Clinical Pharmacology in Drug Development最新文献

The study aimed to evaluate the pharmacokinetics, bioequivalence, and safety of domestic diclofenac sodium sustained-release tablets (0.1 g) and a reference formulation in healthy Chinese subjects. Two independent trials (fasting and fed conditions) were conducted with a single-center, randomized, open-label, single-dose, two-sequence, four-period, fully replicated design. Plasma diclofenac concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated via a noncompartmental model using Phoenix WinNonlin software (version 7.0). Multivariate analysis of variance was performed on the natural logarithm-transformed pharmacokinetic parameters (C_max, AUC_0–t, and AUC_0–∞) of the test and reference formulations using a mixed linear model. Average bioequivalence (ABE) was used for assessment if the within-subject variability (S_WR) of the reference formulation was < 0.294; otherwise, reference-scaled average bioequivalence (RSABE) was applied. In the fasting trial, the 90% confidence intervals (CIs) for the geometric least-squares mean ratios of C_max, AUC_0–t, and AUC_0–∞ (test/reference) were 82.35%−106.55%, 99.77%−105.78%, and 99.87%−105.40%, respectively. In the fed trial, the corresponding 90% CIs were 82.07%−101.66%, 93.00%−102.02%, and 99.38%−104.51%, respectively. Seventeen adverse events (AEs) were recorded in 10 subjects (41.7%) in the fasting trial and 17 AEs in 12 subjects (40.0%) in the fed trial. All AEs were grade 1 (mild). These results demonstrate that the test and reference diclofenac sodium sustained-release tablets are bioequivalent and well tolerated in healthy Chinese subjects, supporting their clinical interchangeability.

This first-in-human phase I trial evaluated RL001, a self-emulsifying soft-capsule abiraterone developed to overcome the low bioavailability and food sensitivity associated with the 1000-mg Zytiga tablet that is used with prednisone according to NCCN guidelines. Plasma concentrations were quantified by LC-MS/MS and modeled in Phoenix WinNonlin 8.1 and SAS; GeoMean confidence intervals compared pharmacokinetics. Against 1000-mg abiraterone acetate tablet, the 200 mg RL001 achieved abiraterone C_max GMR >125% and AUC_0-t, AUC_0-∞ 80–125%, indicating higher bioavailability and enabling a lower therapeutic dose. The GMR of prednisone and its metabolite remained within 80%–125%, confirming no interaction. Fed/fasted exposure ratios stayed around 80% for AUC and <80% for C_max, eliminating food spikes. Hyperbilirubinemia and hypertriglyceridemia were significantly less frequent. The abiraterone self-emulsifying soft capsule represents a safer and more convenient therapeutic option in the management of prostate cancer.

The objective of this study is to evaluate the safety, pharmacokinetics, and pharmacodynamics of LP-001 injection in healthy Chinese subjects. This was a single-center, double-blind, randomized, dose-escalation study. Fifty-six healthy adults were enrolled and randomly assigned to receive LP-001 or matched placebo. A total of 156.0 drug related adverse events occurred during treatment in 38 subjects who received LP-001 injection. The main events were grade 1 serum iron reduction and elevated triglycerides, which were considered related to the drug's erythropoietic effect and reversible. Pharmacokinetic exposure increased with dose (0.5–50 mcg·kg⁻¹), but the increase in maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC) was greater than the dose ratio (non-linear). Pharmacodynamics showed dose-dependent increases in hemoglobin (Hb), red blood cell count (RBC), hematocrit (HCT), and reticulocyte count (Rtc). The pharmacodynamic indicators in the 15 and 30 mcg·kg⁻¹ multiple-dose groups were significantly higher than those in the placebo group, and the increase in RBC count was more pronounced in the 30 mcg·kg⁻¹ group. LP001, a long-acting rhEPO, was safe and well-tolerated at all doses in this Phase I study. These findings support its continued development as a treatment for myelodysplastic syndromes (MDS).

Milvexian is an oral factor XIa inhibitor in development for prevention of major thromboembolic conditions. This randomized, double-blind, placebo- and positive-controlled, multiple-dose, four-period crossover study assessed the cardic safety of milvexian (including effects on the QT interval of the electrocardiogram), with a supporting in vitro component. Sixty-six participants were enrolled. In each treatment period, participants received milvexian (100 or 200 mg) or placebo every 12 h for 4 days. A single-dose moxifloxacin (400 mg) served as a positive control. Electrocardiographs and time-matched pharmacokinetic samples were collected during each period. In mixed-effects models, the upper limit of the two-sided 90% confidence interval for the least squares means for change from baseline QTc (Fridericia [QTcF], as the primary correction method) for milvexian versus placebo (ΔΔQTc) was ˂10 ms at all time points after each milvexian regimen. In addition, there was no apparent relationship between ΔΔQTcF and plasma milvexian concentrations. Moxifloxacin response confirmed assay sensitivity. Milvexian inhibited human ether-a-go-go-related gene potassium, sodium, and L-type calcium ion channel currents with weak-to-moderate potency at concentrations exceeding the highest mean unbound maximum plasma concentrations of TQT study participants. Milvexian regimens were safe and well tolerated. These data indicate that milvexian does not prolong the QTc interval at clinically relevant concentrations.

SGR-1505 is a novel small-molecule inhibitor of MALT1, a key mediator of NF-κB signaling implicated in the pathogenesis of B-cell malignancies. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SGR-1505 in healthy volunteers. In this four-part, open-label study, 73 participants received single or multiple oral doses of SGR-1505 (25–225 mg). A food effect study assessed SGR-1505 exposure with and without a high-calorie, high-fat meal. The CYP3A4 drug–drug interaction potential of SGR-1505 was evaluated by co-administration with posaconazole, a strong CYP3A4 inhibitor. SGR-1505 was rapidly absorbed (median T_max 2–4 h) with a dose-proportional increase in exposure up to 100 mg. Twice daily dosing at 100 mg over 10 days resulted in a 1.6-fold increase in both C_max and AUC and a 2.5-fold increase in C_trough compared to once daily dosing at 150 mg. A high-fat, high-calorie meal increased SGR-1505 C_max 1.6-fold and AUC 1.3-fold compared to the fasted state. Co-administration with posaconazole increased SGR-1505 exposure 3-fold. SGR-1505 inhibited ex vivo stimulated T-cell derived IL-2 production in a concentration-dependent manner. Most adverse events were mild. Asymptomatic, reversible indirect hyperbilirubinemia occurred, consistent with inhibition of UGT1A1. SGR-1505 was well-tolerated and exhibited favorable pharmacokinetic and pharmacodynamic properties, supporting further clinical development.

Phosphodiesterase 4 (PDE4) is a branch of the phosphodiesterase isoenzyme family and plays a crucial role in maintaining intracellular cAMP homeostasis. Mufemilast, a novel PDE4 inhibitor, has demonstrated anti-inflammatory effects in preclinical studies and holds promise for treating inflammatory diseases. The pharmacokinetics, safety, and tolerability profiles of mufemilast were evaluated in healthy participants. In the single ascending dose study, 68 healthy male subjects were randomized to receive single oral doses of mufemilast ranging from 10 to 125 mg. In the multiple ascending dose study, 24 healthy subjects received mufemilast at doses of 15, 30, and 60 mg twice daily for 7 consecutive days. In the two-period, crossover food effect study, 12 healthy subjects were administered a 52.5-mg dose of mufemilast both in the fasted and fed state. The results showed that mufemilast was rapidly absorbed and the exposure increased with dose. Following multiple doses, the mean accumulation ratios indicated some accumulations of mufemilast. The T_max was 3 and 5 h under fasted and fed conditions, while the geometric mean ratio and 90% CIs for AUC_last, AUC_inf, and C_max were 105.76 [92.69%,120.66%], 105.60 [92.52%,120.52%], and 92.85 [78.60%,109.68%], respectively. Most AEs were grade 1 or 2, with positive occult blood test as the most common. Mufemilast was safe and tolerated by healthy participants across all dose groups (10–125 mg). PK analysis revealed that mufemilast exhibited linear PK characteristics. These results support the further evaluation of its efficacy.

Obesity has emerged as a global health crisis requiring innovative therapeutic strategies beyond conventional approaches. While glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists have redefined pharmacological management, their limitations necessitate further innovation. Retatrutide (LY3437943), a novel triple agonist targeting GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors, represents a transformative advance in obesity pharmacotherapy. Phase 2 trials report unprecedented weight reductions, comparable to bariatric surgery, with additional benefits for metabolic comorbidities such as NASH and cardiovascular disease. Retatrutide exemplifies rational multi-agonist peptide engineering and signals a paradigm shift in systems pharmacology. This perspective underscores the urgent need for scientific engagement, equity considerations, and policy preparedness, positioning retatrutide as a watershed in obesity treatment and a blueprint for future poly-agonist therapies.

Guselkumab is approved for the treatment of psoriasis, psoriatic arthritis, as well as ulcerative colitis and Crohn's disease. Two delivery devices for subcutaneous (SC) injection previously had been approved for the administration of 100 mg guselkumab. This study was designed to demonstrate the bioequivalence and tolerability of guselkumab following a single-dose SC administration of 100 mg guselkumab using a 1 mL prefilled syringe (PFS) assembled with an Ypsomate autoinjector (i.e., 1 mL PFS-Y, Test device) as compared to the approved 1 mL PFS assembled with the UltraSafe Plus needle safety guard (i.e., 1 mL PFS-U, Reference device). Mean serum guselkumab concentration–time profiles were nearly superimposable for both devices following a single SC injection. The geometric mean ratios and the corresponding 90% confidence interval [CI] for C_max and AUC_inf were 102.28% (94.85%–110.30%) and 102.10% (95.19%–109.51%), respectively. There were no significant differences in the incidence of treatment-emergent adverse events between the two treatment groups, and the incidence of treatment-emergent anti-drug antibodies was low and comparable between the two groups. Overall, these results suggest that the pharmacokinetics, safety/tolerability, and immunogenicity of guselkumab are comparable when administered via the 1 mL PFS-Y and 1 mL PFS-U.

Non-compartmental analysis (NCA) is commonly used to estimate pharmacokinetic (PK) parameters in individual participants during Phase 1 studies. PK sampling schedules are important for accurately characterizing a drug's PK profile. However, collecting blood samples on time is often challenging, even in Phase 1 studies involving healthy participants, due to tightly scheduled study activities. To address these constraints, sampling windows—defined as permissible time intervals for blood sample collection—are often implemented. These windows provide operational flexibility at clinical study sites while maintaining a reasonable level of accuracy in parameter estimation. To date, no published literature has described the construction of sampling windows for NCA, and the general practice of constructing sampling windows remains unstandardized. In this study, we evaluated the impact of varying sampling window lengths on NCA-derived PK parameters, leveraging bioequivalence criteria as an indicator to assess the effects and provide insights into the construction of sampling windows for NCA. As a result, we were able to quantitatively evaluate how changes in sampling window length affect NCA-based PK parameters. Based on these findings, we provide recommendations for appropriate sampling windows.

Intestinal failure-associated liver disease occurs in 20% to 30% of patients with short bowel syndrome and intestinal failure (SBS-IF). Apraglutide is a glucagon-like peptide-2 (GLP-2) analog in clinical development for the treatment of patients with SBS-IF. This study assessed the potential for changes in exposure of apraglutide in individuals with impaired hepatic function versus healthy volunteers. In this Phase 1, open-label, nonrandomized, single-dose trial, apraglutide 3.5 mg was administered to participants with moderate hepatic impairment (Child-Pugh B) or normal hepatic function. Primary pharmacokinetic endpoints were area under the plasma concentration–time curve (AUC) from time 0 to infinity (AUC_inf) or AUC from time 0 to last quantifiable concentration (AUC_last) if AUC_inf could not be reliably estimated, AUC_{0–168 h}, and maximum observed plasma concentration (C_max). Secondary endpoints included safety and tolerability. Each group comprised eight participants. No increased apraglutide exposure was observed in individuals with moderate hepatic impairment. A lower C_max and AUC_inf of apraglutide was observed in individuals with moderate hepatic impairment versus those with normal hepatic function (C_max = 58.7 vs 71.3 ng/mL; AUC_inf = 4086 vs 5351 h ng/mL, respectively). The respective geometric mean ratios were 0.835 and 0.936 for C_max and AUC_inf, and the upper bounds of their 90% confidence intervals indicate that participants with moderate hepatic impairment were not overexposed to apraglutide versus those with normal hepatic function. Adverse events were mild or moderate in severity. The results of this trial suggest that apraglutide does not require dose alteration in patients with mild and moderate hepatic impairment.