Clinical Pharmacology in Drug Development最新文献

This Phase 1, randomized, placebo-controlled, double-blind study assessed the pharmacokinetic profile of rimegepant (25, 75, or 150 mg once daily for 14 days) in healthy Japanese and Caucasian adults. Exposures were modestly increased in Japanese participants compared with Caucasian participants following a single dose of rimegepant (Day 1); fold-change (expressed as geometric mean ratio) for Japanese versus Caucasian participants ranged 1.13-1.55 for maximum plasma concentration (C_max) and 1.22-1.48 for area under the concentration-time curve to one dosing interval (AUC_tau) across all doses. Generally, rimegepant exposures were also similar or slightly higher in Japanese participants compared with Caucasian participants at steady state (Day 14); fold-change for Japanese versus Caucasian participants ranged 0.97-1.30 for C_max,ss and 1.10-1.38 for AUC_tau,ss across all doses. Analysis of dose-normalized exposures confirmed higher rimegepant exposure in Japanese participants than Caucasian participants. These effects were due to differences in body weight in Japanese and Caucasian participants since post hoc analyses, where exposure parameters were normalized to body weight and to a 75-mg dose of rimegepant, showed that differences in C_max and AUC_tau between the ethnic groups were <20% following a single dose (Day 1) and <5% at steady state (Day 14). Greater than dose-proportional increases in rimegepant exposure were observed in both Japanese and Caucasian participants. Overall, rimegepant demonstrated a favorable safety profile similar to placebo in both Japanese and Caucasian participants, with no serious or severe adverse events and no clinically relevant findings regarding laboratory tests, vital signs, electrocardiograms, Sheehan-Suicidality Tracking Scale scores, or physical examinations observed.

Givinostat is a class I/II histone deacetylase inhibitor indicated for Duchenne muscular dystrophy (DMD). The study evaluated the effect of therapeutic and supratherapeutic givinostat doses on the QT/QTc interval. Healthy volunteers received each treatment-givinostat hydrochloride monohydrate oral suspension as a therapeutic (100 mg) or supratherapeutic (300 mg) dose, placebo oral suspension, or moxifloxacin oral tablet (positive control, 400 mg)-according to a block randomization scheme. Cardiodynamic assessments were paired with pharmacokinetic samples. A small, clinically non-relevant effect on mean placebo-corrected, change-from-baseline QTcF (∆∆QTcF) of 5.5 ms was seen after givinostat 100-mg dose. Clinically relevant QTc prolongation was observed with the supratherapeutic dose, with a mild ∆∆QTcF increase of 13.6 ms. A delay of ≈3 h between T_max and the largest effect on the QTc interval was seen for both doses. In the concentration-QTc analysis, an E_max model captured the data better than the prespecified linear model and showed that an effect on ∆∆QTcF exceeding 10 ms could be excluded within the full range of observed givinostat concentrations in this study and up to ≈745 ng/mL. Givinostat at the maximum labeled dose (up to 53.2 mg twice daily for DMD) is not expected to pose a QT prolongation risk.

Combined treatment with aztreonam (an established intravenous antibiotic) and avibactam (a β-lactamase inhibitor) has the potential to address the unmet need for safe and effective agents to combat infections caused by Gram-negative bacteria producing metallo β-lactamases (MBLs). Aztreonam–avibactam may also address other problematic β-lactamases, such as extended-spectrum β-lactamases and serine carbapenemases, which may be co-expressed with MBLs and contribute to a multidrug-resistant phenotype. Based on completion of two Phase 3 trials, aztreonam–avibactam was approved in Europe (2024), the United States and China (2025). This Phase 1 open-label study assessed the pharmacokinetics, safety, and tolerability of aztreonam–avibactam in healthy Chinese participants after single- and multiple-dose administration (doses equivalent to those evaluated in Phase 3 aztreonam–avibactam trials), with a fixed 3:1 ratio. Pharmacokinetics, safety, and tolerability characteristics of aztreonam and avibactam were consistent with previous knowledge, with no clinically significant differences in exposures between Chinese and non-Chinese participants. Based on population pharmacokinetic modeling which incorporated data from the aztreonam–avibactam Phase 1–3 trials, predicted aztreonam and avibactam exposures at steady state for Phase 3 participants in China and non-China (rest-of-world) regions were numerically similar. These findings indicate that aztreonam–avibactam is well tolerated in healthy Chinese adults and support the use of the approved dose regimen by EMA for Chinese patient populations.

Gantenerumab, a monoclonal antibody targeting amyloid beta plaques in the brain, reduces plaque accumulation and was developed to slow Alzheimer's disease progression. Results from the pivotal GRADUATE I and II studies evaluating gantenerumab in people with early Alzheimer's disease were announced in 2022. The studies did not meet their primary endpoint of slowing clinical decline. This study evaluated the pharmacokinetics, immunogenicity, and safety of a high concentration liquid formulation of gantenerumab administered subcutaneously as a single dose using an autoinjector (AI) or a disposable syringe (DS). The DS was employed in pivotal clinical trials, while the AI was developed in parallel to ease SC administration. The study aimed to demonstrate bioequivalence (BE) between AI and DS administration in healthy participants, defined by 90% confidence intervals (CIs) for geometric least square (LS) mean ratios being within the 0.80-1.25 range for maximum observed plasma concentration (C_max) and area under the plasma concentration–time curve (AUC). Among the 266 healthy participants, 135 received 255 mg gantenerumab via AI and 131 received 255 mg via DS in a parallel group design. BE between AI and DS SC administration was demonstrated with geometric LS mean ratios (90% CIs) for C_max, AUC_0-inf, and AUC_0-last of 1.078 (1.006, 1.155), 1.053 (0.986, 1.124), and 1.054 (0.992, 1.121), respectively, all within the 0.80-1.25 BE range. Safety findings were consistent with the known safety profile of gantenerumab.

Firsekibart is an anti-IL-1β monoclonal antibody for treating acute gout flares in adults. This randomized, double-blind, placebo-controlled study assessed the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of multiple ascending doses of firsekibart in healthy Chinese adults. Participants were assigned to one of the two firsekibart cohorts (120 or 200 mg) every 4 weeks for three doses and randomized in a 5:1 ratio to receive firsekibart or placebo. Twenty-four participants completed the study. After a single dose, the median T_max was 7.0 days for both firsekibart groups. Mean C_max was 16.0 and 29.2 µg/mL; AUC_0–t was 350.6 and 600.0 d·µg/mL for the 120 and 200 mg groups. Following multiple doses, the median T_max,ss was 4.0 days and 5.5 days, C_max,ss was 31.5 and 54.1 µg/mL, AUC_0–t,ss was 1213.3 and 1975.8 d·µg/mL, and AUC_0–∞,ss was 1445.3 and 2355.4 d·µg/mL. Accumulation ratios for C_max and AUC were <2 in both groups. Serum total IL-1β levels showed no dose-related trends and immunogenicity was low. Treatment-emergent adverse events (TEAEs) occurred in 65.0% of firsekibart-treated participants and 75.0% of placebo-treated participants. TEAEs were mostly grade 1 or 2. Firsekibart was safe, well tolerated after multiple administrations in healthy participants, with dose-proportional exposure and modest accumulation.

Co-administration of oral phosphodiesterase 5 inhibitors with oral soluble guanylate cyclase (sGC) stimulators is contraindicated due to the risk of systemic side effects. Frespaciguat, an inhaled sGC stimulator, has been studied in pulmonary hypertension (PH)-related conditions such as pulmonary arterial hypertension (PAH) and PH associated with chronic obstructive pulmonary disease (PH-COPD), and may allow combined use with oral PDE5i due to low systemic exposure. To evaluate a potential interaction between inhaled frespaciguat and oral sildenafil, 19 healthy participants were randomized to two treatment sequences (two periods separated by a 36-h washout). Treatment involved 3 days of dosing with open-label oral sildenafil (20 mg, three times per day) and a single inhaled dose of frespaciguat 240 µg or placebo on Day 3. Primary endpoints included safety assessed by adverse events (AEs) and change from baseline in systolic and diastolic blood pressure, and heart rate. Incidence of AEs was comparable across groups with no serious AEs, discontinuations due to AEs, or deaths. In conclusion, inhaled frespaciguat was well tolerated when administered on background sildenafil, without negative effects on systemic hemodynamics, versus placebo. The lack of additive systemic effects on blood pressure further documents pulmonary selectivity of inhaled frespaciguat, including when co-administered with sildenafil (EudraCT number 2019-001224-35).

This Phase 1 study investigated the pharmacokinetics and safety of a single dose of the FDA-approved doxecitine and doxribtimine (266.6 mg/kg; 133.3 mg/kg of deoxycytidine [dC] and deoxythymidine [dT]) in participants with severe (n = 8) or moderate (n = 8) renal impairment (estimated glomerular filtration rate [eGFR] 15–29 mL/min/1.73 m² and 30–59 mL/min/1.73 m², respectively) versus healthy matched controls (eGFR ≥90 mL/min/1.73 m²; n = 16 [two groups of eight]). Participants underwent serial sampling to determine total dC and dT plasma concentrations before (baseline) and after dosing (up to 96 h).

Participants with renal impairment had higher baseline-corrected dC and dT concentrations than controls, which peaked 0.75–1.5 h post-dose and declined to near baseline levels in ≤18 h. Geometric mean baseline-corrected plasma maximum concentration and area under the concentration–time curve (respectively) for dC and dT were higher in participants with severe (dC: 7.8 ng/mL and 52.8 h × ng/mL; dT: 18.8 ng/mL and 31.5 h × ng/mL) or moderate (dC: 8.2 ng/mL and 56.4 h × ng/mL; dT: 12.2 ng/mL and 23.7 h × ng/mL) renal impairment than in controls (dC: 4.6–5.3 ng/mL and 25.4–31.8 h × ng/mL; dT: 4.0–7.6 ng/mL and 4.3–12.7 h × ng/mL), with substantial variability. Geometric mean apparent terminal-phase half-lives in severe renal impairment, moderate renal impairment, and controls, respectively, were 14.5, 15.3, and 5.2–5.8 h for dC and 3.7, 4.5, and 0.4–1.5 h for dT. One participant experienced treatment-emergent adverse events (severe renal impairment cohort). In conclusion, renal impairment was associated with increased dC and dT exposure following a single dose of doxecitine and doxribtimine. No safety issues were identified.

To investigate the predictive value of interleukin (IL)-4 and IL-21 levels in assessing disease activity score and antihistamine treatment response in chronic spontaneous urticaria (CSU) patients. One hundred and twenty CSU patients treated at our hospital between January 2023 and January 2025 were retrospectively selected as the study group. Eighty healthy individuals undergoing routine physical examinations during the same period were included as the control group. Serum IL-4 and IL-21 levels, and the proportion of peripheral blood follicular helper T (Tfh) cells within CD4⁺ T cells were retrieved from the hospital information system. Based on the Urticaria Activity Score over 7 days (UAS7), CSU patients were divided into three subgroups: mild (UAS7 < 16, n = 43), moderate (UAS7 16-27, n = 52), and severe (UAS7 ≥ 28, n = 25). All patients received standard antihistamine therapy for 4 weeks. According to treatment response, patients were categorized into four groups: complete remission, marked improvement, partial remission, and no response. The correlations of IL-4, IL-21, and Tfh cell levels with disease severity were analyzed, and their predictive value for CSU diagnosis and antihistamine treatment response was evaluated. IL-4 and IL-21 are co-upregulated in CSU patients, and their levels increase with disease activity and are positively correlated with UAS7 score (r =.603, 0.314, P <.001). These biomarkers have a certain reference value for diagnosis and severity assessment of CSU. Baseline levels of IL-4 and IL-21 may serve as predictive biomarkers for antihistamine treatment response, providing a potential reference for individualized treatment strategies.

The growing demand for assisted reproductive technology (ART) has increased the need for effective luteal phase support. Progesterone, essential for maintaining early pregnancy, is a critical component of ART. This open-label, balanced, randomized, two-treatment, crossover, single-dose study compared the bioequivalence of aqueous progesterone 25 mg injection (AqSusten^® [Test, Sun Pharma Laboratories Limited]), compared to the innovator's aqueous progesterone 25 mg injection (Lubion^® [Reference, IBSA Farmaceutici Italia Srl]), in healthy postmenopausal women under fasting conditions. Forty-eight subjects received either treatment in Period 1, followed by alternate treatment in Period 2, with a 14-day washout period. Pharmacokinetics (C_max, AUC_0–t, AUC_0-∞) and mean plasma concentration–time profiles were assessed. Forty-five subjects completed the study. Pharmacokinetic data for both products were comparable, with percentage ratios for AUC_0–t, AUC_0−∞, and C_max of 99.16%, 98.78%, and 103.36%, respectively, within the acceptable bioequivalence range of 80%-125%. Plasma concentration–time profiles were similar, and no serious adverse events were reported. Mild adverse events with Lubion^® included increased white blood cell count and blood glucose. AqSusten^® demonstrated bioequivalence to Lubion^® in healthy postmenopausal women under fasting conditions. Both formulations exhibited similar pharmacokinetic profiles, with favorable safety and tolerability, suggesting AqSusten^® as a viable alternative in ART treatments.

ABP 654, a biosimilar to ustekinumab reference product, is available in a prefilled syringe (PFS) for subcutaneous (SC) use. The ABP 654 autoinjector pen (AIP) has recently been developed with an aim to improve the injection experience for patients and caregivers. This study was designed to assess the similarity of pharmacokinetics (PK), safety, and immunogenicity of a 90-mg SC injection of ABP 654 administered via PFS or AIP in healthy volunteers. A total of 156 adults were randomized at a ratio of 1:1. PK bioequivalence was established between the PFS and AIP groups based on the 90% CIs of the geometric mean ratios for the primary PK endpoints of maximum observed serum concentration (C_max) and area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC_inf) being contained within the prespecified margin of 0.8 to 1.25. The frequency, type, and severity of adverse events as well as the incidence of antidrug antibodies were similar between the PFS and AIP groups. Overall, the results support a conclusion of PK bioequivalency as well as comparable safety and immunogenicity of ABP 654 administered via PFS and AIP.