Sc Dose Research Articles

Abstract A72: A first-in-man Phase I study of the galectin-1 (gal-1) inhibitor OTX008 given subcutaneously as a single agent to patients with advanced solid tumors.

Abstract Background: Gal-1 is a lectin with multiple biological functions including tumor progression, migration, and angiogenesis. OTX008, a small molecule downregulating gal-1 protein level, displays direct antiproliferative and anti-invasive effects in human cancer cells. Objectives: Determine the maximum tolerated dose (MTD) of single agent OTX008 using a subcutaneous (SC) daily dosing based on dose-limiting toxicities (DLTs). Secondary objectives were safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Patients and Methods: Patients (pts) with solid tumors having failed standard therapies, and given a written consent were enrolled. OTX008 was delivered as daily SC injection. In case of DLT, treatment was interrupted until recovery and resumed at the dose level (DL) below. Dose was escalated according to a 3+3 design. The MTD was defined as the highest DL, in which ≤1/6 pt experiences a DLT. Results: 22 pts (50% with colorectal carcinoma) were treated from March 2012 to March 2013. Six were enrolled at DL1 (65mg-flat dose) without DLT. Among the 7 pts enrolled at DL2 (120-130mg), 2 experienced DLT. DL2 was therefore deemed to exceed the MTD and 9 additional pts were enrolled at DL1. No DLT was observed among the 15 patients treated at DL1. The most frequent related adverse event (AE) was G1-2 injection site reaction in 20 patients. Two pts experienced skin ulcerations, resulting in subcutaneous abscess and treatment discontinuation in one and consent withdrawal in another. Transient and fully reversible neurological AEs were observed in 12 pts (55%), and were more frequent (100% vs 33%) and more severe (G3 in 29% vs 0%) at DL2 compared to DL1 respectively. G 1-2 tremor was observed in 8 pts, perioral paresthesia in 5, dizziness in 4 and myoclonia in 2. Two patients experienced G3 ataxia (DLT), and one patient with past history of post-traumatic epilepsy experienced G3 seizure. Gastrointestinal (GI) AEs were reported by 12 pts (55%); G3 vomiting/abdominal pain and G3 diarrhea were reported in 1 pt each; 12 patients developed asymptomatic abnormal lab values (10 hypomagnesemia and 8 transient elevation of CPK without rhabdomyolysis or cardiac ischemia). OTX008 plasma concentrations were >1µM over 12h after administration. PK of OTX008 is best described by a two compartment open model and showed less than proportional exposure increase, possibly due to wide inter-patient variability. The main covariate effect was related to body weight. Plasma gal-1 levels decreased proportionally with increasing OTX008 plasma concentrations. Serial tumor biopsies in 6 patients did not conclude on a PD effect. No objective response was reported. Conclusions: OTX008 recommended flat daily sc dose is 65mg, which achieves significant systemic plasma concentrations based on in vitro models. Weight adapted dosing may optimize systemic exposure. Local tolerance of SC injection is poor.Reversible ataxia was a dose-limiting toxicity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A72. Citation Format: Jean-Pierre Delord, Ahmad Awada, Eric Raymond, François Lokiec, Patrice Herait, Keyvan Rezai, Nicolas Lachaux, Gabriel A. Rabinovich, Carlos Gomez-Roca, Philippe Aftimos, Sandrine Faivre, Juan Carlos Stupirski. A first-in-man Phase I study of the galectin-1 (gal-1) inhibitor OTX008 given subcutaneously as a single agent to patients with advanced solid tumors. [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 A72.

Abstract 19: Blood Pressure Correlates Directly with the Expression Level of High Ouabain Affinity a2 Na+ Pumps in Arterial Smooth Muscle

High ouabain affinity α2 Na + pumps are expressed in arterial smooth muscle (ASM). They help regulate blood pressure (BP) in several forms of hypertension, but their influence on basal BP is controversial. We determined basal BP (telemetry), and the effects of subcutaneous (sc) angiotensin II (Ang II) and dietary salt on BP in: 1) α2 SM/Tg mice, which express an α2 transgene controlled by an α-actin smooth muscle (SM) promoter; 2) α2 SM/DN mice, which express a truncated α2 gene, dominant negative for native α2 Na + pumps, controlled by the SM myosin heavy chain promoter. Expression (immunoblots) of α2 was significantly up- and down-regulated in SM from α2 SM/Tg and α2 SM/DN mice, respectively. Basal 24 hr mean BP (MBP) was reduced in α2 SM/Tg mice: 103±1 ( n =15) vs 110±2 mm Hg ( n =9) in WT controls; P <0.01. Ang II, 400 ng/kg/min sc x 2 wks, increased MBP in both WT and transgenic mice ( n =5 each; P <0.01), but the increase (Δ) was smaller in α2 SM/Tg , Δ=20.3±3.3, than in WT mice, Δ=30.9±6.4 mm Hg . Also, a high (2% x 2 wks) NaCl diet, along with a sc 300 ng/kg/min (low dose) Ang II infusion, elevated systolic BP (SBP) in the WT mice (Δ=12.6±1.8 mm Hg; n =4; P <0.05), but not in the α2 SM/Tg mice (Δ=7.2±2.0 mm Hg; n =9; NS=not significant). In contrast, in α2 SM/DN mice, basal SBP was elevated: 128±4 mm Hg ( n =11) vs 109±4 mm Hg ( n =10) in WT; P <0.01. Furthermore, both high NaCl (HS, 6% x 10 days), and low dose sc Ang II infusion (240 ng/kg/min x 8 days), individually induced significantly greater increases in MBP in α2 SM/DN than in WT mice. In α2 SM/DN mice, the HS diet raised MBP by Δ=6.8±0.7 mm Hg ( n =5; P <0.01); Ang II elevated MBP by Δ=17.1±3.7 mm Hg ( n =5; P <0.05). In WT mice, however, HS did not elevate MBP (Δ=2.6±1.4; n =5; NS), and Ang II elevated MBP by only Δ=6.9±4.0 mm Hg; n =5; P <0.05). Conclusion: ASM α2 Na + pumps help regulate basal BP and vascular reactivity. Reduced α2 expression raises basal BP and augments arterial responses to salt and Ang II; increased ASM α2 expression has the opposite effects. The α2 Na + pumps co-localize with Na/Ca exchangers in plasma membrane (PM) microdomains at MP-sarcoplasmic reticulum junctions; they are a crucial link between circulating endogenous ouabain and the control of ASM Ca 2+ homeostasis, arterial contraction and tone.

Single- and Multiple-Dose Randomized Studies of Blosozumab, a Monoclonal Antibody Against Sclerostin, in Healthy Postmenopausal Women

Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject- and investigator-blind, placebo-controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study (12 to placebo) and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose-dependent responses were observed in sclerostin, N-terminal propeptide of procollagen type 1, bone-specific alkaline phosphatase, osteocalcin, C-terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p=0.002) and up to a 7.71% (p<0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis.

AB0553 Switching from SC to IV abatacept: Pharmacokinetic simulations to support dose regimen

BackgroundAbatacept (ABA) is a selective T-cell co-stimulation modulator approved in the US for RA, available in both IV and SC formulations. There is a need to establish a safe and...

FRI0182 Pharmacokinetics and immunogenicity of mavrilimumab administered subcutaneously in subjects with rheumatoid arthritis

BackgroundMavrilimumab is a high-affinity, fully human immunoglobulin G (IgG) monoclonal antibody that selectively binds to the α subunit of GM-CSF receptor (GM-CSFRα). A Phase 2a randomized, double-blind, placebo-controlled, multiple ascending...

THU0328 Changes in health-related quality of life in systemic juvenile idiopathic arthritis patients after single dose of canakinumab

BackgroundPatient’s quality of life is markedly affected by the persistent and disabling disease features of systemic juvenile idiopathic arthritis (SJIA). We evaluated the direct impact of the disease on patients’...

AB1186 IL-1beta inhibition with canakinumab in patients with systemic juvenile idiopathic arthritis: Efficacy and safety outcomes from a single-dose, placebo-controlled study

BackgroundIL-1β, a key inflammatory cytokine, appears to play a prominent role in systemic juvenile idiopathic arthritis (SJIA). Canakinumab (CAN), a fully human, anti-IL-1β monoclonal antibody selectively binds to IL-1β and...

OP0025 Results from a multicenter, international, randomized, double-blind, placebo-controlled, phase 2 study of sirukumab, a human anti-IL-6 monoclonal antibody, in patients with active rheumatoid arthritis despite methotrexate therapy

ObjectivesTo assess remission rates from a phase 2 study of sirukumab, a human monoclonal antibody against the cytokine interleukin-6 (formerly named CNTO 136), using the new provisional 2011 ACR/EULAR rheumatoid...

THU0100 Results from a 2-part, proof-of-concept, dose-ranging, randomized, double-blind, placebo-controlled, phase 2 study of sirukumab, a human anti-IL-6 monoclonal antibody, in patients with active rheumatoid arthritis despite methotrexate therapy

ObjectivesTo determine the efficacy and safety of SC sirukumab (SRM) dose regimens & to describe PK & PD in active RA pts in a Ph2 dose-ranging Part B study.MethodsPts w/...

FRI0368 GOUT flare prevention with rilonacept in patients with TOPHI and/or polyarticular disease who initiate uric acid-lowering therapy

BackgroundPatients (pts) with visible tophi and/or polyarticular disease (T/PD) may be at greater risk of gout flares (GFs) when initiating uric acid-lowering therapy (ULT).ObjectivesTo determine the risk presented by T/PD...

A phase II study of Recchia's immunomodulatory schedule (RIS) as a maintenance therapy in high-risk tumors after a response.

3074 Background: F. Recchia et al. (Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study. Int J Oncol. 20: 1275-1282, 2002) previously defined the possibility of achieving a chronic immune stimulation through a prolonged low dose sc interleukin 2 (IL2)-based schedule, leading to a prolongation of PFS in advanced cancer patients (pts). A confirmatory phase II study was started. Methods: Pts diagnosed of high risk solid tumors in response to chemotherapy were included. RIS consisted in low dose IL2 (1.8 MU sc per day, 5 days per week, 3 weeks per month) plus oral isotreonin (CRA, 0.5 mg/kg) the same days of IL2 and/or sc PEG-interferon (50 µg per week of treatment). No Chx was allowed with RIS, but concurrent maintenance with TKI or Hx was permitted. Results: Since 08/2007 to 01/2013, 69 pts (39 M/30 F, median age 60 y, range 31-78) were included. 51 pts were treated with stage IV disease. 36 pts entered in complete response (CR), 29 in partial response (PR), 1 with progressive disease, 3 adjuvant. 4/69 grade 3/4 toxicity, (6%): 1 fatal poliserositis resistant to cortisone after 20 months of RIS, 1 stopped RIS for reaction requiring steroids, 1 for multiinfarction dementia, 1 for grade 3 liver toxicity. 3 pts presented other alterations managed along the course of the RIS (1 PVT, 1 ITP, 1 angina resolved after stent placement). Grade 1-2 fever, fatigue and joint pain were commonly observed but usually controlled with NSAIDs. Among the 68 pts evaluable for response, one pt progressed, 26 presented stable disease (median TTP 3 mo, range 2-28), 3 presented PR (1 melanoma, 1 prostatic ca, 1 ovarian ca; 9, 11 and 28 mo respectively), and 38 maintained or presented CR (median TTP 19 mo, range 2-62+). Three pts in PR were converted to a CR during RIS (1 pancreatic ca, 1 ovarian ca, 1 larynx ca). Conclusions: In this study we confirm the previous results reported by F. Recchia et al. RIS represents a good alternative for high risk pts with solid tumors after systemic chemotherapy induced response with acceptable tolerability and offers in selected pts a possibility of obtaining a CR after a PR. Further validation and randomized studies are warranted.

Abstract 679: SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome .

Abstract The DNA methyltransferase inhibitors (DNMTi) Vidaza (5-azacytidine) and Dacogen (5-aza-2′-deoxycytidine, decitabine) are approved by the FDA for chemotherapy against myelodysplastic syndrome, a heterogeneous bone marrow disorder. Vidaza in combination with the HDAC inhibitor entinostat has shown some promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of these DNMTi against solid tumors is likely impacted in part, by their stability and rapid inactivation by cytidine deaminase in the liver. These studies were initiated to test the efficacy of SGI-110, a prodrug for decitabine. SGI-110, a dinucleotide consisting of 5-aza-2′-deoxycytidine followed by a deoxyguanosine, has been shown to be effective in vitro as a DNA methylation inhibitor and less prone to deamination by cytidine deaminase. In this study, we used our in vivo lung cancer model to explore the potential therapeutic effect of SGI-110 alone and in combination with entinostat. In vivo plasma concentrations and pharmacokinetic properties of SGI-110 and its metabolite decitabine were evaluated in nude rats after a single SC dose of SGI-110. Upon SC administration, SGI-110 is rapidly converted to decitabine. Dose proportional pharmacokinetics showed no significant difference in accumulation of SGI-110 or decitabine, while the half life of decitabine was increased to 4hrs. SGI-110 alone or in combination with entinostat significantly reduced tumor burden by 56% of Calu-6, a K-ras/p53 mutant lung adenocarcinoma cell line engrafted orthotopically in nude rats. On a molecular level, global changes in gene profiles were associated with a reduction in tumor burden. Microarray analysis revealed that a 212 and 592 genes were differentially expressed in SGI-110 alone or with combination therapy. Highly significant gene expression changes were seen in key cancer regulatory pathways. In addition, SGI-110 treatment activated p21 and apoptotic genes BIK and BAK in these tumors. SGI-110 caused widespread epigenetic reprogramming that induced demethylation of an average of 291 genes; in particular 208 genes were polycomb target genes. The polycomb targets were enriched for transcription factors. These preclinical in vivo findings demonstrate that SGI-110 alone shows strong demethylating activity and when combined with entinostat more effectively retards tumor growth. (Supported by Astex Pharmaceutical and SU2C) Citation Format: Carmen S. Tellez, Marcie J. Grimes, Maria A. Picchi, Yushi Liu, Tom H. March, Aram Oganesian, Pietro Taverna, Steven A. Belinsky. SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2013-679

Nanosericite as an Innovative Microparticle in Dual-Chemical Paper Retention Systems

Dual-chemical retention systems based on 2 cationic polyacrylamides, a colloidal silica, and a globular anionic polymer microparticles were investigated and an exfoliated nanoparticle indigenous mica mineral, sericite, was examined for its efficacy in substituting commercial microparticle preparations. The results indicated that nanosericite generated FPR between 76.9 and 80.9% for fines and chemicals. Its ash retention values, however, were higher and tended to increase with doses of polymer, nanosericite, or Sc to between 16 and 24%. As for paper physical properties, nanosericite was not amenable to substitute the c-PAMb/polymer with only handsheet stiffness superior to the combination. Nanosericite, however, showed good substitution capacity than the c-PAMa-colloidal silica combination. Regardless of the c-PAMa doses, all examined handsheet physical properties incorporating nanosericite were superior to colloidal silica. The optimal performance was observed with c-PAMa dose of 200 ppm. Optical properties of the handsheets indicated that with nanosericite substitution, brightness values were comparable to the polymer group, while its substitution capacity for colloidal silica decreased with increasing c-PAMb dose. Only at c-PAMa dose of 300 ppm, it appeared to have good substitution for colloidal silica. Substituting nanosericite for colloidal silica appeared to reduce the c-PAMa charge and increased the overall cost effectiveness.

ACE-536 Increases Hemoglobin in Healthy Postmenopausal Women: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study

Abstract Abstract 3194 Background: ACE-536 is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human IgG1 Fc domain. ACE-536 acts as a ligand trap for members of the TGF-β superfamily involved in erythropoiesis. ACE-536 promotes late-stage erythrocyte precursor cell differentiation by inhibiting specific TGF-β family ligands. Studies of ACE-536 in wild type animals across several species demonstrated an erythroid response that was rapid in onset, robust, and sustained. ACE-536 was also shown to significantly improve hematologic parameters and correct ineffective erythropoiesis in mouse models of myelodysplastic syndromes (MDS) and β-thalassemia. This study is the first human clinical trial of ACE-536. Methods: This was a single-center, randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, PK, and PD effects of ACE-536 in healthy, postmenopausal women. Screening and baseline hemoglobin values were to be between 11.0 and 14.5 g/dL. Sequential cohorts of 8 subjects each were randomized to receive either ACE-536 (n=6) or placebo (n=2) administered as SC injections on Day 1 and Day 15. ACE-536 dose levels tested (prior to halting dose escalation per protocol due to positive hemoglobin response) were 0.0625, 0.125 and 0.25 mg/kg. The study included pre-specified individual stopping rules for the Day 15 dose for increases in hemoglobin, changes in blood pressure, or ≥ grade 3 adverse events. From Day 1 through Day 57, subjects were assessed for safety by monitoring adverse events, clinical laboratory tests, ECG, vital signs and physical examination. Longer-term follow up visits occurred on Days 71 and 127. Results: A total of 32 subjects were enrolled. The mean (SD) age was 59.4 (5.8) yr (range: 49–71 yr). All subjects in the first cohort (0.0625 mg/kg or placebo) received both doses of ACE-536; all subjects in the second cohort (0.125 mg/kg or placebo) received only one dose of ACE-536 due to study interruption. This dose level was repeated for the third cohort in which subjects received 2 doses; 1 subject in that cohort did not receive the second dose due to elevated blood pressure. Four subjects in the fourth cohort (0.25 mg/kg or placebo) did not receive the second dose due to hemoglobin increase ≥ 1.0 g/dL and one additional subject did not receive the second dose due to an AE of papular rash. There were no serious adverse events or study discontinuations reported. The majority of AEs were considered mild in severity. No clinically meaningful abnormalities in laboratory measures, vital signs, physical exam, or ECG were observed, and no anti-drug antibodies were detected. The mean serum ACE-536 Cmax and AUC after the first dose increased in a dose-proportional manner, with mean time to Cmax 7.7–11.7 days and mean elimination T½ 15.5–18.5 days. The maximum hemoglobin increase from baseline at any timepoint for subjects in the 0.25 mg/kg cohort ranged from 0.6 to 2.0 g/dL (5 of 6 subjects increased ≥1.1 g/dL), with a mean maximum increase of 1.3 g/dL (p&lt;0.001 vs placebo). Mean hemoglobin levels increased in that dose group by at least 0.6 g/dL from Day 8 through Day 57, compared with a mean decrease in the placebo group of up to 0.6 g/dL through Day 43 (see Figure). Small increases in mean reticulocyte count and EPO levels were seen in groups treated with higher doses of ACE-536 as compared with the placebo group. Conclusions: The preliminary results from this first-in-human phase 1 study show that ACE-536 is associated with a robust and sustained increase in hemoglobin levels in healthy subjects. Dose levels up to 0.25 mg/kg were generally safe and well-tolerated. The PK results support SC dosing of ACE-536 every 3 weeks. These data warrant further evaluation of ACE-536 in clinical trials in patients with disease-associated ineffective erythropoiesis and anemia, such as MDS and β-thalassemia. Disclosures: Attie: Acceleron Pharma, Inc.: Employment. Boyd:Acceleron Pharma, Inc.: Employment. Wilson:Acceleron Pharma, Inc.: Employment. Sherman:Acceleron Pharma, Inc.: Employment.

Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels: Results From 2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1 Studies in Healthy Volunteers and Hypercholesterolemic Subjects on Statins

The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling. Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3. In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.

Pharmacokinetics of tulathromycin in lactating goats

Tulathromycin is a novel long-acting semi-synthetic macrolide antibiotic of the triamilide group that is used to treat respiratory diseases in cattle and pigs. Tulathromycin may therefore be useful in treating respiratory diseases of goats. The objective of this study was to characterize the pharmacokinetics of tulathromycin in lactating goats. Five lactating goats received single IV and IM injections of tulathromycin (2.5 mg/kg) with a 6 week interval between injections. Plasma, milk and urine concentrations of tulathromycin were determined using a microbiological assay method and pharmacokinetic values were calculated. Following a single IV injection of tulathromycin formulation, tulathromycin had a high mean volume of distribution (16.1 L/kg), excellent penetration into milk, slow plasma clearance (126 mL kg −1 h −1 ) and a long elimination half time (88 h). Plasma protein binding was 23%. Tulathromycin was rapidly absorbed following a single IM injection; the mean maximum plasma concentration (0.73 μg/mL) was rapidly reached at 0.5 h and mean bioavailability was 95.8%. Tulathromycin concentrations exceeded 0.1 μg/mL in milk and 0.01 μg/mL in plasma for at least 7 days. We conclude that the pharmacokinetics of a single IM injection of tulathromycin (2.5 mg/kg) in lactating goats are similar to those in non-lactating goats and yearling cattle administered a similar dose of tulathromycin SC. Tulathromycin may therefore be effective in the treatment of respiratory disease in goats. Long withdrawal times (>19 days) are required for milk intended for human consumption when tulathromycin is administered accidentally to lactating dairy goats.

Resorptive Hypercalcemia in Post-Essential Thrombocythemia Myelofibrosis: Treatment with Denosumab

Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known. We report a unique case of hypercalcemia associated with post-essential thrombocythemia myelofibrosis and review the clinical and laboratory features, pathogenesis, and responsiveness to treatment with the bone antiresorptive agent, denosumab. A 62-yr-old woman with essential thrombocythemia presented with progression to myelofibrosis with lytic skull lesions and symptomatic hypercalcemia. Other causes of hypercalcemia were excluded. Her disturbance in calcium homeostasis was not PTH- or vitamin D-mediated, although this has been postulated in cases of hypercalcemia with the related entity of primary myelofibrosis. Her hypercalcemia was refractory to aggressive iv saline administration, furosemide, calcitonin, and pamidronate, but promptly improved after one 120-mg sc dose of the anti-receptor activator of nuclear factor κB (RANK) ligand monoclonal antibody, denosumab, with sustained normocalcemia for approximately 2 months. She died 6 months later from complications due to the leukemic transformation of her hematological disease. The pathogenesis of myelofibrosis-related hypercalcemia could be due to multiple factors, particularly changes in the RANK ligand-RANK-osteoprotegerin system that lead to increased osteoclast activity. Although we did not measure these factors, denosumab holds promise in the treatment of malignancy-associated hypercalcemia and specifically that related to myelofibrosis. Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known.

Application of a Multi-Route Physiologically Based Pharmacokinetic Model for Manganese to Evaluate Dose-Dependent Neurological Effects in Monkeys

Manganese (Mn) is an essential element that is neurotoxic under certain exposure conditions. Monkeys and humans exposed to Mn develop similar neurological effects; thus, an improved understanding of the dose-response relationship seen in nonhuman primates could inform the human health risk assessment for this essential metal. A previous analysis of this dose-response relationship in experimental animals (Gwiazda, R., Lucchini, R., and Smith, D., 2007, Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans, J. Toxicol. Environ. Health Part A 70, 594-605.) relied on estimates of cumulative intake of Mn as the sole measure for comparison across studies with different doses, durations, and exposure routes. In this study, a physiologically based pharmacokinetic model that accurately accounts for the dose dependencies of Mn distribution was used to estimate increases in brain Mn concentrations in monkeys following Mn exposure. Experimental studies evaluated in the analysis included exposures by inhalation, oral, iv, ip, and sc dose routes, and spanned durations ranging from several weeks to over 2 years. This analysis confirms that the dose-response relationship for the neurotoxic effects of Mn in monkeys is independent of exposure route and supports the use of target tissue Mn concentration or cumulative target tissue Mn as the appropriate dose metric for these comparisons. These results also provide strong evidence of a dose-dependent transition in the mode of action for the neurological effects of Mn that needs to be considered in risk assessments for this essential metal.

Pharmacokinetic behavior of marbofloxacin after intravenous, subcutaneous and intramuscular administrations in llamas (Lama glama)

Abstract The purpose of this study was to determine the pharmacokinetic profile of marbofloxacin in llamas following single IV, IM and SC administration of 5 mg/kg bw. To assess whether these routes could be an option for the administration of marbofloxacin in this specie and estimate efficacy predictors (PK/PD) from bibliographic MIC90 values. The principal pharmacokinetic parameters were Vss = 0.72 ± 0.22 L/kg, Cl = 0.09 ± 0.03 L/kg h (for IV administration), Cmax = 7.43 ± 1.28 μg/mL and 6.94 ± 2.19 μg/mL for IM and SC administration, respectively; t1/2λ = 9.16 ± 1.08 h, 8.47 ± 0.31 h and 6.26 ± 0.87 h and MRT = 7.30 ± 1.07 h, 8.21 ± 1.57 h and 8.27 ± 0.96 h for IV, IM and SC administrations, respectively. The values obtained for the pharmacokinetic parameters were not significantly different among routes of administration except Cmax, Vz and t1/2λ. The values obtained from the PK/PD indices were Cmax/MIC90 (12.4–32.3) and AUC0–24/MIC90 (105.7–178.52 h); taking into account these values, it was concluded that a IM or SC dose of 5 mg/(kg day) of marbofloxacin would be adequate in treating infections caused by susceptible bacteria with MIC

Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study

A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection-site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20-40 % across doses. Pasireotide demonstrated fast absorption (T(max,ss): 0.25-0.5 h), low clearance (CL/F(ss): 8.10-9.03 L/h), long effective half-life (T(½,eff): ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (V(z)/F(ss): 251-1,091 L) at steady state. Dose proportionality was confirmed for C(max,ss); other PK parameters (C(max), AUC(0-24 h) and AUC(tau)) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.