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.

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.

Aildenafil citrate is a novel and potent phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction (ED). This study evaluates the pharmacokinetics and bioequivalence of 2 formulations of aildenafil citrate tablets (30 and 60 mg) in healthy Chinese male subjects under both fasting and fed conditions. A single-center, randomized, open-label, 2-period crossover design was employed, with 78 participants enrolled, including 30 in the fasting condition and 48 in the fed condition. Blood samples were collected at multiple time points for pharmacokinetic analysis, which included C_max, AUC_0-t, and AUC_0-∞ as the primary parameters. The results demonstrated that the pharmacokinetic profiles of the test and reference formulations were comparable in both the fasting and fed states, with 90% confidence intervals for the geometric mean ratios of C_max, AUC_0-t, and AUC_0-∞ falling within the 80%-125% range, confirming bioequivalence. Although food intake slightly delayed the time to peak concentration and reduced the absorption rate, it did not significantly affect the overall bioavailability. Both formulations were well tolerated, with adverse events being mild and resolving spontaneously. This study provides evidence supporting the bioequivalence of the 2 aildenafil citrate formulations and their interchangeability for clinical use in treating ED.

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.

Zavegepant is the only calcitonin gene-related peptide antagonist approved as a nasal spray in the United States for acute treatment of migraine in adults with or without aura. This Phase 1, open-label study evaluated the pharmacokinetics, safety, and tolerability of a single intranasal dose of zavegepant 10 mg in 12 healthy Chinese adults. Blood samples were collected for pharmacokinetic assessment prior to dosing and from 5 min to 24 h post dose. Geometric mean values for the primary pharmacokinetic parameters were 53.53 ng h/mL for area under the plasma concentration-time curve (AUC) from time zero to infinity, 44.25 ng h/mL for AUC from time zero to time of last quantifiable concentration, and 20.32 ng/mL for maximum plasma concentration (C_max). Secondary parameters included time to C_max (median, 0.58 h), apparent clearance (geometric mean, 186.8 L/h), apparent volume of distribution (geometric mean, 2943 L), and terminal half-life (arithmetic mean, 11.0 h). Results were comparable to exposures observed previously in non-Asian healthy participants following a single intranasal dose of zavegepant 10 mg. Zavegepant demonstrated a favorable safety profile, with no serious or severe adverse events and no clinically relevant findings regarding laboratory tests, vital signs, or electrocardiograms observed.

Votoplam is a novel, orally bioavailable, small molecule HTT gene splicing modifier that is being developed for the treatment of Huntington's disease. This was a single dose, open-label, two-period, crossover food effect study that evaluated the effect of high- and low-fat meals on 20 mg votoplam in healthy participants. There was a washout of 21 days between the two periods. Twenty-six participants completed the study. There were minimal changes in the bioavailability and pharmacokinetics of votoplam following administration of a single dose of 20 mg votoplam when taken with low-fat and high-fat meals relative to fasted condition. The mean C_max, AUC_0-last, and AUC_0-inf for votoplam following administration of a single dose of 20 mg votoplam were 1.4-fold, 1.2-fold, and 1.1-fold higher, respectively, in high-fat fed conditions, and were 1.3-fold, 1.1-fold, and 1.1-fold higher, respectively, in the low-fat fed conditions, when compared to fasted conditions. There were no relevant safety findings in any of the treatment groups. Votoplam can be administered with or without food in patients.