ABSTRACT
The use of generic specialty medications amongst individuals with multiple sclerosis (MS) has expanded due to an increase in the number of available agents. We describe a woman who was denied continued use of brand name teriflunomide (Aubagioâ), despite being clinically stable for 2.5 years, and switched to generic teriflunomide. She experienced a significant spinal cord exacerbation within a few months of starting treatment. We analyzed 3 generic teriflunomide agents, including the one used for treatment, in addition to Aubagioâ. The generic teriflunomide used by our patient contained 55.5â¯% content of the labeled amount, well below U.S. FDA specifications.
Subject(s)
Crotonates , Drugs, Generic , Hydroxybutyrates , Nitriles , Toluidines , Humans , Female , Drugs, Generic/adverse effects , Crotonates/adverse effects , Crotonates/therapeutic use , Crotonates/administration & dosage , Toluidines/adverse effects , Toluidines/therapeutic use , Toluidines/administration & dosage , Multiple Sclerosis/drug therapy , Middle Aged , AdultABSTRACT
BACKGROUND: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. OBJECTIVES: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. METHODS: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. RESULTS: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. CONCLUSIONS: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.
Subject(s)
Crotonates , Dimethyl Fumarate , Fingolimod Hydrochloride , Hydroxybutyrates , Medication Adherence , Nitriles , Recurrence , Toluidines , Humans , Adult , Female , Male , Medication Adherence/statistics & numerical data , Middle Aged , Crotonates/administration & dosage , Crotonates/therapeutic use , Retrospective Studies , Toluidines/administration & dosage , Toluidines/therapeutic use , Young Adult , Dimethyl Fumarate/administration & dosage , Dimethyl Fumarate/therapeutic use , Fingolimod Hydrochloride/therapeutic use , Fingolimod Hydrochloride/administration & dosage , Adolescent , Multiple Sclerosis/drug therapy , Administration, Oral , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Immunologic Factors/administration & dosageABSTRACT
BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). OBJECTIVES: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. METHODS: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. CONCLUSION: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Treatment Failure , Humans , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Female , Adult , Male , Retrospective Studies , Administration, Oral , Middle Aged , Fingolimod Hydrochloride/administration & dosage , Dimethyl Fumarate/administration & dosage , Crotonates/administration & dosage , Hydroxybutyrates , Toluidines/administration & dosage , Immunosuppressive Agents/administration & dosage , Nitriles/administration & dosage , Prognosis , Immunologic Factors/administration & dosageABSTRACT
BACKGROUND AND OBJECTIVES: To test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models. METHODS: The effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting-sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures. In vivo, TF was administered orally, and remyelination was assessed both in myelin basic protein-GFP-nitroreductase (Mbp:GFP-NTR) transgenic Xenopus laevis demyelinated by metronidazole and in adult mice demyelinated by lysolecithin. RESULTS: In cultures, low concentrations of TF down to 10 nM decreased OPC proliferation and increased their differentiation, an effect that was also detected on adult OPCs. Oligodendrocyte differentiation induced by TF was abrogated by the oxidosqualene cyclase inhibitor Ro 48-8071 and was mediated by the accumulation of zymosterol. In the demyelinated tadpole, TF enhanced the regeneration of mature oligodendrocytes up to 2.5-fold. In the mouse demyelinated spinal cord, TF promoted the differentiation of newly generated oligodendrocytes by a factor of 1.7-fold and significantly increased remyelination. DISCUSSION: TF enhances zymosterol accumulation in oligodendrocytes and CNS myelin repair, a beneficial off-target effect that should be investigated in patients with multiple sclerosis.
Subject(s)
Central Nervous System Diseases/drug therapy , Cholesterol/metabolism , Crotonates/pharmacology , Demyelinating Diseases/drug therapy , Hydroxybutyrates/pharmacology , Immunosuppressive Agents/pharmacology , Nitriles/pharmacology , Oligodendrocyte Precursor Cells/drug effects , Oligodendroglia/drug effects , Remyelination/drug effects , Toluidines/pharmacology , Animals , Animals, Newborn , Cells, Cultured , Central Nervous System Diseases/metabolism , Crotonates/administration & dosage , Disease Models, Animal , Hydroxybutyrates/administration & dosage , Immunosuppressive Agents/administration & dosage , Larva , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nitriles/administration & dosage , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Toluidines/administration & dosage , Xenopus laevisABSTRACT
BACKGROUND: . Teriflunomide is an immunomodulatory drug approved for Multiple Sclerosis (MS) treatment that inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in the de novo pyrimidine synthesis pathway. This mechanism can produce antiviral effects, thus teriflunomide has gained attention during COVID-19 pandemic. Moreover, in the last months, some case-reports have been published describing MS patients treated with teriflunomide who developed mild and self-limiting forms of COVID-19. METHODS: Here, we describe the case of a 57-year-old man affected by MS, and treated with teriflunomide, who developed a mild form of SARS-CoV-2 infection. Moreover, we provide a detailed literature review about the available cases of COVID-19 in MS patients treated with teriflunomide. We report clinical features, disease course and outcome, and we discuss similarities and differences among patients. RESULTS: Apart from the present report, since February 2020, five papers have been published describing 14 MS patients who developed SARS-CoV-2 infection during teriflunomide treatment. Patients were mostly female (53%), with an average age of 50.5 (±11.3) years. Median EDSS was 2.25 (range 0-6). The average time on treatment with teriflunomide was 3.7 (± 1.6) years. Relevant comorbidities were present in 4 patients (27%). Regarding SARS-CoV-2 infection, the most common symptom was fever (100%) followed by gastrointestinal disturbances (67%), fatigue (55%) and cough (55%). 5 patients were hospitalized and 2 required oxygen support. In patient hospitalized (n=5) compared to the others (n=10), age was significantly higher (59.6 vs 45.9 years, p=0.025) while gender, EDSS, duration of teriflunomide therapy and comorbidities were not significantly different. Outcome was good for all patients with a variable recovery time, ranging from few days to some weeks. Teriflunomide was continued during the entire course of SARS-CoV-2 infection in all patients except for two. Compared to the patients already described, our patient was 7 years older, average time on teriflunomide treatment was about 2.5 years shorter, and median EDSS was 1.5 point lower. Despite significant comorbidities, the outcome was good since our patient was hospitalized but he did not require oxygen supplementation nor intensive care and was able to return at home after only 10 days. Teriflunomide therapy was continued throughout the period. CONCLUSION: Available data suggest that teriflunomide therapy should not be discontinued in MS patients who develop SARS-CoV-2 infection, also in presence of significant comorbidities or clinical conditions requiring hospitalization. Additional studies are necessary to assess if the drug can also have a protective role against SARS-CoV-2.
Subject(s)
COVID-19/therapy , Crotonates/administration & dosage , Immunologic Factors/administration & dosage , Multiple Sclerosis/drug therapy , Toluidines/administration & dosage , COVID-19/epidemiology , Comorbidity , Humans , Hydroxybutyrates , Male , Middle Aged , Multiple Sclerosis/epidemiology , NitrilesABSTRACT
Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Crotonates/administration & dosage , Drug Carriers/administration & dosage , Durapatite/chemistry , Hyaluronic Acid/chemistry , Methotrexate/administration & dosage , Nanoparticles/administration & dosage , Toluidines/administration & dosage , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/toxicity , Arthritis, Experimental/pathology , Crotonates/pharmacokinetics , Crotonates/therapeutic use , Crotonates/toxicity , Cytokines/blood , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Evaluation, Preclinical , Drug Liberation , Hydroxybutyrates , Liver/drug effects , Liver/enzymology , Liver/pathology , Methotrexate/pharmacokinetics , Methotrexate/therapeutic use , Methotrexate/toxicity , Mice , Nanoparticles/toxicity , Nitriles , RAW 264.7 Cells , Rats , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Tissue Distribution , Toluidines/pharmacokinetics , Toluidines/therapeutic use , Toluidines/toxicityABSTRACT
Antigen-specific immune responses are crucially involved in both multiple sclerosis (MS) and myasthenia gravis (MG). Teriflunomide is an immunomodulatory agent approved for treatment of MS through inhibition of lymphocyte proliferation. MG associated with muscle-specific tyrosine kinase (MuSK) antibodies often manifests with a severe disease course, prompting development of effective treatment methods. To evaluate whether teriflunomide treatment may ameliorate MuSK-autoimmunity, experimental autoimmune MG (EAMG) was induced by immunizing C57BL/6 (B6) mice three times with MuSK in complete Freund's adjuvant (CFA) (n = 17). MuSK-immunized mice were treated daily with teriflunomide (n = 8) or PBS (n = 9) starting from the third immunization (week 8) to termination (week 14). Clinical severity of EAMG was monitored. Immunological alterations were evaluated by measurement of anti-MuSK IgG, neuromuscular junction deposits, and flow cytometric analysis of lymph node cells. In MS patients under teriflunomide treatment, the peripheral blood B cell subset profile was analyzed. B6 mice treated with teriflunomide displayed relatively preserved body weight, lower EAMG prevalence, reduced average clinical grades, higher inverted screen scores, diminished anti-MuSK antibody and NMJ deposit levels. Amelioration of EAMG findings was associated with reduced memory B cell ratios in the lymph nodes. Similarly, MS patients under teriflunomide treatment showed reduced memory B cell, plasma cell, and plasmablast ratios. Teriflunomide treatment has effectively ameliorated MuSK-autoimmunity and thus may putatively be used in long-term management of MuSK-MG as an auxiliary treatment method. Teriflunomide appears to exert beneficial effects through inhibition of effector B cells.
Subject(s)
B-Lymphocyte Subsets/drug effects , Crotonates/administration & dosage , Hydroxybutyrates/administration & dosage , Multiple Sclerosis/drug therapy , Myasthenia Gravis, Autoimmune, Experimental/drug therapy , Nitriles/administration & dosage , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Toluidines/administration & dosage , Adult , Animals , B-Lymphocyte Subsets/immunology , Female , Humans , Male , Mice , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/diagnosis , Multiple Sclerosis/immunology , Myasthenia Gravis, Autoimmune, Experimental/blood , Myasthenia Gravis, Autoimmune, Experimental/diagnosis , Myasthenia Gravis, Autoimmune, Experimental/immunology , Receptor Protein-Tyrosine Kinases/administration & dosage , Receptors, Cholinergic/administration & dosage , Treatment OutcomeABSTRACT
BACKGROUND: Real-world safety data for the oral multiple sclerosis (MS) disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide are important. We examined laboratory test abnormalities and adverse health conditions in new users. METHODS: Linked laboratory and administrative health data were accessed for all persons with MS (PwMS) filling their first oral DMT prescription in two Canadian provinces. PwMS were followed from first prescription fill until discontinuation, death, emigration or study end. Proportions of PwMS, and incidence rates (IR)/100 person-years, were calculated for ≥1 event of elevated alanine aminotransferase (ALT) (>the upper limit of normal [ULN]; all DMTs), liver toxicity (ALT>3xULN; fingolimod); lymphopenia and proteinuria (DMF), and cardiac arrhythmia, hypertension and pneumonia (all DMTs). RESULTS: Overall, 1,140 PwMS were followed for up to 2 years. De novo elevated alanine aminotransferase affected 13.2% (DMF), 12.4% (teriflunomide), and 30.0% (fingolimod) of users. Liver toxicity affected 2.8% of fingolimod, lymphopenia 3.1% of DMF, and proteinuria 2.9% of DMF users. The incidences of cardiac arrhythmia, pneumonia and hypertension ranged from <1 to 1.86/100 person-years depending on the DMT. CONCLUSIONS: The short-term, real-world incidences of abnormal laboratory results or adverse events were consistent with the pivotal clinical trial findings. Longer-term safety data are still needed.
Subject(s)
Crotonates/adverse effects , Dimethyl Fumarate/adverse effects , Fingolimod Hydrochloride/adverse effects , Multiple Sclerosis/drug therapy , Toluidines/adverse effects , Administration, Oral , Adult , Crotonates/administration & dosage , Databases, Factual , Dimethyl Fumarate/administration & dosage , Female , Fingolimod Hydrochloride/administration & dosage , Follow-Up Studies , Humans , Hydroxybutyrates , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Nitriles , Prospective Studies , Toluidines/administration & dosageABSTRACT
The research work was intended to formulate teriflunomide (TFM) loaded nano lipid-based (TNLC) carbopol-gellan gum in situ gel (TNLCGHG) and to investigate its therapeutic efficacy against glioma, a brain and spine tumor. Nanoformulation was developed using gellan gum and carbopol 974P as gelling and mucoadhesive agents, respectively, Glyceryl di-behenate and Glyceryl mono-linoleate blend as lipids, and Gelucire 44/14: water blend as surfactant system. Globule size, PDI, zeta potential, encapsulation efficiency, mucoadhesive strength, and nasal permeation were found to be 117.80 nm, 0.56, -21.86 mV, 81.16%, 4.80 g, and 904 µg/cm2, respectively. Anticancer efficacy of TFM-loaded nano lipid-based carbopol-gellan gum in situ gel (TNLCGHG) was determined in human U-87MG glioma cell line. IC50 was found 7.0 µg/mL for TNLCGHG, 4.8 µg/mL for pure TFM, and 78.5 µg/mL for TNLC, which approve the superiority of surfactant along with gellan gum as permeation enhancer. Brain Cmax for technetium (99mTC) labeled intranasal (i.n.) 99mTC-TNLCGHG was found 2-folds higher than 99mTC-TNLC (i.n.) and 99mTC-TNLC intravenous (i.v.) because the TNLCGHG formulation contains surfactant with natural gelling polymers, which promisingly improved drug permeability. Finally, this research revealed encouraging outcomes and successfully developed intranasal TNLCGHG nanoformulation as a novel tool for safe delivery of TFM in glioma patients.
Subject(s)
Acrylic Resins/chemistry , Crotonates/administration & dosage , Drug Carriers/chemistry , Drug Delivery Systems , Lipids/chemistry , Nanogels/chemistry , Polysaccharides, Bacterial/chemistry , Toluidines/administration & dosage , Administration, Intranasal , Animals , Brain/drug effects , Brain/metabolism , Calorimetry, Differential Scanning , Cell Line, Tumor , Chemical Phenomena , Chromatography, High Pressure Liquid , Glioma/drug therapy , Hydroxybutyrates , Nanoparticles/chemistry , Nitriles , Particle Size , X-Ray DiffractionABSTRACT
OBJECTIVES: To compare the efficacies, frequencies and reasons for treatment interruption of fingolimod (FTY), dimethyl fumarate (DMF) or teriflunomide (TERI) in a nationwide observational cohort. MATERIALS AND METHODS: Two cohorts of patients with relapsing-remitting multiple sclerosis (RRMS) having started treatment with FTY, DMF or TERI documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 24 months (24 m cohort) or with at least one follow-up visit after start of treatment (total cohort). The 24 m cohort included 629 RRMS patients: 295 in the FTY, 227 in the DMF and 107 in the TERI group. We used multinomial propensity scores for inverse probability weighting in generalized linear and Cox proportional hazards models to correct for the bias of this non-randomised registry study. RESULTS: Estimated mean annualized relapse rates (ARR) over 24 months were 0.13 for FTY, 0.09 for DMF and 0.11 for TERI treatment. For TERI in comparison with DMF, we observed higher probability for treatment interruption (p = 0.023) and reduced sustained EDSS regression for 12 (p = 0.016) and 24 weeks (p = 0.031) and, for the comparison of DMF versus FTY, a reduced sustained EDSS progression for 12 weeks (p = 0.02). CONCLUSIONS: Relapse rates with treatment with FTY, DMF and TERI were similar. Patients treated with DMF showed less sustained disability progression for 12 weeks than FTY-treated patients. However, FTY and DMF treatment was associated with more likely EDSS regression for 12 and 24 weeks and a lower probability for treatment interruption as compared to TERI-treated patients.
Subject(s)
Crotonates/pharmacology , Dimethyl Fumarate/pharmacology , Disease Progression , Fingolimod Hydrochloride/pharmacology , Immunosuppressive Agents/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Outcome Assessment, Health Care/methods , Registries , Toluidines/pharmacology , Administration, Oral , Adult , Austria , Crotonates/administration & dosage , Dimethyl Fumarate/administration & dosage , Female , Fingolimod Hydrochloride/administration & dosage , Follow-Up Studies , Humans , Hydroxybutyrates , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Nitriles , Severity of Illness Index , Toluidines/administration & dosageABSTRACT
BACKGROUND: Peginterferon beta-1a and teriflunomide are both first-line disease-modifying therapies (DMTs) approved for the treatment of relapsing multiple sclerosis (RMS); however, no head-to-head trials have directly compared their clinical efficacy. We performed a matching-adjusted comparison of individual patient data from the peginterferon beta-1a pivotal phase 3 study, ADVANCE, and its extension study, ATTAIN, with pooled aggregated data from the teriflunomide pivotal phase 3 studies, TEMSO and TOWER. METHODS: A total of 512 patients randomized to subcutaneous (SC) peginterferon beta-1a 125 mcg every 2 weeks in ADVANCE and 731 patients randomized to teriflunomide 14 mg daily (359 from TEMSO and 372 from TOWER) were matched on key baseline characteristics. After matching, weighted annualized relapse rate (ARR) and 24-week confirmed disability worsening (CDW) were calculated and compared for peginterferon beta-1a- and teriflunomide-treated patients. A subset analysis comparing weighted ARR in patients who were newly diagnosed with RMS (diagnosis ≤1 year before study enrollment and disease-modifying therapy naïve) was also performed. RESULTS: After matching, the peginterferon beta-1a and teriflunomide treatment groups were identically matched across baseline characteristics. The proportion of patients in the overall study populations with 24-week CDW at 108 weeks was significantly lower in the peginterferon beta-1a group than the teriflunomide group both before matching (8.5% vs 12.6%; P = 0.0249) and after matching (8.4% vs 12.6%; P = 0.0323). ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide both before matching (0.278 vs 0.354; P = 0.1326) and after matching (0.257 vs 0.354; P = 0.0510). Newly diagnosed patients treated with peginterferon beta-1a had numerically lower ARR than patients treated with teriflunomide both at 108 weeks (before matching: 0.225 vs 0.270; P = 0.587; after matching: 0.201 vs 0.270; P = 0.384) and at 5 years (before matching: 0.150 vs 0.196; after matching: 0.142 vs 0.196). CONCLUSIONS: In this matching-adjusted comparison of patients with RMS from three phase 3 trials, a significantly lower proportion of patients treated with SC peginterferon beta-1a 125 mcg every 2 weeks than with oral teriflunomide 14 mg once daily had 24-week CDW at 108 weeks. In addition, in both the overall population and newly diagnosed patient subgroups, ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide. The numerically lower ARR in newly diagnosed patients treated with peginterferon beta-1a compared with those treated with teriflunomide was sustained through up to 5 years of treatment.
Subject(s)
Crotonates/pharmacology , Disease Progression , Immunologic Factors/pharmacology , Interferon-beta/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Outcome Assessment, Health Care , Polyethylene Glycols/pharmacology , Toluidines/pharmacology , Adult , Crotonates/administration & dosage , Female , Humans , Hydroxybutyrates , Immunologic Factors/administration & dosage , Interferon-beta/administration & dosage , Male , Middle Aged , Nitriles , Polyethylene Glycols/administration & dosage , Recurrence , Toluidines/administration & dosageABSTRACT
Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called "needle fatigue", i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients' adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.
Subject(s)
Drug Substitution , Immunosuppressive Agents/administration & dosage , Medication Adherence , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Administration, Oral , Adult , Crotonates/administration & dosage , Dimethyl Fumarate/administration & dosage , Female , Humans , Hydroxybutyrates , Injections, Subcutaneous , Interferon alpha-2/administration & dosage , Interferon-alpha/administration & dosage , Male , Middle Aged , Nitriles , Polyethylene Glycols/administration & dosage , Product Surveillance, Postmarketing , Propensity Score , Recombinant Proteins/administration & dosage , Retrospective Studies , Toluidines/administration & dosage , Young AdultABSTRACT
Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 µmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 µmol/L. TER (5 µmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.
Subject(s)
Acyclovir/pharmacokinetics , Kidney/metabolism , Leflunomide/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Organic Anion Transport Protein 1/antagonists & inhibitors , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Acyclovir/administration & dosage , Acyclovir/metabolism , Administration, Intravenous , Animals , Cells, Cultured , Crotonates/administration & dosage , Crotonates/metabolism , Crotonates/pharmacology , Dogs , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Hydroxybutyrates , Leflunomide/administration & dosage , Leflunomide/metabolism , Madin Darby Canine Kidney Cells/drug effects , Madin Darby Canine Kidney Cells/metabolism , Male , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/metabolism , Nitriles , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Probenecid/administration & dosage , Probenecid/metabolism , Probenecid/pharmacology , Propionates/administration & dosage , Propionates/metabolism , Propionates/pharmacology , Quinolines/administration & dosage , Quinolines/metabolism , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley , Tissue Distribution , Toluidines/administration & dosage , Toluidines/metabolism , Toluidines/pharmacologyABSTRACT
Multiple sclerosis, which is characterized by inflammation and neurodegeneration, is considered a chronic disease of the central nervous system. Given the lack of pharmacokinetic evaluation of teriflunomide in the Iranian context, the present 2-way crossover study aimed to assess the pharmacokinetic properties and bioequivalence of 2 teriflunomide formulations. To this end, 2 single-dose generic and branded teriflunomide formulations were orally administered to 14 healthy Iranian male volunteers. A washout period of 21 days was allowed between the treatments. The plasma samples containing teriflunomide were analyzed by a simple and sensitive high-performance liquid chromatography method using standard ultraviolet detection. In addition, the pharmacokinetic parameters were calculated for bioequivalence evaluation. The peak area ratio between the teriflunomide and the internal standard was the source of calibration curves, which were linear over the range of 20-40,000 ng/mL (R2 = 0.9994). The results indicated that the 2 formulations had similar pharmacokinetics. Further, the 90%CI of the mean ratios of the test versus the reference formulations of log-transformed area under the concentration-time curve over 72 hours (93% to 107%) and peak concentration (92% to 108%) were within the acceptable range of 80% to 125%. Based on the obtained results, the test formulation of teriflunomide could be similar to that of the reference formulation.
Subject(s)
Crotonates/administration & dosage , Drugs, Generic/administration & dosage , Toluidines/administration & dosage , Administration, Oral , Adult , Area Under Curve , Chromatography, High Pressure Liquid , Cross-Over Studies , Crotonates/pharmacokinetics , Drugs, Generic/pharmacokinetics , Humans , Hydroxybutyrates , Iran , Male , Middle Aged , Nitriles , Therapeutic Equivalency , Toluidines/pharmacokinetics , Young AdultABSTRACT
The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2⯱â¯46.8⯵g/cm2) and 1.2 times (502.92⯱â¯24.0⯵g/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTgâ¯=â¯-17.7⯰C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.
Subject(s)
Analgesics/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Arthritis, Experimental/prevention & control , Azepines/administration & dosage , Crotonates/administration & dosage , Ketoprofen/administration & dosage , Pain/prevention & control , Skin Absorption/drug effects , Toluidines/administration & dosage , Transdermal Patch , Acetic Acid , Administration, Cutaneous , Analgesics/chemistry , Analgesics/pharmacokinetics , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Arthritis, Experimental/chemically induced , Azepines/chemistry , Crotonates/chemistry , Crotonates/pharmacokinetics , Drug Combinations , Drug Compounding , Drug Interactions , Drug Liberation , Freund's Adjuvant , Hydrogen Bonding , Hydroxybutyrates , Ketoprofen/chemistry , Ketoprofen/pharmacokinetics , Male , Mice , Nitriles , Pain/chemically induced , Permeability , Rabbits , Rats , Toluidines/chemistry , Toluidines/pharmacokineticsABSTRACT
With the emergence of drug-resistant strains of influenza A viruses (IAV), new antivirals are needed to supplement the existing counter measures against IAV infection. We have previously shown that brevilin A, a sesquiterpene lactone isolated from C. minima, suppresses the infection of influenza A/PR/8/34 (H1N1) in vitro. Here, we further investigate the antiviral activity and mode of action of brevilin A against different IAV subtypes. Brevilin A inhibited the replication of influenza A H1N1, H3N2, and H9N2 viruses in vitro. The suppression effect of brevilin A was observed as early as 4-8 hours post infection (hpi). Furthermore, we determined that brevilin A inhibited viral replication in three aspects, including viral RNA (vRNA) synthesis, expression of viral mRNA, and protein encoded from the M and NS segments, and nuclear export of viral ribonucleoproteins (vRNPs). The anti-IAV activity of brevilin A was further confirmed in mice. A delayed time-to-death with 50% surviving up to 14 days post infection was obtained with brevilin A (at a dose of 25 mg/kg) treated animals compared to the control cohorts. Together, these results are encouraging for the exploration of sesquiterpene lactones with similar structure to brevilin A as potential anti-influenza therapies.
Subject(s)
Antiviral Agents/administration & dosage , Crotonates/administration & dosage , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/drug effects , Influenza A Virus, H9N2 Subtype/drug effects , Influenza, Human/drug therapy , Sesquiterpenes/administration & dosage , Animals , Female , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/physiology , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/physiology , Influenza A Virus, H9N2 Subtype/genetics , Influenza A Virus, H9N2 Subtype/physiology , Influenza, Human/virology , Mice , Mice, Inbred BALB C , Virus Replication/drug effectsABSTRACT
BACKGROUND: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed. OBJECTIVES: The objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS. METHODS: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared. RESULTS: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (pâ¯=â¯0.02) and 2 (pâ¯=â¯0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001). CONCLUSION: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. The two oral therapies exhibited similar effects on disability outcomes.
Subject(s)
Crotonates/pharmacology , Fingolimod Hydrochloride/pharmacology , Immunologic Factors/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Outcome Assessment, Health Care , Toluidines/pharmacology , Adult , Crotonates/administration & dosage , Female , Fingolimod Hydrochloride/administration & dosage , Humans , Hydroxybutyrates , Immunologic Factors/administration & dosage , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Nitriles , Propensity Score , Retrospective Studies , Secondary Prevention , Severity of Illness Index , Toluidines/administration & dosageABSTRACT
AIM: Head-to-head clinical trials of teriflunomide (TFM) versus dimethyl fumarate (DMF) have not been conducted. OBJECTIVES: To compare the real-world effectiveness of TFM versus DMF. METHODS: Anonymized data were collected from patients with relapsing multiple sclerosis (MS) initiating treatment with teriflunomide (N = 50) or DMF (N = 50). RESULTS: On follow-up magnetic resonance imaging (MRI) compared with baseline, with TFM versus DMF treatment, the proportion of patients with new/enlarging T2 or gadolinium-enhancing lesions was 30.0 versus 40.0% (p = 0.2752). However, median annualized percent whole brain volume change was -0.1 versus -0.5 (p = 0.0212). There were no significant treatment differences on additional MRI and clinical end points and no unexpected safety signals. CONCLUSION: The effectiveness of teriflunomide was superior to DMF on whole brain atrophy and similar to DMF on other MRI/clinical end points.
Subject(s)
Crotonates/therapeutic use , Dimethyl Fumarate/therapeutic use , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Toluidines/therapeutic use , Adolescent , Adult , Aged , Brain/pathology , Comparative Effectiveness Research , Crotonates/administration & dosage , Crotonates/adverse effects , Dimethyl Fumarate/administration & dosage , Dimethyl Fumarate/adverse effects , Female , Humans , Hydroxybutyrates , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Nitriles , Retrospective Studies , Single-Blind Method , Socioeconomic Factors , Toluidines/administration & dosage , Toluidines/adverse effects , Young AdultABSTRACT
BACKGROUND: Multiple sclerosis (MS) is one of the most severe autoimmune disorder of the central nervous system (CNS). OBJECTIVE: The present research work was aimed to formulate and investigate teriflunomide (TFM)-loaded intranasal (i.n.) nanostructured lipid carriers (NLC) for the treatment of multiple sclerosis (MS). METHODS: The TFM-loaded NLC (TFM-NLC) nanoparticles were prepared by melt emulsification ultrasonication method using biodegradable and biocompatible polymers. The Box-Behnken statistical design was applied to optimize the formulation. The optimized NLC formulation was subjected to evaluate for particle size, entrapment efficiency (%), in vitro and ex vivo permeation. The safety and efficacy of optimized formulations were demonstrated using pharmacodynamic, subacute toxicity and hepatotoxicity data. RESULTS: Experimental data demonstrated that optimized NLC formulation (F17) showed significant size (99.82 ± 1.36 nm), zeta potential (-22.29 ± 1.8 mV) and % entrapment efficiency (83.39 ± 1.24%). Alternatively, ex vivo permeation of TFM mucoadhesive NLC (TFM-MNLC) and TFM-NLC was observed 830 ± 7.6 and 651 ± 9.8 µg/cm2, respectively. Whereas, TFM-MNLC shows around 2.0-folds more Jss than the TFM-NLC. Finally, TFM-MNLC (i.n.) formulation produced the rapid remyelination in cuprizone-treated animals and decreases the number of entries in open compartment of EPM when compared with negative control and TFM-NLC (oral) animals. Simultaneously, the nanoformulation did not reflect any gross changes in hepatic biomarkers and subacute toxicity when compared with control. CONCLUSIONS: Hence it can be inferred that the nose-to-brain delivery of TFM-MNLC can be considered as effective and safe delivery for brain disorders.
Subject(s)
Crotonates/administration & dosage , Drug Carriers/chemistry , Multiple Sclerosis/drug therapy , Toluidines/administration & dosage , Adhesiveness , Administration, Intranasal , Administration, Oral , Animals , Biocompatible Materials/chemistry , Biomarkers/metabolism , Crotonates/pharmacokinetics , Cuprizone/toxicity , Disease Models, Animal , Drug Liberation , Humans , Hydroxybutyrates , Lipids/chemistry , Liver/drug effects , Liver/metabolism , Male , Multiple Sclerosis/chemically induced , Nanoparticles/chemistry , Nasal Mucosa/metabolism , Nitriles , Particle Size , Polymers/chemistry , Rats , Rats, Wistar , Sheep , Toluidines/pharmacokinetics , Toxicity Tests, SubacuteABSTRACT
BACKGROUND AND OBJECTIVE: Teriflunomide is a once-daily oral immunomodulatory agent approved in 80 countries for the treatment of patients with relapsing multiple sclerosis (RMS). The study objective was to estimate the cost effectiveness of teriflunomide (14 mg tablet, daily) versus interferon beta-1b (250 mcg subcutaneous injection, every other day) among RMS patients from the Chinese healthcare system perspective. METHODS: A Markov model with annual cycles and a lifetime horizon was utilized to assess cost-effectiveness of teriflunomide in comparison with interferon beta-1b in RMS patients. Treatment effects, including 3-month confirmed disability worsening and annualized relapse rate, were derived from a network meta-analysis. Cost inputs included costs related to treatment acquisition, administration, monitoring, natural disease management through Expanded Disability Status Scale states, relapse treatment, and adverse event management. These costs were calculated as the product between unit costs from published sources and healthcare resource utilization patterns identified in a survey conducted among 11 neurologists across different areas in China. Health effects were expressed as quality-adjusted life years (QALYs) with costs in local currency (¥) and US dollars (US$), 2018. RESULTS: Teriflunomide dominated interferon beta-1b and was associated with lower total costs (teriflunomide ¥1,887,144 vs interferon beta-1b ¥2,061,393) and higher QALYs (teriflunomide 9.60 QALYs vs interferon beta-1b 8.88 QALYs). In probabilistic sensitivity analysis, teriflunomide was dominant in 62.2% of model runs. CONCLUSION: Teriflunomide is a cost-effective therapy over a lifetime time horizon compared to interferon beta-1b in the treatment of RMS patients in China. Results should be interpreted with caution as head-to-head comparisons are not available.