1.5 h for immediate-release zaleplon; mean terminal phase half-life was in the range 1-2 h for A, B and immediate-release zaleplon. No significant differences were noted between day and night administration in the SOM002 study. Zaleplon, 15 mg, in a novel, modified-release formulation (SKP-1041) had a time to peak plasma concentrations at 4-5 h postdose compared to 1.5 h for immediate-release zaleplon, 10 mg. The pharmacokinetic profile suggests this formulation may be useful for treating middle-of-the-night awakening.

Relative bioavailability of trimeprazine tablets investigated in man using HPLC with electrochemical detection.

The stability, partition coefficient, plasma protein binding, red blood cell distribution, and whole blood concentrations of trimeprazine were investigated. Trimeprazine solution was stable for 6 months at -20 degrees C and 3.5 months at 40 degrees C. In whole blood trimeprazine was stable for 5 weeks at -20 degrees C, 24 h at 4 degrees C, 4 h at 25 degrees C and 1 h at 37 degrees C. The apparent hexane-water partition coefficient varied from 1.50 (at pH 4.83) to over 100 (at pH 10.54). The fraction bound to plasma protein exceeded 0.9 as estimated by equilibrium dialysis with correction for volume shift. The mean plasma/red blood cell concentration ratio was 1.17 and the mean red blood cell/plasma distribution coefficient was 8.65. Six healthy adult males received single 5 mg doses of trimeprazine in a syrup (5 mg in 10 ml) and tablets with at least two weeks between doses. Blood was collected for 48 h. The mean (+/- s.e.m.) times for peak blood concentrations were 3.5 +/- 0.22 h for the syrup and 4.5 +/- 0.43 h for the tablets. There were no significant differences in Cmax values. The overall mean (+/- s.e.m.) terminal phase half-life was 4.78 +/- 0.59 h. Mean (+/- s.e.m.) areas under the concentration time curves from 0 to infinity (AUC infinity) were 11.0 +/- 1.99 ng h-1 ml-1 and 7.67 +/- 1.05 ng h-1 ml-1 for syrup and tablets, respectively. The mean relative bioavailability for the tablets was approximately 70% with respect to the syrup.

Pharmacokinetics and Pharmacodynamics of Mepolizumab, an Anti-Interleukin-5 Monoclonal Antibody

Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.

Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects. In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of 0.1-100 mg or placebo (n = 25) and 30-400 mg or placebo (n = 13). Absorption of ticagrelor was rapid [median time to peak plasma concentration (t(max)) 1.3-2 h], as was the formation of its main (active) metabolite, AR-C124910XX (t(max) 1.5-3 h). For both ticagrelor and AR-C124910XX, the peak plasma concentration (C(max)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased in an apparently dose-proportional manner over the dose range studied, indicating linear pharmacokinetics. The mean terminal-phase half-life (t(1/2)) was approximately 7-8.5 h for ticagrelor and 8.5-10 h for AR-C124910XX; AR-C124910XX exposure was approximately one third that of ticagrelor. Inhibition of platelet aggregation (IPA) was dose related and was nearly complete at 2 h (mean 88-95%; final extent, with 20 microM adenosine diphosphate ADP) at doses of 100-400 mg. Linear and predictable pharmacokinetics of ticagrelor and AR-C124910XX were observed. A consistent and high IPA was maintained over 2-12 h, gradually decreasing with declining plasma concentration starting around 12 h post-dose, indicating that the IPA is reversible. Ticagrelor was well tolerated, with no serious or dose-related adverse events or notable changes in laboratory values observed.

Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.

The pharmacokinetics of factor VIII replacement therapy in preschool previously treated patients (PTPs) with hemophilia A have not been well characterized. To assess the pharmacokinetics, efficacy and safety of a plasma-free recombinant FVIII concentrate, ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method, rAHF-PFM], in children < 6 years of age with severe hemophilia. Fifty-two boys, one girl, mean (+/- SD) age 3.1 +/- 1.5 years and >or= 50 days of prior FVIII exposure, were enrolled in a prospective study of ADVATE rAHF-PFM at 23 centers. The mean terminal phase half-life (t(1/2)) was 9.88 +/- 1.89 h, and the mean adjusted in vivo recovery (IVR) was 1.90 +/- 0.43 IU dL(-1) (IU kg(-1))(-1). Over the 1-6-year age range, t(1/2) of rAHF-PFM increased by 0.40 h year(-1). IVR increased by 0.095IU dL(-1)(IU kg(-1))(-1) (kg m(-2))(-1) in relation to body mass index (BMI). Patients primarily received prophylaxis. Median (range) annual joint bleeds were 0.0 (0.0-5.8), 0.0 (0.0-6.1) and 14.2 (0.0-34.5) for standard prophylaxis, modified prophylaxis and on-demand treatment, respectively. Bleeds were managed in 90% (319/354) of episodes with one or two rAHF-PFM infusions; response was rated excellent/good in 93.8% of episodes. Over a median 156 exposure days, no FVIII inhibitors were detected and no related severe adverse events or unusual non-serious adverse events were seen. Children < 6 years of age appear to have shorter FVIII t(1/2) and lower IVR values than older subjects. However, these parameters increased with age (t(1/2)) and BMI (adjusted IVR), respectively. rAHF-PFM was clinically effective and well tolerated, with no signs of increased immunogenicity in previously treated young children with hemophilia A.

Dasatinib (SPRYCEL®) in Children and Adolescents with Relapsed or Refractory Leukemia: Preliminary Results of the CA180018 Phase I/II Study.

Leukemia is the most common type of cancer in pediatric patients (pts). Treatment options for Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) include: risk-adapted chemotherapy, imatinib (im) and stem cell transplant (SCT). Relapsed leukemia has few therapeutic options. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, KIT, and SRC kinases that was recently granted approval for adults with CML, and Ph+ ALL with resistance or intolerance to prior therapy. CA180018 is the first trial evaluating dasatinib in pediatric patients pts and Ph+ and in Ph- leukemias. CA180018 is a phase I/II dose-finding study of dasatinib in pts aged 1–20 with CML or relapsed Ph+ ALL resistant or intolerant to im, or Ph- ALL or AML in ≥2nd relapse performed in collaboration with 12 centers (6 countries) from the ITCC Consortium. Preliminary data are available on the first 15 pts treated from March-July 2006 (2 chronic phase (CP) CML, 7 Ph+ ALL, 1 accelerated phase (AP) CML, 3 Ph- ALL, and 2 Ph- AML) at a starting dose of 60 mg/m2 daily (course = 3 weeks). Intra-patient dose escalation was allowed for lack of initial response, and a 3+3 design for maximum tolerated dose (MTD) determination. Hematologic, cytogenetic, and molecular responses, as well as plasma and cerebrospinal fluid (CSF) pharmacokinetic (PK) analysis and BCR-ABL mutational analysis are ongoing. Median age was 11 yrs (range 4–17), median time from diagnosis of leukemia was 19.5 months (range 1.4–89.9). Prior therapy included chemotherapy, im, and stem cell transplant. Median duration on study is 0.69 month (range 0.03–3.45). Intra-patient dose escalation to 80 or 100 mg/m2 occurred in 7 pts. Six pts remain on study. There have been 7 responders: 4 complete hematologic responses (CHR): 1 CP CML, 1 AP CML, 2 Ph+ ALL; 5 cytogenetic responses (CyR): 2 Ph+ ALL complete CyR (CCyR), 1 AP CML CCyR, 1 CP CML partial CyR (PCyR), 1 Ph+ ALL minor CyR who never achieved a CHR, and then progressed; and 2 Ph+ ALL pts with CNS disease who cleared the CSF of leukemic blasts with single agent dasatinib. Preliminary PK in 7 pts showed rapid absorption with a median Tmax of 1.0 h, and mean terminal phase half-life (SD) of 2.7 (1.1) h. There is one dose-limiting toxicity (DLT): grade 4 anaphylactic shock which occurred 5 hours after the first dose. Dasatinib has otherwise been well tolerated up to 100 mg/m2 with toxicities including grade 3/4 thrombocytopenia, and sepsis. Nine pts are off study: 8 for progressive disease (2 Ph+ ALL pts with a resistant T315I BCR-ABL mutation), and 1 DLT. These preliminary results provide evidence supporting the safety and efficacy of dasatinib in pediatric pts with relapsed or refractory leukemia. An updated analysis including further enrollment, safety data, PK, cytogenetic and molecular responses, and mutational analyses will be presented.

Single-Dose Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitor, in HIV-Infected Children

A phase I, open-label, dose-escalating trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of single, oral doses of amprenavir (141W94), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, in 20 HIV-infected children 4 to 12 years of age. The doses of amprenavir evaluated, 5, 10, 15, and 20 mg/kg of body weight, were comparable to those evaluated in adult phase I and II studies. The most common clinical adverse event associated with amprenavir, administered as soft gelatin capsules, was nausea. Amprenavir was rapidly absorbed, with a mean time to maximum concentration (T(max)) occurring 0.95 to 1.58 h after dosing. The area under the concentration-time curve (AUC(0)(-->)(infinity)) was dose proportional, and the mean maximum plasma concentration (C(max)) increased linearly in a less than dose-proportional manner. Amprenavir was eliminated relatively slowly, with a mean terminal-phase half-life (t(1/2)) of 6.17 to 8.28 h. The t(1/2), apparent total clearance, and apparent volume of distribution during the elimination phase were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters of amprenavir. The results of this study suggest that 20 mg of amprenavir/kg administered twice a day should be used in future pediatric studies.

Phase I dose-escalation study of the highly potent VEGF receptor kinase inhibitor, AZD2171, in patients with advanced cancers with liver metastases

3055 Background: Antiangiogenic therapy is a promising strategy to inhibit tumor growth and the formation of metastases. Vascular endothelial growth factor (VEGF) is a key proangiogenic factor essential for the development of new tumor blood vessels. AZD2171 is an orally available, highly potent inhibitor of VEGF receptor tyrosine kinase that has been assessed in a Phase I study of patients with advanced cancer and liver metastases. This study was designed to evaluate the safety and tolerability of ascending doses of AZD2171. Additional assessment of pharmacokinetics (PK), surrogate markers of activity and antitumor effects was also made. Methods: Cohorts of three patients received a single oral dose of AZD2171 (0.5, 1, 2.5, 5 or 10 mg p.o.) followed by a 7-day washout period and then received daily dosing at the same dose for a total of 28 days. Further 28-day treatment cycles were administered until a withdrawal criterion was met. Results: To date, 16 patients with advanced cancers and liver metastases (9 female, 7 male, median age 57 years) have been treated with AZD2171. Preliminary PK data indicate that AZD2171 is rapidly absorbed with a median time to maximal plasma concentration of 3.0 hours and a grand arithmetic mean terminal phase half-life of 20 hours. The exposure observed following continuous once-daily dosing for 28 days was entirely consistent with the terminal phase half-life obtained after a single oral dose. The PK profile appears to be linear following single and multiple doses. Treatment was well tolerated at the dose levels evaluated and the MTD has not been established. In the 10 mg cohort, one patient developed CTC grade 2 dizziness. No other drug-related toxicities have been observed. Conclusion: Continuous, once-daily, oral treatment with the highly potent VEGF receptor tyrosine kinase inhibitor, AZD2171, was well tolerated in this ongoing Phase I study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; ProQinase AstraZeneca

A dose-escalation study of the quinoxaline antitumor agent R(+)XK469 (XK) in patients with refractory solid tumors

2021 Background: XK is a member of the quinoxaline family of antitumor agents. COMPARE analysis of cytotoxicity data from the NCI-60 cell line screen showed that its mechanism of action is not comparable to that of any marketed cytotoxic agent. In vitro studies suggest that the antitumor activity of XK may be due to inhibition of topoisomerase IIβ, induction of G2-M cell cycle arrest by p53-dependent and mitogen-activated protein (MAP) kinase pathways, and/or pro-apoptotic interactions with the peripheral benzodiazepine receptor. Methods: XK was administered as a 30-minute intravenous infusion for 5 days at 15, 30, 60, 120, and 240 mg/d and every other day for 3 doses at 360, 540, 675, 850, 1100, and 1400 mg/d, repeated every 21 days. The dosing schedule was changed when pharmacokinetic (PK) analysis revealed a long half-life. Results: To date 42 pts (21 male/21 female, median age 60, median Karnofsky performance status 90%) have been treated at 11 dose levels. The principle site of toxicity has been bone marrow. Grade 3 anemia and thrombocytopenia have been observed at 1100 and 1400 mg. Grade 4 neutropenia on the scheduled day 1 of cycle 2 and fever in the setting of grade 4 neutropenia have been the only dose-limiting toxicities (DLT). Non-hematologic toxicities include grade 1–2 alopecia, anorexia, diarrhea, fever, headache, nausea, peripheral neuropathy, rash, stomatitis, and vomiting and grade 3 fatigue. Plasma concentrations of XK decline in a biphasic manner with a long mean terminal phase half-life of 60 h (CV 63%). Steady-state volume of distribution is 13 L (CV 23%); and mean total body clearance (CL) is 0.20 L/h (CV 50%), which is not correlated with dose (p=0.69) or BSA (p=0.93). All pts who experienced DLT had CL < 1 standard deviation (SD) below the mean. Conclusions: XK can be safely administered on a d 1, 3, 5 schedule without BSA-based dosing. As AUC increases with dose and 15% of our pts had CL ≤ 1 SD below the mean, safety concerns preclude further dose escalation > 1100 mg/d on this schedule. Cohort expansion continues at the phase II recommended dose of 1100 mg/d. Pharmacogenomic studies are ongoing to investigate the basis for the large PK variability. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Phase I dose-escalation study of the highly potent VEGF receptor kinase inhibitor, AZD2171, in patients with advanced cancers with liver metastases

3055 Background: Antiangiogenic therapy is a promising strategy to inhibit tumor growth and the formation of metastases. Vascular endothelial growth factor (VEGF) is a key proangiogenic factor essential for the development of new tumor blood vessels. AZD2171 is an orally available, highly potent inhibitor of VEGF receptor tyrosine kinase that has been assessed in a Phase I study of patients with advanced cancer and liver metastases. This study was designed to evaluate the safety and tolerability of ascending doses of AZD2171. Additional assessment of pharmacokinetics (PK), surrogate markers of activity and antitumor effects was also made. Methods: Cohorts of three patients received a single oral dose of AZD2171 (0.5, 1, 2.5, 5 or 10 mg p.o.) followed by a 7-day washout period and then received daily dosing at the same dose for a total of 28 days. Further 28-day treatment cycles were administered until a withdrawal criterion was met. Results: To date, 16 patients with advanced cancers and liver metastases (9 female, 7 male, median age 57 years) have been treated with AZD2171. Preliminary PK data indicate that AZD2171 is rapidly absorbed with a median time to maximal plasma concentration of 3.0 hours and a grand arithmetic mean terminal phase half-life of 20 hours. The exposure observed following continuous once-daily dosing for 28 days was entirely consistent with the terminal phase half-life obtained after a single oral dose. The PK profile appears to be linear following single and multiple doses. Treatment was well tolerated at the dose levels evaluated and the MTD has not been established. In the 10 mg cohort, one patient developed CTC grade 2 dizziness. No other drug-related toxicities have been observed. Conclusion: Continuous, once-daily, oral treatment with the highly potent VEGF receptor tyrosine kinase inhibitor, AZD2171, was well tolerated in this ongoing Phase I study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; ProQinase AstraZeneca