Clinical Pharmacology in Drug Development最新文献

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.

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.

This was a single-center, randomized, open-label, two-formulation, and two-cycle crossover trial conducted in 52 healthy Chinese volunteers, under fasting and fed conditions. The participants received oral doses of the test formulation (gliclazide modified-release tablets) and reference formulation (30 mg) during each study period. Blood samples were collected before and up to 72 h after the formulations were administered to determine changes in the pharmacokinetic parameters and adverse reactions, which were then used to evaluate bioequivalence and safety. The geometric mean ratios (GMRs) of C_max, AUC_0–t, and AUC_0–∞ for gliclazide were as follows: 93.9%, 99.2%, and 101.8%, respectively (under fasting conditions); 99.0%, 94.6%, and 98.8%, respectively (under fed conditions). The 90% confidence intervals for the GMRs were within the 80%–125% equivalence interval for both the fasting and fed tests. Ingesting high-fat and high-calorie foods accelerate the absorption rate of gliclazide, does not meaningfully alter the extent of absorption. The safety profiles of the two preparations were similar.

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.

This study evaluated the bioequivalence and safety of two fixed-dose combination (FDC) tablet formulations of metformin/empagliflozin (1000 mg/5 mg) in healthy Chinese subjects. A single-center, open-label, randomized, two-period, two-treatment, and two-sequence crossover study was conducted, enrolling 56 subjects who were assigned to either fasting or fed conditions in a 1:1 ratio. Each subject received both the test and reference formulations, with a 7-day washout period between administrations. Blood samples were collected up to 48 h post-dose, and plasma concentrations of metformin and empagliflozin were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Bioequivalence was assessed based on key pharmacokinetic parameters—C_max, AUC_0–t, and AUC_0–∞—with the geometric least-squares mean ratios of the test to reference formulation falling within the accepted bioequivalence range of 80.00% to 125.00% for all 90% confidence intervals under both fasting and fed states. High-fat meals significantly reduced the C_max of metformin and empagliflozin by approximately 47% and 28%, respectively, and their overall exposure (AUC_0−∞) by approximately 29% and 15%, respectively. No serious adverse events were reported. In conclusion, the test and reference formulations of metformin/empagliflozin FDC tablets were bioequivalent and well-tolerated under both fasting and fed conditions.

Ubrogepant is a calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine with or without aura in adults. The mass balance and metabolism of ubrogepant was evaluated in six healthy male adults administered a single oral dose of [¹⁴C]-ubrogepant 50 mg (∼200 µCi). Overall, the mean total radioactivity recovery was 92.4% (95% CI: 77.8%-107%) of the administered dose, with 82.9% in feces (95% CI: 66.7%-99.1%) and 9.52% in urine (95% CI: 7.78%-11.3%). Ubrogepant was eliminated mainly via metabolism, primarily via biliary/fecal excretion. Approximately 42% and 6% of the dose was excreted as unchanged parent drug in feces and urine, respectively. The major circulating components of drug-related material (DRM) in pooled plasma samples were ubrogepant (55%), M15 (13%), and M20 (3.5%). M15 (glucuronide of methylated catechol) and M20 (glucuronide of mono-oxygenated ubrogepant [M8]) also were the main metabolites in urine, together representing about 2% of DRM. In feces, the main metabolites were the oxidative metabolites M6 (di-oxygenated ubrogepant) and M8, together representing about 29% of DRM. In vitro assays showed that ubrogepant metabolism occurs predominantly via CYP3A4.

Fibrodysplasia ossificans progressiva is a rare, progressive autosomal dominant genetic disease caused by an activin receptor-like kinase 2 (ALK2) mutation with a need for effective prophylactic therapies. This single-center, randomized, double-blind, placebo-controlled study evaluated the pharmacokinetics and safety of DS-6016a, a novel humanized monoclonal anti-ALK2 antibody, in healthy Japanese adults. In each of the 5–1000 mg DS-6016a or placebo single subcutaneous dose cohorts, eight male participants were randomly assigned at a 3:1 ratio. DS-6016a had median times to maximum plasma concentration of 144–240 h and elimination half-lives of 391–844 h. The increase in DS-6016a exposure was greater than dose-proportional across the dose range of 5–1000 mg. The incidence of study drug-related treatment-emergent adverse events (TEAEs) was 17% in the placebo group and 11% across all DS-6016a groups; all were mild and resolved without treatment. No deaths, serious or severe TEAEs, or TEAEs leading to study discontinuation were reported. Ferritin showed a statistically significant dose-dependent decrease from baseline, while serum iron showed no clear dose-dependency. No relationship was observed between DS-6016a dose and the development of anti-drug antibodies. DS-6016a had an acceptable safety profile at single subcutaneous doses of 5–1000 mg.

Antihypertensive drugs are more potent when administered in combinations of two or three different classes of drugs. The objective of this study was to evaluate the pharmacokinetic interaction among amlodipine, losartan, and chlorthalidone. A randomized, open-label, four-sequence, four-period, four-treatment, single-dose study was conducted in healthy Korean male subjects, with oral administrations of two tablets of amlodipine 5 mg, one tablet of losartan 100 mg, one tablet of chlorthalidone 25 mg, or co-administration of all three investigational products. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Twenty-six subjects completed the study. The geometric mean ratios and 90% confidence intervals of C_max and AUC_last, respectively, were 1.0928 (1.0412-1.1469) and 1.0360 (0.9958-1.0778) for amlodipine; 1.1016 (0.9136-1.3284) and 1.1606 (1.0885-1.2375) for losartan; 1.0720 (1.0119-1.1356) and 1.0902 (1.0350-1.1148) for EXP3174 (active metabolite of losartan); and 0.9462 (0.8626-1.0379) and 1.0266 (0.9752-1.0807) for chlorthalidone. All the treatments were well tolerated overall. Besides the slight increase in losartan C_max, the combination therapy did not show clinically significant pharmacokinetic interactions in terms of systemic drug exposure.