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.

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.

Ilaprazole enteric-coated tablets are a novel proton pump inhibitor primarily used for the treatment of gastroesophageal reflux disease, with metabolism not affected by CYP2C19 genetic polymorphism. This study evaluated the pharmacokinetics and bioequivalence of two formulations of ilaprazole enteric-coated tablets in Chinese healthy volunteers under fasting and fed conditions using a single-center, randomized, open-label, single-dose, two-formulation, four-period, two-sequence, fully replicated crossover design. A total of 72 volunteers were enrolled, with 36 in each group. In the fasting group, volunteers received a single dose of 5 mg of the test or reference formulation in each period, while in the fed group, a high-fat meal was consumed 30 min before drug administration. Blood samples were collected within 36 h postdose, and plasma concentrations of ilaprazole were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. The geometric means and 90% confidence intervals of AUC_0-t, AUC_0-∞, and C_max for both fasting and fed conditions were within the 80%-125% bioequivalence range, and the upper limit of the one-sided 95% confidence interval was ≤0. Both formulations demonstrated bioequivalence under these conditions, with no serious adverse reactions observed.

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.