The tolerability of sofosbuvir/velpatasvir for 12 weeks in patients treated in the ASTRAL 1, 2 and 3 studies: A pooled safety analysis.

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.

Global Real-World Evidence of Sofosbuvir/Velpatasvir as a Highly Effective Treatment and Elimination Tool in People with Hepatitis C Infection Experiencing Mental Health Disorders.

Hepatitis C virus (HCV) is prevalent in people with mental health disorders, a priority population to diagnose and cure in order to achieve HCV elimination. This integrated analysis pooled data from 20 cohorts in seven countries to evaluate the real-world effectiveness of the pangenotypic direct-acting antiviral (DAA) sofosbuvir/velpatasvir (SOF/VEL) in people with mental health disorders. HCV-infected patients diagnosed with mental health disorders who were treated with SOF/VEL for 12 weeks without ribavirin as part of routine clinical practice were included. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with an available SVR assessment. Secondary outcomes were reasons for not achieving SVR, characteristics of patients with non-virological failures, adherence, and time from HCV RNA diagnosis to SOF/VEL treatment initiation. A total of 1209 patients were included; 142 did not achieve an SVR for non-virological reasons (n = 112; 83 lost to follow-up, 20 early treatment discontinuations) or unknown reasons (n = 30). Of the 1067 patients in the EP, 97.4% achieved SVR. SVR rates in the EP were ≥95% when stratified by type of mental health disorder and other complicating baseline characteristics, including active injection drug use and antipsychotic drug use. Of 461 patients with data available in the EP, only 2% had an adherence level < 90% and 1% had an adherence level < 80%; all achieved SVR. Patients with mental health disorders can be cured of HCV using a well-tolerated, pangenotypic, protease inhibitor-free SOF/VEL regimen. This DAA allows the implementation of a simple treatment algorithm, with minimal monitoring requirements and fewer interactions with central nervous system drugs compared with protease-inhibitor DAA regimens.

Guidelines Have a Key Role in Driving HCV Elimination by Advocating for Simple HCV Care Pathways.

The availability of pangenotypic direct-acting antivirals for treatment of hepatitis C (HCV) has provided an opportunity to simplify patient pathways. Recent clinical practice guidelines have recognised the need for simplification to ensure that elimination of HCV as a public health concern remains a priority. Despite the move towards simplified treatment algorithms, there remains some complexity in the recommendations for the management of genotype 3 patients with compensated cirrhosis. In an era where additional clinical trial data are not anticipated, clinical guidance should consider experience gained in real-world settings. Although more experience is required for some pangenotypic therapeutic options, on the basis of published real-world data, there is already sufficient evidence to consider a simplified approach for genotype 3 patients with compensated cirrhosis. The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to minimise the need for complex patient pathways and clinical practice guidelines need to continue to evolve in order to ensure that patient outcomes remain optimised.

Global real-world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts.

BACKGROUND AND AIMS: Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real-world analysis to date, the effectiveness of pangenotypic, panfibrotic, single-tablet, sofosbuvir/velpatasvir (SOF/VEL) once-daily for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. METHODS: Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post-treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. RESULTS: Overall, 5552 patients were included: 13.3% treatment-experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non-virological reasons (67% lost to follow-up; 26.5% early treatment discontinuation). CONCLUSIONS: In this large cohort, representative of clinical practice, a simple 12-week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.

Posaconazole plasma exposure correlated to intestinal mucositis in allogeneic stem cell transplant patients.

PURPOSE: Low posaconazole plasma concentrations (PPCs) are frequently encountered in allogeneic hematopoietic stem cell transplant (HSCT) patients, due to variable gastrointestinal absorption. In this study, the impact of intestinal mucositis on posaconazole exposure is investigated. PATIENTS AND METHODS: A prospective pharmacokinetic study was performed including allogeneic HSCT patients receiving posaconazole prophylaxis with the oral suspension or tablets. Steady state PPCs were determined using high-performance liquid chromatography-fluorescence detection at the day of transplantation (=day 0), day +7, and +14. Citrulline was measured using liquid chromatography-tandem mass spectrometry to evaluate severity of mucositis, at baseline (day -7 or -6), and at day 0, +7 and +14. Additionally, citrulline plasma concentrations and steady state trough PPCs were determined in hematological patients without HSCT or mucositis. RESULTS: Thirty-four HSCT patients received posaconazole oral suspension together with 25 cL of Coca Cola, 6 HSCT patients received posaconazole tablets and 33 hematological patients not receiving HSCT received posaconazole oral suspension. The median (interquartile range) average PPC was 0.26 mg/L (0.17-0.43), 0.67 mg/L (0.27-1.38), and 1.08 mg/L (0.96-1.38), with suspension in HSCT patients, suspension in hematological patients and tablets in HSCT patients, respectively. A higher trough PPC was encountered with the oral suspension when citrulline plasma concentrations were above 10 µmol/L compared to values below 10 µmol/L (p < 0.001), whereas for tablets, average PPCs remained high with citrulline plasma concentrations below or above 10 µmol/L (p = 0.64). CONCLUSION: Posaconazole tablets should be preferred to suspension in HSCT patients immediately after transplantation to prevent insufficient plasma exposure due to intestinal mucositis.

Chemotherapy-Induced Intestinal Mucosal Barrier Damage: a Cause of Falsely Elevated Serum 1,3-Beta-d-Glucan Levels?

Blood citrulline and intestinal fatty acid binding protein were determined as biomarkers for intestinal mucositis. Biomarker levels were correlated with corresponding serum 1,3-beta-D-glucan levels in 56 samples obtained from 33 cases with underlying hematological malignancies receiving induction chemotherapy. No correlation between biomarkers of intestinal mucositis and BDG levels was observed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01576653.).

Pharmacokinetics of Posaconazole Oral Suspension in Children Dosed According to Body Surface Area.

BACKGROUND: Antifungal prophylaxis remains challenging in immunocompromised children as no clear consensus has yet been reached about which drug to be used. Posaconazole has a broad spectrum of activity, a favorable safety profile and excellent prophylactic activity in adults. However, a lack of pharmacokinetic studies in pediatric patients hampers routine implementation. This study investigates the pharmacokinetics of a newly introduced posaconazole dosing regimen based on the body surface area in pediatric hematologic patients. METHODS: In this prospective pharmacokinetic study, 8 blood samples were taken during 1 dosing interval at steady state in children aged 13 years or younger with hematologic malignancy, who were treated prophylactically with posaconazole oral suspension at a dose of 120 mg/m 3 times daily. Posaconazole plasma concentrations were determined using high-performance liquid chromatography fluorescence detection. RESULTS: One hundred twelve samples were taken from 14 patients with a mean age of 6.7 ± 2.8 years. A median posaconazole daily dose of 100.0 mg (77.3-100.0) 3 times daily (tid), corresponding to a median of 117.9 mg/m (112.2-120.4) tid, resulted in mean trough posaconazole plasma concentrations of 0.85 ± 0.56 mg/L. Pharmacokinetic analysis revealed a clearance of 0.8 L/(h kg) (0.5-1.4). No invasive fungal infections or adverse events were encountered during treatment. CONCLUSIONS: Posaconazole is a promising antifungal agent to be used prophylactically in hematologic patients aged 13 years or younger. Administering posaconazole oral suspension in a dosage of 120 mg/m tid results in adequate posaconazole plasma exposure, without significant adverse events.

Factors impacting unbound vancomycin concentrations in different patient populations.

The unbound drug hypothesis states that only unbound drug concentrations are active and available for clearance, and highly variable results regarding unbound vancomycin fractions have been reported in the literature. We have determined the unbound vancomycin fractions in four different patient groups by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and identified factors that modulate vancomycin binding. We have further developed and validated a prediction model to estimate unbound vancomycin concentrations. Vancomycin (unbound and total) concentrations were measured in 90 patients in four different hospital wards (hematology [n = 33 samples], intensive care unit [ICU] [n = 51], orthopedics [n = 44], and pediatrics [age range, 6 months to 14 years; n = 18]) by a validated LC-MS/MS method. Multiple linear mixed model analysis was performed to identify patient variables that were predictive of unbound vancomycin fractions and concentrations. The variables included in the model were patient age, ward, number of coadministered drugs with high protein binding, kidney function (estimated glomerular filtration rate [determined by Chronic Kidney Disease Epidemiology Collaboration formula]), alpha-1-acid glycoprotein, albumin, total bilirubin, IgA, IgM, urea, and total vancomycin concentrations. In the pediatric cohort, the median unbound vancomycin fraction was 81.3% (range, 61.9 to 95.9%), which was significantly higher (P < 0.01) than the unbound fraction found in the three adult patient cohorts (hematology, 60.6% [48.7 to 90.6%]; ICU, 61.7% [47.0 to 87.6%]; orthopedics, 56.4% [45.9 to 78.0%]). The strongest significant predictor of the unbound vancomycin concentration was the total drug concentration, completed by albumin in the pediatric cohort and albumin and IgA in the adult cohorts. Validation of our model was performed with data from 13 adult patients. A mean difference of 0.3 mg/liter (95% confidence interval [CI], -1.3 to 0.7 mg/liter; R(2) = 0.99 [95% CI, 0.95 to 0.99]) between measured and calculated unbound vancomycin concentrations demonstrated that the predictive performance of our model was favorable. Unbound vancomycin fractions vary significantly between pediatric and adult patients. We developed a formula to estimate the unbound fraction derived from total vancomycin, albumin, and IgA concentrations in adult patients.

Investigation of Saliva as an Alternative to Plasma Monitoring of Voriconazole.

BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring (TDM) of voriconazole is increasingly being implemented in clinical practice. However, as blood sampling can be difficult in paediatric and ambulatory patients, a non-invasive technique for TDM is desirable. The aim of this study was to compare the pharmacokinetics of voriconazole in saliva with the pharmacokinetics of unbound and total voriconazole in plasma in order to clinically validate saliva as an alternative to plasma in voriconazole TDM. METHODS: In this pharmacokinetic study, paired plasma and saliva samples were taken at steady state in adult haematology and pneumology patients treated with voriconazole. Unbound and bound plasma voriconazole concentrations were separated using high-throughput equilibrium dialysis. Voriconazole concentrations were determined with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using log-linear regression. RESULTS: Sixty-three paired samples were obtained from ten patients (seven haematology and three pneumology patients). Pearson's correlation coefficients (R values) for saliva versus unbound and total plasma voriconazole concentrations showed a very strong correlation, with values of 0.970 (p < 0.001) and 0.891 (p < 0.001), respectively. Linear mixed modelling revealed strong agreement between voriconazole concentrations in saliva and unbound plasma voriconazole concentrations, with a mean bias of -0.03 (95 % confidence interval -0.14 to 0.09; p = 0.60). For total concentrations below 10 mg/L, the mean ratio of saliva to total plasma voriconazole concentrations was 0.51 ± 0.08 (n = 63), which did not differ significantly (p = 0.76) from the unbound fraction of voriconazole in plasma of 0.49 ± 0.03 (n = 36). CONCLUSIONS: Saliva can serve as a reliable alternative to plasma in voriconazole TDM, and it can easily be implemented in clinical practice.

Impact of hypoalbuminemia on voriconazole pharmacokinetics in critically ill adult patients.

Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P = 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

Protein-binding characteristics of voriconazole determined by high-throughput equilibrium dialysis.

Plasma protein binding (PPB) can possibly alter the already variable pharmacokinetics of voriconazole. Voriconazole PPB was determined only once, being 58%, according to equilibrium dialysis (ED). We investigated voriconazole PPB more in detail, with a convenient and newer high-throughput ED assay (HT-ED), in human blank plasma spiked with voriconazole and in plasma from intensive care unit (ICU) patients treated with voriconazole. HT-ED was conducted in a 96-well plate, setup against phosphate-buffered saline. Voriconazole concentrations were measured by liquid chromatography-tandem mass spectrometry. The median PPB was 47.6% [interquartile range (IQR) 45.3%-50%] in vitro, and 49.6% (IQR 42.5%-52.5%) in ICU samples (p = 0.35), and is not depending on total voriconazole concentration (0.7-11.2 mg/L, p = 0.65). The drug mainly binds to albumin (25.5 ± 5.1%), and to a lesser extent to α-1-acid glycoprotein (AAG; 4.8 ± 1.2%). The HT-ED assay can be performed at 37 °C or 25 °C (p = 0.44) and in batch: PPB variations during freeze-thaw cycles (p = 0.13) and during frozen storage up to 12 months (p = 0.10) were not clinically relevant. Voriconazole PPB is approximately 50%, according to HT-ED. As albumin and AAG only account for approximately 30% of total voriconazole PPB, other plasma components could influence PPB and therefore efficacy or toxicity because of variations in unbound fractions.

The Eagle-like effect of echinocandins: what's in a name?

Despite several years of research, a lot of questions remain about the paradoxical attenuation of echinocandin activity against Candida and Aspergillus species at certain drug concentrations above the MIC values, the so-called paradoxical growth effect or Eagle-like effect. Although this phenomenon has been observed in several in vitro studies, confirming in vivo data are scarce. The clinical relevance remains unknown, although more and more data suggest that the clinical impact of this phenomenon might be heavily overrated. Detailed knowledge about the mechanisms responsible for this phenomenon and further research about the presence of the effect in the human body is necessary to decide whether the paradoxical growth effect of echinocandins can really interfere with an adequate treatment of invasive fungal diseases in clinical practice.