10-mg Dose Research Articles

Hyoscine butylbromide in pain reduction associated with ultrasound-guided manual vacuum aspiration: a randomized placebo-controlled trial

Research questionWhat is the effect of adding an anti-spasmodic drug to an existing ultrasound-guided manual vacuum aspiration (USG-MVA) protocol to alleviate immediate post-procedure abdominal cramping pain in women treated for early pregnancy loss? DesignDouble-blind, placebo-controlled, randomized controlled trial conducted between February 2018 and January 2020. Participants were assigned to receive a 1-ml intravenous injection containing 20-mg hyoscine butylbromide (HBB) (n=55) or saline (n =56) as a control immediately before USG-MVA. Primary outcome was reduced abdominal pain after adding a 20-mg dose of HBB to the current pain control regimen. Secondary outcomes were vaginal pain, complications and side-effects, women's pre- and post-procedure psychological state, physiological stress (saliva alpha-amylase) and procedure pain control satisfaction. Two-way mixed ANOVA was used to evaluate the main effects and interactions. ResultsVAS abdominal pain scores in the HBB group were 16% lower immediately after and 21% lower 2 h after surgery (not statistically significant). Two-way ANOVA indicated that time (F[1108] = 83.41, P < 0.001) was the only significant main effect for reduced abdominal pain after the procedure and vaginal pain score (F[1108] = 180.1, P < 0.0001) but not drug received. No adverse events were reported. No significant difference was found for psychological state, physiological stress and procedure pain control satisfaction between the two groups. ConclusionsAnti-spasmodic drugs can help to reduce abdominal cramping pain associated with USG-MVA; HBB produced an insignificant decrease in abdominal pain score. Further studies with longer acting or larger doses of anti-spasmodic drugs are warranted.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Amiodarone and Digoxin in Healthy Subjects.

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P‐glycoprotein (P‐gp), which can result in drug‐drug interactions. Two phase 1, open‐label studies assessed the effect of coadministration of OM (50‐mg single dose) on the pharmacokinetics of digoxin (0.5‐mg single dose; N = 15), a P‐gp substrate, and the effect of coadministration of amiodarone (600‐mg single dose), a P‐gp inhibitor, on the pharmacokinetics of OM (50‐mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration–time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99‐1.14), 1.06 (90%CI, 0.98‐1.14), and 1.08 (90%CI, 0.92‐1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08‐1.36), 1.21 (90%CI, 1.07‐1.36), and 1.08 (90%CI, 0.96‐1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug‐drug interactions.

Sustainable Chromium Recovery From Wastewater Using Mango and Jackfruit Seed Kernel Bio-Adsorbents.

Wastewater is a rich source of valuable chemicals of industrial importance. However, their economic recovery is crucial for sustainability. The objective of the present work is to recover hexavalent chromium (Cr VI) as a value-added transition metal from wastewater cost-effectively; the biosorbent derived from seed kernels of mango (M) and jackfruit (JF) were applied for removing the metal from simulated wastewater. The functional groups of the biomass were analysed with the help of Fourier transform infrared (FTIR) spectroscopy, micrographs were generated using a scanning electron microscope, and crystallinity was determined by an x-ray diffractometer (XRD). The concentration of Cr VI in wastewater was analysed by an inductively coupled plasma optical emission spectrometer (ICP-OES). Process parameters (pH, dose, contact time, temperature, and initial concentration) were optimized for efficient Cr VI adsorption using a response surface methodology-based Box–Behnken design (BBD) employing Design-software 6.0.8. The batch experiment at room temperature at pH 4.8 and Cr VI removal ∼94% (M) and ∼92% (JF) was achieved by using a 60-mg dose and an initial Cr (VI) concentration of 2 ppm in 120 min. The equilibrium Cr binding on the biosorbent was well explained using Freundlich isotherm (R2 = 0.97), which indicated the indirect interactions between Cr (VI) and the biosorbent. Biosorption of Cr (VI) followed the pseudo-order and intra-particle diffusion models. The maximum adsorption capacity of the M and JF bio-adsorbent is 517.24 and 207.6 g/mg, respectively. These efficient, cost-effective, and eco-friendly biosorbents could be potentially applied for removing toxic Cr (VI) from polluted water.

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis.

Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimization, we aimed to characterize the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV coinfection, on drug exposure. Data were obtained from pharmacokinetic substudies in a randomized controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using nonlinear mixed-effects modeling and performed simulations to estimate attainment of putative efficacy and toxicity targets. A total of 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and their median weight was 56 kg (interquartile range [IQR], 50 to 63). In the final model, typical values for clearance and central volume were 3.57 liters/h and 40.2 liters, respectively. HIV coinfection had no significant effect on linezolid exposure. Simulations showed that 600-mg dosing achieved the efficacy target (area under the concentration-time curve for the free, unbound fraction of the drug [[Formula: see text] at a MIC level of 0.5 mg/liter) with 96% probability but had 56% probability of exceeding safety target ([Formula: see text]. The 300-mg dose did not achieve adequate efficacy exposures. Our model characterized population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600-mg daily dose with safety monitoring.

Selective Histone Deacetylase Inhibitor ACY-241 (Citarinostat) Plus Nivolumab in Advanced Non-Small Cell Lung Cancer: Results From a Phase Ib Study.

BackgroundHistone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer (NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.MethodsThe orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.ResultsA total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3+ T cells was observed following treatment.ConclusionsThe study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).

FAST DISSOLVING ORAL DISINTEGRATING FILMS OF VALSARTAN

- Valsartan orodispersible tablets have been developed at 40-mg dose, with the intention of facilitating administration to patients experiencing problems with swallowing and hopefully, improving its poor oral bioavailability. Work started with selecting drug compatible excipients depending on differential scanning calorimetric analysis. A 33 full factorial design was adopted for the optimization of the tablets prepared by freeze-drying technique. The effects of the filler type, the binder type, and the binder concentration were studied. The different tablet formulas were characterized for their physical properties, weight variation, disintegration time, surface properties, wetting properties, and in vitro dissolution. Amongst the prepared 27 tablet formulas, formula number 6 (consisting of 4:6 valsartan:mannitol and 2% pectin) was selected to be tested in vivo. Oral bioavailability of two 40 mg valsartan orodispersible tablets was compared to the conventional commercial tablets after administration of a single dose to four healthy volunteers. Valsartan was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of valsartan from the prepared tablets (Cmax = 2.879 μg/ml, tmax = 1.08 h) was significantly higher than that of the conventional tablets (Cmax = 1.471 μg/ml, tmax = 2.17 h), P ≤ 0.05. The relative bioavailability calculated as the ratio of mean total area under the plasma concentration–time curve for the orodispersible tablets relative to the conventional ones was 135%. The results of the in vivo study revealed that valsartan orodispersible tablets would be advantageous with regards to improved patient compliance, rapid onset of action, and increase in bioavailability.

The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers

PurposeDeutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and β-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites.MethodsIn this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4–12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1–4 and 11–14. Paroxetine trough concentrations were obtained pre-dose on days 9–13. Safety examinations occurred throughout the study.ResultsParoxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0–∞) and β-HTBZ (2.1-fold Cmax and 5.6-fold AUC0–∞), and correspondingly, 1.6-fold Cmax and threefold AUC0–∞ for total (α + β)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine).ConclusionsParoxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.

An alternative start regimen with aripiprazole once-monthly in patients with schizophrenia: population pharmacokinetic analysis of a single-day, two-injection start with gluteal and/or deltoid intramuscular injection

Background The single-injection start regimen for aripiprazole once-monthly 400 mg (AOM 400) in patients with schizophrenia requires a single intramuscular injection in the gluteal or deltoid site and 14 days of concurrent oral therapy. A simplified, single-day regimen of two injections at separate gluteal and/or deltoid injection sites, together with a single 20-mg dose of oral aripiprazole on the 1st day, was assessed. Patients and methods A previously developed population-pharmacokinetic (popPK) model for characterizing aripiprazole PK following oral administration and gluteal intramuscular depot injection was expanded to include deltoid injection. Simulations were conducted to assess PK profiles following various (including two-injection) start regimens. Postmarketing data on patients who received higher-than-recommended AOM doses were used to assess overall safety/tolerability. Results The two-injection start regimen with a single concurrent oral dose displayed a comparable PK profile to the single-injection start regimen with concurrent 14-day oral administration in simulations. The safety assessment indicated the two-injection start regimen was unlikely to be associated with safety concerns beyond those expected with a single-injection start regimen. Conclusion These data support use of the two-injection start regimen in clinical practice to reduce reliance on daily oral administration and optimize the therapeutic benefits of AOM 400 in patients with schizophrenia.

Atogepant for the Preventive Treatment of Migraine

BackgroundAtogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist that is being investigated for the preventive treatment of migraine.MethodsIn a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine–Diary (AIM-D).ResultsA total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were −3.7 days with 10-mg atogepant, −3.9 days with 30-mg atogepant, −4.2 days with 60-mg atogepant, and −2.5 days with placebo. The mean differences from placebo in the change from baseline were −1.2 days with 10-mg atogepant (95% confidence interval [CI], −1.8 to −0.6), −1.4 days with 30-mg atogepant (95% CI, −1.9 to −0.8), and −1.7 days with 60-mg atogepant (95% CI, −2.3 to −1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group.ConclusionsOral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.)

Clinical advances in multiple sclerosis and amyotrophic lateral sclerosis treatment: A review

Neurodegenerative diseases are clinical manifestations that depend on the anatomy and function of the affected areas. Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are some of these diseases, but they are also autoimmune and their etiology makes treatments limited and of little therapeutic efficacy. Currently, some clinical research advances can be pillars for the development of new treatments for these diseases. Therefore, the objective of this review is to describe the latest clinical advances in ALS and MS as well as their results in clinical recovery in randomized clinical trials, meta-analyzes, and full-text systematic reviews conducted in humans and rats, published in English and Spanish in the last 5 years, using PubMed, SciELO, and Cochrane. For clinical trials to be included, they had to provide a detailed breakdown of randomization methods, diagnostic criteria, intervention details, and efficacy evaluation. The results show that, so far, available medications, like riluzole and edaravone for ALS and fingolimod, dimethyl fumarate, and IFN β-1b for MS, only prolong the life of the patient. Among these drugs are also glutamate neurotransmitter antagonists, immunomodulators and even antioxidants; each of them showed significant improvement in the reviewed trials. Similarly, other non-pharmaceutical treatments, as the 600-mg dose of curcumin in the diet for ALS, showed improvement of the patients’ conditions. Regarding MS, more studies should be carried out on autotransplantation with adiposederived mesenchymal stem cells (AdMSCs) to investigate the potential therapeutic benefit of this technique in phases prior to secondary-progressive (SPMS).

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication.

Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients. Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation. Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour-1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day). Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.

Endometrial and follicular development following stair-step and traditional protocols in women with polycystic ovary syndrome: An RCT

Background Various strategies have been proposed for polycystic ovary syndrome (PCOS) treatment.Objective To investigate and compare the number and size of ovarian follicles, endometrial thickness, and ovulation rate by traditional protocol (TP) and stair-step protocol (SSP).Materials and MethodsSixty infertile PCOS women were allocated into two groups (SSP = 30 and control TP = 30) between May and October 2019 in the Besat Hospital, Sanandaj, Iran. In the SSP group, the infertile women were treated with 50 mg/daily clomiphene citrate (CC) for five days, while the nonresponsive women were prescribed 100 mg daily CC for five days in the same cycle. The maximum dose (150 mg) was administered until ovulation occurred. In the control group, in non-ovulatory cases, the dose was increased in the next cycle. Ultrasound was used to detect ovulation.ResultsEndometrial thickness changes with various doses of CC were significantly different in the TP. The comparison of both protocols showed a significant difference in endometrial thickness only at 50 mg CC. The number of follicles in the left ovary was significantly different in both protocols at 150-mg CC. The size of ovarian follicles in the left ovary was significantly different between the two protocols at 100-mg CC. The ovulation rate was significantly different in the SSP at 100- and 150-mg doses of CC. Moreover, 86% of ovulation occurred at 100-mg CC in the SSP, while this rate was 73% in the TP.ConclusionThe most appropriate dose for ovulation in patients with PCOS is 100 mg CC.

Characteristics of patients receiving extended treatment after incident venous thromboembolism

Given high recurrence risk after venous thromboembolism (VTE), guidelines recommend extended dose rivaroxaban (10mg OD) or apixaban (2.5mg BID) to be considered after 6months of initial treatment. This study aimed to provide insight into clinical practice regarding the use of extended preventive treatment and to describe duration of the initial treatment. Linkage of nationwide health registers identified all in- and outpatients with VTE from April 2017 through 2018. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated adjusting for other VTE-related factors. The study included 6030 patients with VTE. Among rivaroxaban users, 2.2% (n= 113) received the extended 10-mg dose after mean 9.4 (SD 3.1) months of standard treatment. For apixaban, 4.7% (n= 40) received extended 2.5-mg dose after mean 8.0months (SD 3.9). After adjustments, incident pulmonary embolism (HR 1.81 95% CI 1.12;2.91) and trauma/fracture (HR 1.42 95% CI 0.46;4.43) were associated with switching to extended dose, whereas patients with unprovoked VTE were less likely to receive the extended dose (HR 0.68 95% CI 0.30;1.55). Less than 3% of patients with incident VTE received extended treatment after initial standard treatment. Even though international guidelines suggest that the risk-benefit balance is in favour of extended VTE treatment, this was yet to be translated into clinical practice as of 2018. Studies using contemporary data are warranted to investigate routine clinical practice of extended treatment for VTE recurrence.

Pharmacokinetic Drug‐Drug Interaction Study of Omecamtiv Mecarbil With Omeprazole, a Proton Pump Inhibitor, in Healthy Subjects

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure (HF) with reduced ejection fraction. OM is administered as a 25-, 37.5-, or 50-mg modified-release formulation in patients with HF. Proton pump inhibitors are one of the most commonly prescribed drugs in this patient population. Given the potential for coadministration of both drugs in patients with HF, we evaluated the potential for omeprazole to affect the pharmacokinetics of OM in an open-label study in 14 healthy subjects. Subjects received a single 50-mg dose of OM on day 1, followed by 40-mg once-daily doses of omeprazole on days 4 to 8. On day 9, a single 40-mg dose of omeprazole was administered first and immediately followed by 50-mg of OM. Blood samples were collected up to 144 hours after dosing following administration of OM on days 1 and 9 to characterize plasma concentrations of OM. The ratios of the geometric least-square means (90% confidence intervals) of OM coadministered with omeprazole compared to OM alone were 94.5% (81.7%-109.3%), 94.3% (81.5%-109.1%), and 101.2% (95.4%-107.3%) for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and maximum observed plasma concentration, respectively. Coadministration of OM with omeprazole was not associated with any clinically significant pharmacokinetic drug interactions. Single doses of OM were safe and well tolerated when coadministered with omeprazole.

Omecamtiv mecarbil does not prolong QTc intervals at therapeutic concentrations.

Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval. In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n= 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7ms at 1 hour postdose to -0.8ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7ms (4h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1ms (90% CI: 11.71-14.57) at 3hours; lower bound of the 1-sided 95% CI was > 5ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. OM does not have a clinically relevant effect on the studied ECG parameters.

First-in-Human Study of the Biodistribution and Pharmacokinetics of 89Zr-CX-072, a Novel Immunopet Tracer Based on an Anti-PD-L1 Probody.

CX-072, a PD-L1-targeting Probody therapeutic, is engineered to be activated by tumor proteases that remove a masking peptide. To study effects on biodistribution and pharmacokinetics, we performed 89Zr-CX-072 positron emission tomography (PET) imaging. Patients received ∼1 mg, 37 MBq 89Zr-CX-072 plus 0, 4, or 9 mg unlabeled CX-072 and PET scans at days 2, 4, and 7. After that, treatment comprised 10 mg/kg CX-072 q2 weeks (n = 7) + 3 mg/kg ipilimumab q3w 4× (n = 1). Normal organ tracer uptake was expressed as standardized uptake value (SUV)mean and tumor uptake as SUVmax. PD-L1 expression was measured immunohistochemically in archival tumor tissue. Three of the eight patients included received 10-mg protein dose resulting in a blood pool mean SUVmean ± SD of 4.27 ± 0.45 on day 4, indicating sufficient available tracer. Tumor uptake was highest at day 7, with a geometric mean SUVmax 5.89 (n = 113) and present in all patients. The median follow-up was 12 weeks (4-76+). One patient experienced stable disease and two patients a partial response. PD-L1 tumor expression was 90% in one patient and ≤1% in the other patients. Mean SUVmean ± SD day 4 at 10 mg in the spleen was 8.56 ± 1.04, bone marrow 2.21 ± 0.46, and liver 4.97 ± 0.97. Four patients out of seven showed uptake in normal lymph nodes and Waldeyer's ring. The tracer was intact in the serum or plasma. 89Zr-CX-072 showed tumor uptake, even in lesions with ≤1% PD-L1 expression, and modest uptake in normal lymphoid organs, with no unexpected uptake in other healthy tissues.

Abstract CT128: Effect of futibatinib on QT/QTc interval: a randomized, controlled, double-blind study

Abstract Background Futibatinib is an oral selective irreversible FGFR inhibitor with clinical activity in cholangiocarcinoma and other FGFR-deregulated tumors. A phase 1 thorough QT study was conducted to evaluate the effect of futibatinib on the heart rate (HR)-corrected QT (QTc) interval. Methods Healthy nonsmoking adults 18-55 years of age were randomized to receive single doses of each of the following treatments in different sequences: futibatinib (20 or 80 mg [therapeutic and supratherapeutic doses, respectively]), placebo, or moxifloxacin (positive QTc-prolongation control; 400 mg). At least 7 days were allowed between administration of each of the 4 treatments. Administration of futibatinib and placebo was double-blind; that of moxifloxacin was open-label. The primary endpoint was the difference in change from baseline in QTcF (QT interval corrected using Fridericia's formula) between futibatinib and placebo (ddQTcF) at the time points tested. Upper limits of the 2-sided 90% confidence intervals (CIs) of these differences of &amp;lt;10 ms indicated lack of QTc prolongation (per ICH E14 guidance). Secondary endpoints included change from baseline in other electrocardiogram (ECG) parameters, pharmacokinetics (PK), and safety. Results Enrolled participants (N=48) received ≥1 dose of futibatinib, were evaluable for futibatinib PK, and were included in the analysis population. The ddQTcF ranged from 0.13 to 2.47 ms with 20 mg futibatinib and from -0.04 to 2.46 ms with 80 mg futibatinib from 0.5 to 24 h after dosing. Upper limits of the 2-sided 90% CIs of these values remained well below 10 ms (&amp;lt;5 ms) throughout. The lower limits of 2-sided 97.5% CIs of the difference in change from baseline in QTcF between moxifloxacin and placebo all exceeded 5 ms (8.06-11.43 ms) at the time points analyzed (1.5, 2, 3, and 4 h), demonstrating assay sensitivity. No clinically significant effects of futibatinib on HR, other ECG parameters (eg, PR, QRS, or QT intervals), or ECG morphology were identified. Exposure-response modeling indicated no significant relationship between plasma futibatinib concentration and the QTcF interval. The futibatinib area under the concentration curve from time 0 to infinity and maximum plasma concentration (Cmax) increased by 4.5- and 3.3-fold, respectively, after administration of a single dose of 80 vs 20 mg. The Cmax values observed with 80 mg futibatinib (median, 553 ng/mL; range, 71-1160) exceeded any Cmax observed or expected with the 20-mg daily therapeutic dose at steady state. Seven participants (15%) experienced adverse events of any cause after receiving either futibatinib dose, all grade 1/2. Conclusions A single therapeutic or supratherapeutic dose of futibatinib did not prolong the QTc interval or adversely affect other measures of heart function. Futibatinib exposure increased dose-dependently, and administration was safe and well tolerated in healthy participants. Citation Format: Ikuo Yamamiya, John Laabs, Daryl Sonnichsen, Mark Mina, Yaohua He, Karim Benhadji. Effect of futibatinib on QT/QTc interval: a randomized, controlled, double-blind study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT128.

A photodistributed eruption in an immunosuppressed patient

A 30-year-old African American woman with a history of hidradenitis suppurativa, who was taking ustekinumab (one 90-mg subcutaneous loading dose, 1 month previously) and was 2 weeks into a prednisone taper (week 1, 40 mg daily; week 2, 30 mg daily), presented with a tender, pruritic eruption that began 5 days previously on sun-exposed areas of the shoulders then spread to her face, abdomen, and left leg. The patient discontinued prednisone 1 day after the eruption appeared. Systemic symptoms included sore throat and myalgia.

Assessment of the Effect of Pyrimethamine, a Potent Inhibitor of Multidrug and Toxin Extrusion Protein 1/2K, on the Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist.

Gefapixant (MK-7264, AF-219) is a first-in-class P2X3 antagonist in development for refractory or unexplained chronic cough. Gefapixant is primarily cleared by renal excretion. To assess the importance of the multidrug and toxin extrusion protein 1 (MATE1) and MATE2K transporters in the elimination of gefapixant, a drug-drug interaction study was conducted evaluating the effect of coadministration of a single dose of pyrimethamine, a competitive inhibitor of MATE1 and MATE2K, on the single-dose pharmacokinetics of gefapixant in healthy participants. Safety and tolerability were also assessed. In this open-label, 2-period, fixed-sequence study, a 45-mg dose of gefapixant was administered to 12 participants in period 1. After a 7-day washout, a 50-mg dose of pyrimethamine was administered 3hours before a 45-mg dose of gefapixant in period 2. Compared with the administration of gefapixant alone, concomitant dosing of gefapixant with pyrimethamine increased the total gefapixant plasma exposure (area under the plasma concentration-time curve from time 0 to infinity) by 24%, reduced gefapixant renal clearance by 30%, and increased gefapixant mean terminal half-life from 7.7 to 10.3hours. The most frequently reported adverse events were dysgeusia, hypogeusia, and dry mouth; all adverse events were considered of mild intensity and resolved by the end of the study. These results support that MATE1 and/or MATE2K contribute to the renal clearance of gefapixant, but the effect of inhibition of these transporters on gefapixant pharmacokinetics is not considered clinically meaningful.