Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

ABSTRACT Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUC ave ]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate. </jats:p

Fezolinetant in the treatment of vasomotor symptoms associated with menopause

Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS). Areas covered: This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS. Expert opinion: Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the 'hot flash' response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS

Personal non-commercial use only. The Journal of Rheumatology Registered as NCT00175019. (First Release

ABSTRACT. Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and &lt; 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance. Results. After 1 month initial treatment, &gt; 80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA &lt; 6.0 mg/dl. After ULT reassignment, &gt; 80% of all remaining subjects maintained the primary efficacy endpoint of SUA &lt; 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA &lt; 6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA &lt; 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups. Conclusion. Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time

Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout

ABSTRACT. Objective. To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout. Methods. Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and &lt; 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance. Results. After 1 month initial treatment, &gt; 80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA &lt; 6.0 mg/dl. After ULT reassignment, &gt; 80% of all remaining subjects maintained the primary efficacy endpoint of SUA &lt; 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA &lt; 6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA &lt; 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups. Conclusion. Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time

Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.status: publishe

Evaluation and performance of a newly developed patient-reported outcome instrument for diarrhea-predominant irritable bowel syndrome in a clinical study population

Background: To evaluate the psychometric properties of the newly developed seven-item Irritable Bowel Syndrome – Diarrhea predominant (IBS-D) Daily Symptom Diary and four-item Event Log using phase II clinical trial safety and efficacy data in patients with IBS-D. This instrument measures diarrhea (stool frequency and stool consistency), abdominal pain related to IBS-D (stomach pain, abdominal pain, abdominal cramps), immediate need to have a bowel movement (immediate need and accident occurrence), bloating, pressure, gas, and incomplete evacuation. Methods: Psychometric properties and responsiveness of the instrument were evaluated in a clinical trial population [ ClinicalTrials.gov identifier: NCT01494233]. Results: A total of 434 patients were included in the analyses. Significant differences were found among severity groups ( p < 0.01) defined by IBS Patient Global Impression of Severity (PGI-S) and IBS Patient Global Impression of Change (PGI-C). Severity scores for each Diary and Event Log item score and five-item, four-item, and three-item summary scores were calculated. Between-group differences in changes over time were significant for all summary scores in groups stratified by changes in PGI-S ( p < 0.05), two of six Diary items, and three of four Event Log items; a one-grade change in PGI-S was considered a meaningful difference with mean change scores on all Diary items −0.13 to −0.86 [standard deviation (SD) 0.79–1.39]. Similarly, for patients who reported being ‘slightly improved’ (considered a clinically meaningful difference) on the PGI-C, mean change scores on Diary items ranged from −0.45 to −1.55 (SD 0.69–1.39). All estimates of clinically important change for each item and all summary scores were small and should be considered preliminary. These results are aligned with the previous standalone psychometric study regarding reliability and validity tests. Conclusions: These analyses provide evidence of the psychometric properties of the IBS-D Daily Symptom Diary and Event Log in a clinical trial population

Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial

Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA. A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count 10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed. One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P 0.05 for both). Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes