Efficacy and Safety of Remdesivir in People With Impaired Kidney Function Hospitalized for COVID-19 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Few antiviral therapies have been studied in patients with COVID-19 and kidney impairment. Herein, efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-beta-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. METHODS: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury (AKI), chronic kidney disease (CKD), or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on Day 1; 100 mg daily up to Day 5) or placebo (enrollment: March 2021-March 2022). The primary efficacy endpoint was the composite of all-cause mortality or invasive mechanical ventilation (IMV) through Day 29. Safety was evaluated through Day 60. RESULTS: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 (37.0%) participants had AKI (remdesivir, 60; placebo, 30), 64 (26.3%) had CKD (remdesivir, 44; placebo, 20), and 89 (36.6%) had kidney failure (remdesivir, 59; placebo, 30); 31 (12.8%) were COVID-19 vaccinated. Composite all-cause mortality or IMV through Day 29 was 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = 0.61). Treatment-emergent adverse events were reported in 80.4% versus 77.5% and serious adverse events in 50.3% versus 50.0% of participants who received remdesivir versus placebo, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. CONCLUSIONS: Although underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in those with COVID-19 and severe kidney impairment. (EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351). TRIAL REGISTRATION: EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351.

Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study.

BACKGROUND: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. METHODS: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. FINDINGS: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. INTERPRETATION: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. FUNDING: Janssen Research & Development.

B-Mode Ultrasound and Contrast-Enhanced Ultrasound for the Detection of Splenic Involvement in Hodgkin Lymphoma: A Retrospective Analysis of 112 Patients.

PURPOSE: To assess splenic involvement using B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) compared with standard imaging with contrast-enhanced computerized tomography (CT) / 18-fluorodeoxyglucose positron-emission tomography (PET-CT) in patients with Hodgkin lymphoma. MATERIALS AND METHODS: Imaging data from 112 patients from 12/2003 to 10/2022 with histologically confirmed Hodgkin lymphoma during staging or relapse were analyzed for splenic lymphoma involvement. In all patients, standard imaging (CT/PET-CT), along with B-mode US and CEUS examinations, was performed. Evidence of focal splenic lesions (FSLs) found by imaging procedures was suggestive of splenic involvement. Follow-up imaging was performed in each patient after treatment, and treatment response indicated definitive splenic involvement. RESULTS: 40 patients (35.7%) were identified by imaging modalities as having splenic involvement, which was confirmed by response during follow-up. Standard CT/PET-CT imaging detected splenic involvement in 36/112 patients (32.1%). FSLs were detected with B-mode US in 38 patients (33.9%) and CEUS in 36 patients (32.1%). The sensitivity of standard imaging, B-mode US, and CEUS was 90%, 95%, and 90%, respectively. CONCLUSION: B-mode US examination is a diagnostic method used in addition to standard imaging for the detection of splenic involvement in Hodgkin lymphoma. CEUS does not provide additional benefit compared to B-mode US and the standard reference procedure.

Consistency of Violence: Implications for Effective Inpatient Psychiatric Care.

Instances of violence and aggression in acute psychiatric settings are common and highly distressing for service users and staff. They also incur financial costs. This study aimed to identify the proportion of service users at risk of consistent violence/aggression enactment. It also aimed to analyse associated service use to explore the potential need for specialised, targeted approaches. Five years' worth of data were extracted from 2016 to 2020 on inpatient stays across South London and Maudsley NHS Foundation Trust (SLaM) acute adult wards and Psychiatric Intensive Care Units (PICUs). Service users were divided into cohorts based on relative number of violent/agressive incidents enacted. Differences in frequency of acute service use during the period 1st January-31st December 2020 were analysed. In total, 2524 service users had at least one inpatient stay during 2020. 679 were recorded as having enacted at least one incident of violence or aggression. Just 4% of all service users accounted for 50% of all violence/aggression enactment. Results further showed strong evidence of group differences between violence cohorts in the following domains: internal transfers, occupied bed days, admissions and Place of Safety (PoS) referrals. There was weaker evidence for group differences in referrals to Home Treatment teams (HTTs) and Psychiatric Liaison Teams. A small proportion of service users disproportionately account for the majority of violent and aggressive incidents and higher levels of violence and aggression are associated with more acute service use. The provision of targeted, personalised interventions for this cohort may reduce the enactment of violence and aggression, leading to improved quality life and a reduction in financial expenditure.

Absence of Pharmacokinetic Interactions between the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate.

Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.

In Vitro, in Silico, and in Vivo Assessments of Intestinal Precipitation and Its Impact on Bioavailability of a BCS Class 2 Basic Compound.

In this study, a multipronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets. The in vitro precipitate was found to be noncrystalline with higher solubility than the crystalline API, and was readily soluble when the drug concentration was lowered by dilution. A gastric transit and biphasic dissolution (GTBD) model was developed to better mimic gastric transfer and intestinal absorption. Precipitation was also observed in GTBD, but the precipitate redissolved and partitioned into the organic phase. In vivo data from the phase 1 clinical trial showed linear and dose proportional PK for the formulations with no evidence of in vivo precipitation. While the in vitro precipitation observed in the 2-stage dissolution appeared to overestimate in vivo precipitation, the GTBD model provided absorption profiles consistent with in vivo data. In silico simulation of plasma concentrations by GastroPlus using biorelevant in vitro dissolution data from the tablets and capsules and assuming negligible precipitation was in line with the observed in vivo profiles of the two formulations. The totality of data generated with Compound-A indicated that the bioavailability differences among the three formulations were better explained by the differences in gastric dissolution than intestinal precipitation. The lack of intestinal precipitation was consistent with several other BCS class 2 basic compounds in the literature for which highly supersaturated concentrations and rapid absorption were also observed.

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

Review of non-medical prescribing among acute and community staff.

All employers of non-medical prescribers (NMPs) have a duty to ensure they remain competent and current, and have access to relevant continuing professional development as identified through their staff appraisals. This article describes a survey that was undertaken to evaluate non-medical prescribing in one trust that operates an acute district hospital and community services. Five themes emerged from the results: prescribing activity, patient safety, effect of non-medical prescribing on care, workforce planning and organisational support. The findings also suggested that most NMPs surveyed were compliant with local and national policy. Non-compliance was addressed through line manager intervention. Support for NMPs must be addressed at organisational level to ensure safety of all stakeholders.

Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants.

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 µCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

Effect of a high-calorie, high-fat meal on the bioavailability and pharmacokinetics of PA-824 in healthy adult subjects.

PA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios of Cmax and AUC0-∞ revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The median Tmax in the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the median Tmax was 4 h for the 50- and 200-mg doses and 6.5 h for the 1,000-mg dose. All doses were well tolerated, and no serious adverse events occurred in either study. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01828827 and NCT01830439.).

Evaluation of pharmacokinetic interaction between PA-824 and midazolam in healthy adult subjects.

This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC0-t, AUC(0-∞), and C(max) for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of C(max), AUC(0-t), and AUC(0-∞) parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The Cmax of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs.

Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis.

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.

BACKGROUND: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. METHODS: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. FINDINGS: The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. INTERPRETATION: PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. FUNDING: The Global Alliance for TB Drug Development (TB Alliance).

Exposure-safety and exposure-efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors.

The antibody-drug conjugate (ADC) tisotumab vedotin (TV) received accelerated approval from the US Food and Drug Administration for treatment of adults with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. A population pharmacokinetic (PK) model, developed using dosing data from four clinical TV studies, was used to estimate individual exposure and explore safety and efficacy exposure-response (ER) relationships. Because PK analysis showed no appreciable accumulation of TV and monomethyl auristatin E (MMAE) with repeated dosing, cycle 1 exposure metrics and predicted average concentrations from time zero until end of the cycle in which an event occurred (CavgLast ) were used for ER analyses. The probability of achieving objective response increased significantly as the ADC cycle 1 maximum serum concentration (Cmax ) increased. The probability of treatment-related adverse events (AEs) leading to dose modification increased significantly as ADC cycle 1 area under the concentration-time curve (AUC) increased. Number of grade 2+ ocular AEs increased significantly as ADC cycle 1 AUC, Cmax , and ADC CavgLast increased. MMAE cycle 1 AUC predicted risk of serious treatment-related AEs. The relationship between ADC exposure and efficacy end points suggests ADC treatment was associated with clinically meaningful response across the observed exposures; greater exposure was associated with increased efficacy. The relationship between ADC and MMAE exposure and safety end points suggests increased exposure was associated with increased AE risk. These results align with clinical findings showing TV 2 mg/kg (≤200 mg for patients ≥100 kg) every 3 weeks is efficacious and tolerable for patients with r/mCC.

Pharmacokinetics, safety, and tolerability of inhaled remdesivir in healthy participants.

Intravenous remdesivir (RDV) is US Food and Drug Administration-approved for hospitalized and nonhospitalized individuals with coronavirus disease 2019. RDV undergoes intracellular metabolic activation to form the active triphosphate, GS-443902, and other metabolites. Alternative administration routes, including localized pulmonary delivery, can lower systemic exposure and maximize exposure at the site of action. This study evaluated the pharmacokinetics (PK) and safety of inhaled RDV in healthy adults. This phase Ia, randomized, placebo-controlled study evaluated inhaled RDV in healthy participants randomized 4:1 to receive RDV or placebo as single doses (4 cohorts) or multiple once-daily doses (3 cohorts). Doses in cohorts 1-6 were administered as an aerosolized solution for inhalation through a sealed facemask; doses in cohort 7 were administered as an aerosolized solution for inhalation through a mouthpiece. Safety was assessed throughout the study. Seventy-two participants were enrolled (inhaled RDV, n = 58 and placebo, n = 14). Following single RDV doses, RDV, GS-704277, and GS-441524 plasma PK parameters indicated dose-proportional increases in area under the concentration-time curve (AUC) extrapolated to infinite time, AUC from time zero to last quantifiable concentration, and maximum observed concentration. Analyte plasma concentrations after multiple RDV doses were consistent with those for single-dose RDV. Analyte plasma exposures were lower when RDV was administered with a mouthpiece versus a sealed facemask. The most common adverse events included nausea, dizziness, and cough. Single- and multiple-dose inhaled RDV exhibited linear and dose-proportional plasma PK. Administration of RDV via inhalation was generally safe and well-tolerated.

Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects.

UNLABELLED: AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects. METHODS: Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed. RESULTS: PF-04457845 was rapidly absorbed (median t(max) 0.5-1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5- to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. CONCLUSIONS: PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.

Staff support in a National Health Service mental health trust in response to the COVID-19 pandemic: qualitative study.

BACKGROUND: The COVID-19 pandemic has highlighted the impact work can have on healthcare workers and the importance of staff support services. Rapid guidance was published to encourage preventive and responsive support for healthcare workers. AIMS: To understand mental healthcare staff's help-seeking behaviours and access to support at work in response to the COVID-19 pandemic, to inform iterative improvements to provision of staff support. METHOD: We conducted a formative appraisal of access to support and support needs of staff in a National Health Service mental health trust. This involved 11 semi-structured individual interviews using a topic guide. Five virtual staff forums were additional sources of data. Reflexive thematic analysis was used to identify key themes. RESULTS: Peer-based, within-team support was highly valued and sought after. However, access to support was negatively affected by work pressures, physical distancing and perceived cultural barriers. CONCLUSIONS: Healthcare organisations need to help colleagues to support each other by facilitating open, diverse workplace cultures and providing easily accessible, safe and reflective spaces. Future research should evaluate support in the evolving work contexts imposed by COVID-19 to inform interventions that account for differences across healthcare workforces.

Population pharmacokinetic analysis for tisotumab vedotin in patients with locally advanced and/or metastatic solid tumors.

Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) for treatment of solid tumors expressing tissue factor with accelerated approval from the US Food and Drug Administration for treatment of recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. This study describes development of a population pharmacokinetic (PK) model to assess the PK profile of tisotumab vedotin and microtubule-disrupting agent monomethyl auristatin E (MMAE) using data from 399 patients with solid tumors across four phase I/II trials. The ADC-MMAE model describes ADC and MMAE concentrations following intravenous administration of tisotumab vedotin. This four-compartment model comprises a two-compartment ADC model with parallel linear and Michaelis-Menten elimination, a delay compartment, and a one-compartment MMAE model. Nonspecific linear clearance of ADC was 1.42 L/day, central volume of distribution (Vc ) was 3.10 L, and median terminal half-life of ADC was 4.04 days. Apparent clearance of MMAE was 42.8 L/day, and apparent volume of distribution was 2.09 L. Terminal slope of the MMAE concentration-time curve was defined by the delay compartment rate with a half-life of 2.56 days. Patients with higher body weight and lower albumin concentration had faster ADC clearance. Male patients and those with higher body weight and lower albumin concentration had higher Vc . Body weight was the most influential covariate influencing distribution and elimination of ADC and MMAE, thus supporting weight-based dosing of tisotumab vedotin. Presence of antidrug antibodies (detected in 3.3% of patients) did not affect key PK parameters or exposures for ADC and MMAE.

Understanding the time course of pharmacological effect: a PKPD approach.

The key concepts that underpin the choice of drug and dosing regimen are an understanding of the drugs' effectiveness, the potential for adverse effects, and the expected time course over which both desired and adverse effects are likely to occur. Research in clinical pharmacology should therefore address three fundamental questions: (1) What is the magnitude of drug effects (beneficial or adverse) from a given dose? (2) How quickly will any given effects occur? (3) How long will these effects last? Under steady-state conditions, only the magnitude of drug effects can be examined. This requires researchers to consider non-steady-state conditions, which require more complex models and an understanding of the mechanisms that drive the time course of drug effect. The aim of this review is to provide a conceptual framework for understanding the time course of drug effects using pharmacokinetic-pharmacodynamic models. Key examples will illustrate how this can inform the optimal use of drugs in the clinic.