10-mg Dose Research Articles

Deconvoluting zavegepant drug-drug interactions: A phase I study to evaluate the effects of rifampin and itraconazole on zavegepant pharmacokinetics.

Zavegepant is a calcitonin gene-related peptide receptor antagonist for acute migraine treatment. This Phase I, open-label, fixed-sequence study evaluated the effects of itraconazole (a strong cytochrome P450 3A4 [CYP3A4] and P-glycoprotein [P-gp] inhibitor) on the pharmacokinetics of intranasal/oral zavegepant and the effects of rifampin (a strong inducer of CYP3A4 and P-gp; and an inhibitor of organic anion transporting polypeptide 1B3 [OATP1B3]) on oral zavegepant in healthy participants. In the intranasal/oral zavegepant-itraconazole cohort, participants received a single 10-mg dose of zavegepant nasal spray on Day 1, followed by oral zavegepant (50 mg) on Day 3. Itraconazole 200 mg once daily was administered from Days 4 to 12. On Day 7 zavegepant nasal spray and on Day 11 oral zavegepant were coadministered with itraconazole. In the oral zavegepant-rifampin cohort, participants received oral zavegepant (100 mg) on Day 1, rifampin 600 mg once daily on Days 2-10, and rifampin with zavegepant on Day 11. No significant change in zavegepant exposure was observed following coadministration of itraconazole with zavegepant nasal spray. For oral zavegepant coadministered with itraconazole, the area under the curve from 0 to infinity (AUC0-inf) and the maximum observed concentration (Cmax) of oral zavegepant increased by 59% and 77%, respectively. For oral zavegepant coadministered with rifampin, the AUC0-inf and Cmax of oral zavegepant increased by approximately 2.3- and 2.2-fold, respectively. These results suggest that OATP1B3 and intestinal P-gp are the more prominent pathways, as opposed to CYP3A4, for a zavegepant drug-drug interaction. Coadministration of OATP1B3 inhibitors with zavegepant nasal spray should be avoided.

The pharmacokinetics of brensocatib in participants with renal impairment following a single oral administration.

Brensocatib is an oral, selective, competitive and reversible dipeptidyl peptidase 1 inhibitor in development for the treatment of bronchiectasis. This study evaluated the pharmacokinetics (PKs), safety and tolerability of brensocatib in participants with varying degrees of renal impairment and normal renal function. In this phase 1, multicentre, open-label study, 28 participants with mild, moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 60 to <90, 30 to <60 and 15 to <30 mL/min/1.73 m2, respectively) or normal renal function (≥90 mL/min/1.73 m2) received a single oral 25-mg dose of brensocatib. Blood samples were collected to measure brensocatib PKs at predetermined time points over the 14-day study period. PK parameters were derived using noncompartmental methods. Demographic and baseline characteristics were similar across groups. There were no significant differences between groups in brensocatib PK parameters. The mean coefficient of variation (CV) of elimination half-life of brensocatib was 37.0 (15.3), 42.8 (21.7), 36.3 (22.9) and 39.1 (17.8) h for mild, moderate, severe and normal renal function groups, respectively. Single-dose brensocatib was quickly absorbed; all groups had a median time to maximum observed plasma concentration of 1h. Regression model analyses indicated no significant relationships between selected brensocatib PK parameters and eGFR. No treatment-emergent adverse events were reported during the study. Single-dose brensocatib was well tolerated. The study data do not indicate a significant effect of renal impairment on brensocatib elimination and systemic exposure, suggesting that dose adjustment of brensocatib is not necessary in participants with renal impairment. NCT05673603.

In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers.

Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (Cmax) and area under the curve from time of dosing extrapolated to infinity (AUCinf) to 182% and 939%, respectively, while ES259564 Cmax decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant Cmax and AUCinf decreased to 71.7% and 48.3%, respectively, while ES259564 Cmax increased to 130.2% and AUCinf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.

Four-weekly dosing intervals with subcutaneous spesolimab appear to be required for optimal prevention of generalized pustular psoriasis flares: Data from the EFFISAYIL® 2 and EFFISAYIL® ON trials

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Pharmacokinetics and Pharmacodynamics of Rusfertide, a Hepcidin Mimetic, Following Subcutaneous Administration of a Lyophilized Powder Formulation in Healthy Volunteers.

Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide. A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials. Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus. Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.

Tirzepatide for Obesity Treatment and Diabetes Prevention.

Obesity is chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes. We performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods. At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified. Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo. (Funded by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).

Home Sotalol Initiation for the Management of Atrial and Ventricular Arrhythmias Using Remote Electrocardiographic Monitoring.

Sotalol is a class III antiarrhythmic drug used for the management of patients with atrial fibrillation to maintain sinus rhythm. Sotalol-induced QT interval prolongation can be proarrhythmic and is conventionally initiated in an inpatient setting where routine electrocardiographic (ECG) monitoring is available while sotalol reaches the steady state. The emergence of cellular-compatible home ECG devices, such as AliveCor's Kardia Mobile 6L, which offers 6-lead ECG, has made it possible to accurately measure QT intervals outside the hospital. This study aimed to evaluate the safety, feasibility, and patient adherence to protocol-driven, pharmacist-led outpatient sotalol initiation using the Kardia Mobile 6L for remote ECG monitoring and to compare these outcomes with patients completing inpatient sotalol protocol for initiation. Patients who underwent outpatient sotalol initiation through an antiarrhythmic clinic for the treatment of both atrial and ventricular arrhythmias over a period of approximately 3 years, from September 1, 2020, to June 16, 2023, were retrospectively reviewed and compared with a cohort of inpatients initiated on sotalol. The outpatient cohort had a minimum longitudinal follow-up of 90days. A total of 263 patients using the outpatient sotalol initiation protocol were compared with 28 age- and sex-matched inpatients who underwent inpatient sotalol initiation. The outpatient cohort included 179 men (68%), with an age of 68.8 ± 10.1 years, CHA2DS2-VASc score of 3.48 ± 1.43, baseline 12-lead QTc interval of 440.77 ± 33.42ms, and a left ventricular ejection fraction of 57.4% ± 9.23%. Outpatients were started on a median (minimum-maximum) dose of 120 (80-160) mg of sotalol twice a day (120-mg dose; n=227; 86.3%) and ended at a median (minimum-maximum) dose of 120 (60-160) mg twice a day (120-mg dose; n=217; 82.5%). The proportions of patients prescribed low-, moderate-, or high-dose sotalol twice a day (60mg, 80mg, 120mg, and 160mg) at the end of initiation were similar between the inpatient and outpatient groups (P=0.5). The majority (98.9%; 260 of 263) of patients completed the 3-day outpatient initiation. Outpatient adherence was high during the 3-day initiation period among patients with varied age and socioeconomic background; 258 patients (98.1%) completed the ECG on day 1, and 240 (91.3%) completed the ECG on day 3. No significant QTc interval prolongation was observed during the outpatient postinitiation study period. There were similar sotalol discontinuation rates within 30days of initiation in the inpatient vs outpatient cohorts (7% vs 8%; P > 0.90). A total of 17 (6.5%) patients stopped sotalol because of symptomatic bradycardia, and 1 death was observed over a 90-day follow-up period in the outpatient cohort. Outpatient initiation of sotalol through a protocol-driven, pharmacist-led antiarrhythmic clinic is feasible and safe, with high adherence rates in a diverse range of patients using personal remote ECG.

Comparison of 600 mg VS 300 mg clopidogrel loading dose for patients with ischemic heart disease: a meta-analysis of randomized controlled trials

Abstract Background While a 600-mg loading dose (LD) of clopidogrel has demonstrated superior inhibition of platelet function compared to 300-mg LD, the clinical evidence supporting this superiority is limited. The debate centers on whether a higher clopidogrel LD regimen in primary percutaneous coronary intervention outperforms the standard 300 mg LD, with potential benefits being more pronounced in higher-risk patients. Balancing enhanced platelet inhibition to reduce ischemic events against the associated risk of increased bleeding remains a critical consideration in determining the optimal loading dose of clopidogrel for patients with ischemic heart disease. Purpose The objective of this meta-analysis is to validate current randomized trials that investigate the efficacy and safety of two clopidogrel loading regimens (600 mg vs 300 mg) in patients with ischemic heart disease treated with primary percutaneous coronary intervention. Method A systematic literature search for randomized controlled trials was performed comparing 600 mg with 300 mg LD of clopidogrel using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov. and Herdin PH. Studies included those between 2010 - 2023 involving human subjects. The primary efficacy endpoint was a 1-month rate of major adverse cardiac event (MACE) and the primary safety outcome was bleeding adverse effects. Result Nine randomized control studies involving 29,827 patients were included in the efficacy analysis. Mean duration of follow-up was 30 days. Only 8 studies were eligible for safety analysis. Compared with standard LD clopidogrel, high LD significantly reduced incidence of overall MACE (OR:0.82, 95% CI:0.74-0.91, p=0.0002), nonfatal myocardial infarction (OR:0.56; 95% CI:0.32-0.99, p = 0.15) and target vessel revascularization (OR 0.63; 95% CI 0.41 to 0.95, p = 0.03 ), without significant difference in terms of cardiac death (OR:0.89; 95% CI:0.76-1.04, p=0.15) and stroke (OR 0.92; 95% CI 0.67 to 1.26, p = 0.61). However, major bleeding risk was higher in the 600 mg LD (1.9%; 261/13288) compared with 300 mg LD (2.4%; 328/13242) [OR:1.27; 95% CI:1.08-1.49, p=0.005] without significant difference in minor bleeding (OR:1.05; 95% CI:0.94-1.17, p=0.35). Conclusion The administration of 600 mg of clopidogrel LD reduces the overall risk of MACE with an associated increased risk of major bleeding in patients with ischemic heart disease undergoing primary percutaneous coronary intervention.MACE OUTCOMES

Pharmacokinetics and Bioequivalence of 2 Oral Formulations of Vildagliptin in Healthy Chinese Subjects.

A randomized, open-label, 2-period, 2-sequence crossover study was conducted to evaluate the pharmacokinetics and bioequivalence of 2 oral formulations of vildagliptin tablets under both fasting and fed conditions in healthy Chinese subjects. A total of 56 healthy subjects were randomized to receive a single 50-mg dose of either a generic vildagliptin tablet (T) or the reference formulation (R). The washout period was 3 days. Blood samples were collected up to 24hours postdosing during each period and analyzed for vildagliptin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time 0 to the last measurable concentration, and area under the serum concentration-time curve from time 0 to infinity were all within the predefined bioequivalence range of 80%-125%. This indicates that the generic and reference formulations are bioequivalent under both fasting and fed states. All adverse events reported were mild and transient. High-fat meals delayed absorption and reduced the maximum peak concentration of both formulations; however, they did not affect the overall exposure. Therefore, vildagliptin can be taken without regard to meals.

Liver copper concentration dynamics with different methods of injectable copper supplementation in dairy cows in New Zealand

ABSTRACT Aims To compare the responses of liver Cu concentrations in dairy cows between three forms of injectable Cu supplementation and a negative control group. Methods Across two dairy farms in North Canterbury, New Zealand, 80 mid-lactation dairy cows (n = 28 and 52 per farm) were randomly allocated to four treatment groups: (a) 100-mg or (b) 200-mg dose of Cu administered as Ca Cu EDTA; (c) 75-mg dose of Cu as disodium Cu EDTA combined with Se, Zn, and Mn; or (d) no treatment (negative control). Each treatment group contained 20 cows. Groups were balanced for age, plasma Cu and pre-treatment liver Cu concentration. Blood samples and liver biopsies were collected prior to treatment. Six liver biopsies were performed on the same cow over a period of 70 days and the concentration of liver Cu was measured over time and compared to pre-treatment baseline. A mixed, multivariable, linear regression model was constructed to determine the effect of treatment on the change in liver Cu concentration compared to pre-treatment concentrations, accounting for repeated measurements taken from each cow. Results There was a difference in the distribution of pre-treatment liver Cu concentration between farms (p = 0.008), with medians of 1,400 (IQR 1,200–1,625) and 1,050 (IQR 805–1,425) µmol/kg on Farms 1 and 2, respectively. There was an interaction between treatment group, study day, and farm, with a treatment effect confirmed only on Farm 2. In the final model, the predicted change in liver Cu concentration (compared to pre-treatment concentrations) among cows on Farm 2 that were treated with 200 mg of Ca Cu EDTA was significantly higher than that of control cows on Days 3, 14, 28 and 42, peaking on Day 14 with a difference of 325.35 (95% CI = 97.00–554.03) µmol/kg. The study found no associations between changes in liver Cu concentration and age or prior plasma Cu concentration. The intraclass correlation coefficient was 0.57 (95% CI = 0.45–0.66), indicating the proportion of variability in changes in liver Cu concentration attributable to inter-cow variation. Conclusions and clinical relevance This study shows there are differences in response to injectable Cu supplementation at the farm level and wide variation in liver Cu among cows from the same farm. On one farm, a 200-mg dosage of Ca Cu EDTA significantly increased liver Cu concentration for at least 42 days.

Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

Population Pharmacokinetic Modeling and Simulation for Dose Optimization of GB-5001, a Long-Acting Intramuscular Injection of Donepezil, in Healthy Participants.

GB-5001 is an intramuscular (IM) formulation of donepezil under development for the treatment of Alzheimer's disease. The objective of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the IM dosage of GB-5001 using bioequivalence (BE) simulation. A population PK model of donepezil was developed using NONMEM. It was based on plasma concentration data from a Phase 1 dose escalation study, which involved a single administration of donepezil IM formulation at doses of 70, 140, and 280mg, and the oral formulation at 10mg. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, visual predictive checks, and bootstrapping. BE simulations were conducted using a parallel design between various doses of the IM formulation and the 10-mg dose of oral formulation. The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM (dual first-order absorption and simultaneous zero-order absorption with lag time) and oral (first-order absorption with lag time) formulations. Based on the simulation results, an IM dosage range of 210-215 mg in a sample size of over 92 was estimated to achieve a success rate of approximately 80% for BE. The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials. ClinicalTrials.gov identifier, NCT05525780.

Comparing the efficacy and safety of monotherapy and combination therapy with tadalafil, tamsulosin, and silodosin for distal ureteral stones: A systematic review and meta-analysis

ObjectiveMedical expulsive therapy (MET) is a suitable option for facilitating stone expulsion in patients with distal ureteral stones. This meta-analysis was conducted to compare the efficacy of tamsulosin, silodosin, tadalafil monotherapy, and combinations on stone expulsion rate (SER) and stone expulsion time (SET), as well as their comparative safety, number of colic pain episodes, and need for analgesics. MethodsRandomized controlled trials were retrieved by searching PubMed, Scopus, and Web of Science up to November 27, 2023. Papers in-English that compared the safety and efficacy of at least two of the above agents in adults with distal ureteral stones ≤10 mm were included. ResultsIn total, 27 studies were identified. More than half of them (n=15, 55.6%) were conducted in India. SER significantly improved with silodosin compared with tamsulosin (odds ratio [OR] 2.24, p<0.001), whereas the difference in SET was non-significant. Tadalafil achieved a significantly higher SER compared with tamsulosin (OR 1.42, p=0.040) without any difference in SET. Subgroup analysis of 5- and 10-mg doses of tadalafil showed no significant difference in SER and SET. We found no significant difference in need for analgesic (mean difference [MD −53.73, p=0.200) or the mean number of colic episodes (MD −0.42, p=0.06) between tadalafil and tamsulosin. SER and SET were not significantly different between silodosin and tadalafil. Tadalafil plus tamsulosin led to a significantly higher SER (OR 1.87, p<0.001) and SET (MD −2.99, p=0.002) compared with tamsulosin, without any significant difference in the adverse effects. ConclusionCompared with tamsulosin, SER significantly improved with silodosin, tadalafil, and the combination of tadalafil plus tamsulosin. Meanwhile, the difference in SET was only significant between tadalafil plus tamsulosin versus tamsulosin. It appears that tadalafil and silodosin have similar efficacy in SET and SER. All METs had comparable safety.

A Phase 1, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Bepirovirsen in Adults with Hepatic Impairment and Healthy Participants (B-Assured).

Bepirovirsen is a developmental antisense oligonucleotide (ASO) for treatment of chronic hepatitis B virus infection. No pharmacokinetic (PK) studies comparing participants with hepatic impairment (HI) and healthy participants (HPs) have been conducted with ASOs. Given the target patient population, characterization of bepirovirsen PK in HI was imperative. This phase 1, nonrandomized, open-label study (NCT04971928) evaluated the PKs of a single 300-mg dose of bepirovirsen in participants with HI and matched HPs, enrolled in 2 parts (Part 1: moderate HI; Part 2: mild HI). If no predefined difference in the area under the concentration-time curve from time 0 (predose) to infinite time (AUC0-∞) and maximum observed concentration (Cmax; geometric mean ratio [GMR] 0.5-1.5) was identified in Part 1, findings were applied to mild HI, eliminating Part 2. Participants were monitored for 50days post-treatment and noncompartmental analysis estimated PK parameters. Twenty-four participants (moderate HI, n=12; HP, n=12) received bepirovirsen and completed Part 1. AUC0-∞ and Cmax were lower in participants with moderate HI (GMR 0.69 and 0.67, respectively) than in HPs, while apparent clearance (CL/F)and apparent terminal phase volume of distribution (Vz/F) were higher (GMR 1.44 and 1.64, respectively), but fell within the predefined thresholds of difference for this study. Part 2 was omitted. Adverse events were mild. Moderate HI did not have a clinically relevant impact on bepirovirsen PK or safety.

A Phase I Open-Label Study of Cediranib Plus Etoposide and Cisplatin as First-Line Therapy for Patients With Extensive-Stage Small-Cell Lung Cancer or Metastatic Neuroendocrine Non–Small-Cell Lung Cancer

IntroductionSmall cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC). MethodsPatients received up to six 21-day cycles of etoposide (100 mg/m2, days 1-3) and cisplatin (80 mg/m2, day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose. ResultsTwenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage. ConclusionsCediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity.

Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma

Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear. The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 154 patients were enrolled (120 mg: n= 76; 200 mg: n= 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P= 0.5312;-0.5%, 95% confidence interval (CI)-14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

Informing the Recommended Phase III Dose of Alnuctamab, a CD3 × BCMA T-Cell Engager, Using Population Pharmacokinetics and Exposure-Response Analysis.

Alnuctamab, a B-cell maturation antigen (BCMA)-targeting T-cell engager, has demonstrated encouraging antitumor activity in the phase I study CC-93269-MM-001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure-response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15-10 mg) or in step-up doses to a maximum 10-mg target dose. Subcutaneous (SC) step-up doses of 3 and 6 mg were followed by a target dose range of 10-60 mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two-compartment PopPK model with first-order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure-response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade ≥2 CRS events. A significant exposure-CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure-safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure-response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg.

Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial.

Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis. Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death. Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively. In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid. Clinical Trial Registry of India (CTRI/2021/03/032189).

Bioequivalence study of two formulations of afatinib dimaleate tablets in healthy subjects under fasting conditions: A randomized, open-label, single-dose, crossover trial.

To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles. This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit. Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC0-t, 90.26 - 105.52% for Cmax, and 93.49 - 104.05% for AUC0-∞. The 90% CI for the geometric mean ratios (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.

Population Pharmacokinetics of Naloxegol in Pediatric Subjects Receiving Opioids.

The pharmacokinetics (PK) of naloxegol were characterized in pediatric subjects, aged 6months or older to less than 18years who either have or are at risk of developing opioid-induced constipation following single dose administration. Subjects grouped as aged 12 years or older to less than 18years, 6 months or older to less than 12years, and 6months or older to less than 6years, received a single oral dose of naloxegol at doses that were estimated to achieve plasma exposures comparable to adult 12.5- or 25-mg doses. Intensive and sparse plasma naloxegol samples were collected to assess naloxegol concentrations. Data were combined with previously collected adult PK data and used to estimate PK parameters using population PK analyses. Naloxegol PK was described using a 2-compartment model with Weibull-type absorption. Neither age nor body weight was identified as a significant covariate indicating similar PK properties in adult and pediatric subjects. PK estimates in the youngest age group were approximately 80% less than those in adults (12.5-mg equivalent dose). Exposures in the other pediatric groups were similar to those in adult equivalent doses. The PK of naloxegol were characterized as linear over the dose range, with no clinically significant covariates and comparable PK characteristics in adults and pediatric subjects aged 6months or older.