Clinical Pharmacology in Drug Development最新文献

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.

Tinlarebant is an oral retinol binding protein 4 antagonist in clinical development for geographic atrophy, an advanced stage of dry age-related macular degeneration, and Stargardt disease, an inherited juvenile-onset macular degeneration. A randomized, open-label, two-period, interaction study in healthy adults was conducted in four parts to determine the effects of gastric acid suppression (omeprazole 40 mg QD), cytochrome P4503A (CYP3A) inhibition (itraconazole 200 mg BD) and induction (rifampin 600 mg QD), and food on the pharmacokinetics of tinlarebant (5 mg single dose). The effects on tinlarebant exposure were quantified by geometric least squares (GLS) mean C_max and AUC_inf ratios, where GLS mean C_max or AUC_inf with potential perpetrator is divided by GLS mean C_max or AUC_inf without potential perpetrator. Steady-state dosing of omeprazole had no effect on tinlarebant exposure (C_max ratio = 1.16 and AUC_inf ratio = 1.03). The C_max and AUC_inf ratios of tinlarebant following itraconazole dosing were 1.29 and 2.42, respectively. Rifampin co-administration decreased tinlarebant C_max and AUC_inf ratios to 0.53 and 0.19, respectively. Compared with the fasting state, taking tinlarebant with food gave C_max and AUC_inf ratios in the range 1.08–1.22. No unexpected safety signals occurred and tinlarebant was well tolerated in all participants. These data show that the pharmacokinetics of tinlarebant is not significantly altered by gastric acid suppression or food. Dosing patients with tinlarebant and strong CYP3A inhibitors is unlikely to compromise safety based on its pharmacokinetic–pharmacodynamic relationships, but tinlarebant should be contraindicated with strong CYP3A inducers due to potential treatment failure.

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.

This randomized, open-label, 2-period crossover study evaluated food effects on SPH3348 pharmacokinetics (PK) and safety in 16 healthy participants receiving a single 480-mg dose under fasting and high-fat fed conditions. PK profiling involved serial blood sampling at 15 predefined time points per period, while safety assessments included continuous monitoring of adverse events throughout the study. PK analysis revealed pronounced food-dependent alterations. Under fed conditions, the median time to peak concentration was delayed by 1 hour compared to fasting (4.00 vs. 3.00 hours), reflecting a slowdown in absorption rate (median time to peak concentration delay was statistically significant [P < .05 by Wilcoxon signed-rank test]). PK analysis demonstrated marked food-induced increases in systemic exposure. The fed-to-fasted geometric mean ratios and 90% confidence intervals were 1.9023 (1.5975-2.2653) for maximum concentration and 2.3667 (2.1140-2.6490) for AUC from time zero extrapolated to infinity, both exceeding the 1.25 threshold for bioequivalence. These exposure increases (greater than 2-fold) confirm that meal-induced enhancement of absorption is clinically significant. Safety profiles remained comparable between dosing conditions, with adverse event incidence rates of 13.3% (fasting) versus 18.8% (fed) and predominantly mild severity, primarily involving transient gastrointestinal events. These findings indicate that while food intake significantly increases SPH3348 bioavailability and slightly delays absorption kinetics, both fasting and fed administrations are well tolerated following single-dose exposure. The observed PK modifications highlight the necessity of standardizing dietary conditions in clinical use to ensure consistent drug exposure. The systematic characterization of these food effects provides critical evidence for optimizing dosing regimens and informing subsequent-phase clinical development, particularly regarding administration guidelines to manage variability between patients.

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.