Comparison of efficacy between subcutaneous and intravenous application of moss‐aGal in the mouse model of Fabry disease
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ABSTRACT:
SUBMITTER: Dabrowska‐Schlepp P
PROVIDER: S-EPMC10623099 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Project description:Apidaecins are cationic, proline-rich antimicrobial peptides originally isolated from honeybees and exhibit high Gram-negative activity by inhibiting bacterial protein translation. Pharmacokinetics of apidaecin derivative Api137 was studied using single and multiple intravenous or subcutaneous injections as well as continuous subcutaneous infusion and correlated to its efficacy in a lethal murine Escherichia coli infection model. Survival rates of infected CD-1 mice were monitored and Api137 and its metabolites were quantified in plasma of uninfected CD-1 mice and Sprague Dawley rats using reversed-phase chromatography coupled online to mass spectrometry. The highest Api137 plasma levels of 23 mg/L were obtained after a single intravenous injection of 20 mg/kg body weight, which declined fast over the next 120 min (half-life time < 30 min). In contrast, continuous subcutaneous infusion of a similar dose over an hour (19.2 mg/kg/h) lead to stable plasma levels of ∼6 mg/L, which was above the minimal inhibitory concentration against E. coli ATCC 25922 (4 mg/L). The increased exposure by continuous subcutaneous administration of Api137 at 19.2 mg/kg/h over 48 h improved efficacy in the murine intraperitoneal sepsis model with survival rates of 67% over 5 days compared to 33% after intravenous and subcutaneous administration in different dosing schemes. To the best of our knowledge, continuous subcutaneous infusion using osmotic pumps was successfully utilized for delivery of an antimicrobial peptide for the first time. Additionally, the potential of apidaecin analogs as novel antibiotics is demonstrated even in a scenario where the infection site is clearly separated from the route of administration.
| S-EPMC6783563 | biostudies-literature
Project description:BackgroundIt has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa.ObjectivesTo investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms.MethodsEighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph).ResultsThere was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG.ConclusionAlthough DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa.
| S-EPMC11452806 | biostudies-literature
Project description:Background Belimumab is a recombinant, human, IgG1λ monoclonal antibody that targets B-lymphocyte stimulator. The intravenous formulation is indicated for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Belimumab has been formulated for subcutaneous (SC) administration to improve patient convenience. This post-hoc modeling and simulation analysis characterizes the population pharmacokinetics (PK) of SC belimumab, and compares the exposure profiles of the approved belimumab IV dose-10 mg/kg every four weeks-to the 200 mg SC weekly dose in SLE patients, highlighting key pharmacological differences relevant for clinicians. Methods Data from two Phase 1 studies in US American and Japanese healthy subjects were analyzed with a non-linear mixed effects modeling approach. The resulting SC population PK model and a previously developed IV population PK model were used to conduct simulation trials in a Phase 3 IV belimumab SLE patient population, comparing chronic exposure profiles and exposure ranges stratified by body weight tertiles for IV vs SC dosing. Results The PK of belimumab following SC administration was best described by a linear two-comment model. The estimates for clearance, steady-state volume of distribution, and bioavailability were 208 mL/day, 5250 mL, and 76%, respectively. After four weeks of SC dosing, simulated belimumab concentrations exceeded the steady-state trough concentrations of the IV dosing regimen. At steady state simulated serum profiles demonstrated comparable average belimumab concentrations (Cavg,ss) after IV and SC dosing. Simulated belimumab exposures demonstrated largely overlapping concentration ranges following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. Discussion The predicted Cavg,ss of belimumab in SLE patients was comparable following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. The simulated belimumab accumulation following SC weekly dosing indicated that administration of a loading dose was not required. Similar Cavg,ss ranges were predicted for fixed dose SC and weight-proportional IV regimens in the simulated SLE population, albeit with a reversed body-size-to-exposure relationship for the SC regimen. These findings provide rheumatologists with a better understanding of expected differences in belimumab exposure when comparing IV and SC dosing regimens.
| S-EPMC5054300 | biostudies-literature
Project description:Recombinant human follicle stimulating hormone (r-hFSH) is effective and safe for controlled ovarian stimulation. Bemfola(®) (Finox AG, Burgdorf, Switzerland), a new biosimilar r-hFSH, has proven comparable non-clinical pharmacological profiles to those of the widely used Gonal-f(®) (Serono Pharma S.p.A., Bari, Italy). The objective of this study was to show that Bemfola(®) yields comparable clinical pharmacokinetic (PK) and safety profiles to Gonal-f(®) in healthy female subjects. In this randomized, Phase I trial conducted in healthy female volunteers (N = 32), a 2-period, balanced 2-treatment crossover design was used. A single subcutaneous dose of 225 IU Bemfola(®) or Gonal-f(®) was administered in each treatment period per sequence. Blood was collected for pharmacokinetic analysis until 10 days after each r-hFSH treatment. For down-regulation of endogenous FSH subjects were given a depot injection with leuprolide acetate prior to the study drug in either sequence. Pharmacokinetic data was available for 23 subjects. No appreciable differences in key PK parameters were detected between the r-hFSH products as per non-compartmental PK analysis [i.e. for Bemfola(®) and Gonal-f(®) respectively AUC0-192 424.90 and 432.75 IU h/L, C max 0.98 and 0.95 IU/L, T max 24.0 h (range 6.0-24.0) and 24.0 h (range 9.0-24.0), t 1/2 43.58 h [standard deviation (SD 14.17)] and 42.58 h (SD 16.47), and K e 0.0075 1/h (SD 0.003) and 0.0077 1/h (SD 0.002)]. Subgroup analysis for estradiol (E2) response was similar for Bemfola(®) and Gonal f(®) (AUC(0--120) p = 0.21 and C max p = 0.82). No major safety issues were identified and no immunogenic reaction to r-hFSH was observed. The results of this study indicate that a single dose of Bemfola(®) exhibits pharmacokinetic and safety profiles comparable to Gonal-f(®) in healthy young women.
| S-EPMC4866993 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients.MethodsPatients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching).ResultsOverall, 319 patients received ≥1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC.ConclusionEfficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.
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Project description:A relatively low clearance is one of the prominent favorable features of immunoglobulin G1-based therapeutic monoclonal antibodies (mAbs). Various studies have observed differential clearance of mAb glycoforms, including oligomannose glycoforms, which are considered a critical quality attribute because they show higher clearance than complex type glycoforms. Glycoform clearance, however, has not previously been studied after subcutaneous injection or in a porcine model system. Here, we performed glycoform-resolved pharmacokinetic (PK) analysis of two mAbs in Göttingen minipigs. We found glycoform effects on clearance to be largely the same for subcutaneous and intravenous injection and in line with observations in other species. Oligomannose glycoforms were cleared up to 25% faster and monoantennary glycoforms up to 8% faster than agalactosylated complex glycoforms. Sialylated glycoforms were cleared at approximately the same rate as fully galactosylated glycoforms. Importantly, we report here an impact of galactosylation on the PK of a mAb for the first time. Whether increased galactosylation led to slower or faster clearance seemed to depend on the overall glycosylation profile. When clearance of galactosylated glycoforms was slower, the mAb showed higher galactosylation in serum at maximum concentration after subcutaneous injection compared to both intravenous injection and the injected material. Whether this higher galactosylation after subcutaneous injection has consequences for therapeutic efficacy remains to be investigated. In conclusion, preferential clearance of antibody glycoforms can be simulated in the minipig model with intravenous as well as subcutaneous injections. Furthermore, we observed a glycoform bias in the absorption from skin into circulation after subcutaneous injection based on galactosylation.Abbreviations: AUC - area under the curve; CL/F - apparent clearance as a function of bioavailability following SC administration; Cmax - maximum serum concentration; CQA critical quality attribute; FcγR - Fc gamma receptor; IgG - immunoglobulin G; IV - intravenous; LC-MS - liquid chromatography - mass spectrometry; mAb - therapeutic monoclonal antibody; PK - pharmacokinetics; SC - subcutaneous; TMDD - target-mediated drug disposition.
| S-EPMC9673920 | biostudies-literature
Project description:Approval of B-cell-depleting therapies signifies an important advance in the treatment of multiple sclerosis (MS). However, it is unclear whether the administration route of anti-CD20 monoclonal antibodies (mAbs) alters tissue distribution patterns and subsequent downstream effects. This study aimed to investigate the distribution and efficacy of radiolabeled ofatumumab and ocrelizumab in humanized-CD20 (huCD20) transgenic mice following subcutaneous (SC) and intravenous (IV) administration. For distribution analysis, huCD20 and wildtype mice (n = 5 per group) were imaged by single-photon emission computed tomography (SPECT)/CT 72 h after SC/IV administration of ofatumumab or SC/IV administration of ocrelizumab, radiolabeled with Indium-111 (111In-ofatumumab or 111In-ocrelizumab; 5 µg, 5 MBq). For efficacy analysis, huCD20 mice with focal delayed-type hypersensitivity lesions and associated tertiary lymphoid structures (DTH-TLS) were administered SC/IV ofatumumab or SC/IV ocrelizumab (7.5 mg/kg, n = 10 per group) on Days 63, 70 and 75 post lesion induction. Treatment impact on the number of CD19+ cells in select tissues and the evolution of DTH-TLS lesions in the brain were assessed. Uptake of an 111In-labelled anti-CD19 antibody in cervical and axillary lymph nodes was also assessed before and 18 days after treatment initiation as a measure of B-cell depletion. SPECT/CT image quantification revealed similar tissue distribution, albeit with large differences in blood signal, of 111In-ofatumumab and 111In-ocrelizumab following SC and IV administration; however, an increase in both mAbs was observed in the axillary and inguinal lymph nodes following SC versus IV administration. In the DTH-TLS model of MS, both treatments significantly reduced the 111In-anti-CD19 signal and number of CD19+ cells in select tissues, where no differences between the route of administration or mAb were observed. Both treatments significantly decreased the extent of glial activation, as well as the number of B- and T-cells in the lesion following SC and IV administration, although this was mostly achieved to a greater extent with ofatumumab versus ocrelizumab. These findings suggest that there may be more direct access to the lymph nodes through the lymphatic system with SC versus IV administration. Furthermore, preliminary findings suggest that ofatumumab may be more effective than ocrelizumab at controlling MS-like pathology in the brain.
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Project description:Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.
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Project description:Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intellectual disability, autism, hydrocephalus, and epilepsy. In a stochastic mouse model of TSC1 brain lesions, complete loss of Tsc1 is achieved in homozygous Tsc1-floxed mice in a subpopulation of neural cells in the brain by intracerebroventricular (i.c.v.) injection at birth of an adeno-associated virus (AAV) vector encoding Cre recombinase. This results in median survival of 38 days and brain pathology, including subependymal lesions and enlargement of neuronal cells. Remarkably, when these mice were injected intravenously on day 21 with an AAV9 vector encoding hamartin, most survived at least up to 429 days in apparently healthy condition with marked reduction in brain pathology. Thus, a single intravenous administration of an AAV vector encoding hamartin restored protein function in enough cells in the brain to extend lifespan in this TSC1 mouse model.
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Project description:Fabry disease (FD) is a life-threatening X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Small fiber pathology and pain are major FD symptoms of unknown pathophysiology. α-GAL deficient mice (GLA KO) age-dependently accumulate globotriaosylceramide (Gb3) in dorsal root ganglion (DRG) neurons paralleled by endoplasmic stress and apoptosis as contributors to skin denervation. Old GLA KO mice show increased TRPV1 protein in DRG neurons and heat hypersensitivity upon i.pl. capsaicin. In turn, GLA KO mice are protected from heat and mechanical hypersensitivity in neuropathic and inflammatory pain models based on reduced neuronal Ih and Nav1.7 currents. We show that in vitro α-GAL silencing increases intracellular Gb3 accumulation paralleled by loss of Nav1.7 currents, which is reversed by incubation with agalsidase-α and lucerastat. We provide first evidence of a direct Gb3 effect on neuronal integrity and ion channel function as potential mechanism underlying pain and small fiber pathology in FD.
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