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Effect of CYP3A Inhibition and Induction on the Pharmacokinetics of Suvorexant: Two Phase I, Open-Label, Fixed-Sequence Trials in Healthy Subjects.
Wrishko, RE, McCrea, JB, Yee, KL, Liu, W, Panebianco, D, Mangin, E, Chakravarthy, M, Martinez-Cantarin, MP, Kraft, WK
Clinical drug investigation. 2019;(5):441-451
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BACKGROUND AND OBJECTIVES Suvorexant is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. As suvorexant is metabolized primarily by Cytochrome P450 3A (CYP3A), and its pharmacokinetics may be affected by CYP3A modulators, the effects of CYP3A inhibitors (ketoconazole or diltiazem) or an inducer (rifampin [rifampicin]) on the pharmacokinetics, safety, and tolerability of suvorexant were investigated. METHODS In two Phase I, open-label, fixed-sequence trials (Studies P008 and P038), healthy subjects received a single oral dose of suvorexant followed by co-administration with multiple once-daily doses of strong/moderate CYP3A inhibitors (ketoconazole/diltiazem) or a strong CYP3A inducer (rifampin). Treatments were administered in the morning: suvorexant 4 mg with ketoconazole 400 mg (Study P008; N = 10), suvorexant 20 mg with diltiazem 240 mg (Study P038; N = 20), and suvorexant 40 mg with rifampin 600 mg (Study P038; N = 10). Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), half-life (t½), and time to Cmax (tmax) were derived from plasma concentrations of suvorexant collected at prespecified time points up to 10 days following CYP3A inhibitor/inducer co-administration. Adverse events (AEs) were recorded. RESULTS Co-administration with ketoconazole resulted in increased exposure to suvorexant [AUC0-∞: geometric mean ratio (GMR); 90% confidence interval (CI) 2.79 (2.35, 3.31)] while co-administration with diltiazem resulted in a lesser effect [GMR (90% CI): 2.05 (1.82, 2.30)]. Co-administration with rifampin led to a marked decrease (88%) in suvorexant exposure. Consistent with morning administration and known suvorexant pharmacology, somnolence was the most frequently reported AE. CONCLUSIONS These results are consistent with expectations that strong CYP3A inhibitors and inducers exert marked effects on suvorexant pharmacokinetics. In the context of a limited sample size, single suvorexant doses were generally well tolerated in healthy subjects when co-administered with/without a CYP3A inhibitor/inducer.
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Limitations of serum ferritin to predict liver iron concentration responses to deferasirox therapy in patients with transfusion-dependent thalassaemia.
Porter, JB, Elalfy, M, Taher, A, Aydinok, Y, Lee, SH, Sutcharitchan, P, El-Ali, A, Han, J, El-Beshlawy, A
European journal of haematology. 2017;(3):280-288
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Abstract
BACKGROUND In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable. OBJECTIVES AND METHODS This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox. RESULTS Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL (r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively. CONCLUSIONS As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone.
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New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study.
Taher, AT, Origa, R, Perrotta, S, Kourakli, A, Ruffo, GB, Kattamis, A, Goh, AS, Cortoos, A, Huang, V, Weill, M, et al
American journal of hematology. 2017;(5):420-428
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Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naïve or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.
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Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia.
Taher, AT, Porter, JB, Viprakasit, V, Kattamis, A, Chuncharunee, S, Sutcharitchan, P, Siritanaratkul, N, Origa, R, Karakas, Z, Habr, D, et al
British journal of haematology. 2015;(2):284-90
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Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).
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Effect of maraviroc on non-R5 tropic HIV-1: refined analysis of subjects from the phase IIb study A4001029.
Surdo, M, Alteri, C, Puertas, MC, Saccomandi, P, Parrotta, L, Swenson, L, Chapman, D, Costa, G, Artese, A, Balestra, E, et al
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2015;(1):103.e1-6
Abstract
We characterized maraviroc susceptibility of dual/mixed tropic viruses from subjects enrolled onto phase IIb study A4001029. Maraviroc baseline plasma samples from 13 multidrug-experienced subjects were sequenced and the HIV-1-env gene cloned into pNL4.3Δenv to obtain recombinant viruses. The V3 region was sequenced by the Sanger method and ultradeep sequencing. By analysing subjects having a weighted optimized background therapy susceptibility (wOBT) score of <1, 3/7 subjects were characterized by good in vivo and in vitro response to maraviroc therapy. Molecular docking simulations allowed us to rationalize the maraviroc susceptibility of dual/mixed tropic viruses. A subset of subjects with dual/mixed tropic viruses responded to maraviroc. Further investigations are warranted of CCR5 antagonists in subjects carrying dual/mixed tropic virus that explore the feasible use of maraviroc in subjects that is potentially larger than those infected with a pure R5 virus.
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The durability of sitagliptin in elderly patients with type 2 diabetes.
Hsieh, CJ, Shen, FC
Clinical interventions in aging. 2014;:1905-11
Abstract
AIM: To evaluate the durability of sitagliptin and to assess changes in clinical chronic complications following sitagliptin monotherapy for 48 months in elderly patients with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS We enrolled 76 drug-naïve patients (40 women and 36 men; mean age: 71.3±11.7 years) with T2DM who received 25-100 mg of sitagliptin therapy from an outpatient clinic. The observational period for each patient was >48 months, beginning at the time sitagliptin therapy was initiated. The following were measured or performed at the beginning of each year: body mass index; serum total cholesterol, low-density lipoprotein, high-density lipoprotein; triglyceride levels; creatinine (Cr) levels; urine albumin and urine Cr; nonmydriatic fundusgraphy; and semiquantified neuropathy. The fasting plasma glucose and glycated hemoglobin (HbA1c) was measured every 3-6 months. RESULTS The change in HbA1c was significantly reduced after 6 months of therapy (7.1%±0.8% to 6.3%±0.2%). No changes in fasting plasma glucose, Cr, serum total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, body mass index, and microvascular complications were apparent. Using repeated measures to test the sequential changes in HbA1c from month 6 to month 48, the test of within-subjects effect was not significant (P=0.34). CONCLUSION Sitagliptin has a durable effect and stabilizes microvascular complication progression in elderly patients. This study can provide useful data for clinicians and health care professionals using sitagliptin monotherapy in the treatment of elderly patients with T2DM.
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Diabetes-related quality measure attainment: canagliflozin versus sitagliptin based on a pooled analysis of 2 clinical trials.
Bailey, RA, Vijapurkar, U, Meininger, GE, Rupnow, MF, Blonde, L
The American journal of managed care. 2014;(13 Suppl):s296-305
Abstract
OBJECTIVE To evaluate attainment of diabetes-related quality measures with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus. STUDY DESIGN This post hoc analysis used pooled data from two 52-week, randomized, double-blind, phase 3 clinical trials that evaluated the comparative efficacy of canagliflozin and sitagliptin. One trial evaluated patients on metformin at baseline with add-on canagliflozin 100 mg, canagliflozin 300 mg, or sitagliptin 100 mg; the other trial evaluated patients on metformin and a sulfonylurea at baseline with add-on canagliflozin 300 mg or sitagliptin 100 mg. METHODS Individual diabetes-related quality measures, including glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), and change in body weight, were assessed. RESULTS At baseline, the proportions of patients meeting criteria for all quality measures were similar between groups. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 100 mg demonstrated either comparable or superior glycemic control. Additionally, canagliflozin 100 mg versus sitagliptin 100 mg demonstrated superior attainment of BP, BMI, and weight-related quality measures; no difference was seen with respect to LDL-C. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 300 mg demonstrated superior glycemic control at all thresholds of A1C, and superior BP, BMI, and weight-related quality measures; there was no difference in LDL-C quality measure attainment. CONCLUSION We evaluated the comparative efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg on quality measure attainment after 52 weeks of treatment. Compared with sitagliptin 100 mg, canagliflozin 100 mg demonstrated comparable or superior attainment of diabetes-related quality measures. Compared with sitagliptin 100 mg, canagliflozin 300 mg demonstrated superior diabetes-related quality measure attainment, including glycemic, BP, and weight-related quality measures; there was no difference in LDL-C quality measure attainment between either dosage of canagliflozin and the 100-mg dosage of sitagliptin.
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Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with β-thalassemia major.
Casale, M, Citarella, S, Filosa, A, De Michele, E, Palmieri, F, Ragozzino, A, Amendola, G, Pugliese, U, Tartaglione, I, Della Rocca, F, et al
American journal of hematology. 2014;(12):1102-6
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Iron overload in β-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P = 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre-exisisting was observed in a real clinical practice setting.
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Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial.
Schernthaner, G, Gross, JL, Rosenstock, J, Guarisco, M, Fu, M, Yee, J, Kawaguchi, M, Canovatchel, W, Meininger, G
Diabetes care. 2013;(9):2508-15
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OBJECTIVE To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea. RESEARCH DESIGN AND METHODS In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports. RESULTS At 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (-1.03% [-11.3 mmol/mol] and -0.66% [-7.2 mmol/mol], respectively; least squares mean difference between groups, -0.37% [95% CI, -0.50 to -0.25] or -4.0 mmol/mol [-5.5 to -2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin (P < 0.001). Overall AE rates were similar with canagliflozin (76.7%) and sitagliptin (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. Higher incidences of genital mycotic infections and osmotic diuresis-related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both groups. CONCLUSIONS Findings suggest that canagliflozin may be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea.
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Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes.
Ferrannini, E, Berk, A, Hantel, S, Pinnetti, S, Hach, T, Woerle, HJ, Broedl, UC
Diabetes care. 2013;(12):4015-21
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OBJECTIVE To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin. RESULTS Changes from baseline in HbA1c at week 90 were -0.34 to -0.63% (-3.7 to -6.9 mmol/mol) with empagliflozin, -0.56% (-6.1 mmol/mol) with metformin, and -0.40% (-4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were -2.2 to -4.0 kg with empagliflozin, -1.3 kg with metformin, and -0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2-74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0-5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8-12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin. CONCLUSIONS Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.