Clinical Pharmacology in Drug Development最新文献

Sirtuin 6 activation is a novel epigenetic mechanism proposed for treatment of depression. Two Phase 1 studies, SP-624-101 and SP-624-102, examined the pharmacokinetics and safety of SP-624, an orally active sirtuin 6 activator, in healthy adults. SP-624-101 was a single-ascending-dose study. In Part A, participants were randomized 6:2 to SP-624 (single oral doses of 3, 10, or 30 mg) or placebo. Part B compared results in 8 participants receiving SP-624 while fasting or after a high-fat, high-calorie breakfast. In SP-624-102, a multiple-ascending-dose study, participants were randomized 6:2 to SP-624 (3 or 10 mg SP-624 daily) or placebo for 5 days and 5:2 to SP-624 20 mg daily or placebo for 10 days. At all doses, maximum concentration (C_max) exceeded predicted target plasma concentrations of 3.28 ng/mL. Area under the concentration-time curve and C_max increased dose proportionally. A food effect resulted in significantly lower C_max, later time to maximum concentration_, and comparable AUC for fed versus fasting participants. No serious adverse events were observed. In SP-624-101 and SP-624-102, respectively, 3 (12%) and 5 (29%) SP-624–treated participants experienced treatment-emergent adverse events. SP-624 was well tolerated and reached target concentrations in healthy adults, supporting progression of SP-624 20 mg daily into Phase 2 studies of major depressive disorder.

The aim of this study was to investigate the pharmacokinetics, bioequivalence, and safety of generic trazodone hydrochloride sustained-release tablet and its reference listed product in healthy Chinese subjects. An open, randomized, single-dose, and 2-period crossover study was involved under fasting and fed conditions, with a 7-day washout period. A single oral dose of 150 mg of 2 trazodone hydrochloride sustained-release tablets was administered to 84 healthy volunteers, with 36 in the fasting group and 48 consuming a high-fat diet, respectively. The plasma concentrations of trazodone were analyzed using a liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were obtained from concentration-time profiles. The geometric mean ratio with 90% confidence intervals of the maximum trazodone concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were within the bioequivalence acceptance criteria (80%-125%) under fasting and fed conditions, which indicated that the test and reference formulations were bioequivalent. Compared with the fasting study, the concomitant administration of trazodone with a high-fat diet had a negligible influence on the drug pharmacokinetic behavior. Adverse events were recorded, and no serious adverse events were observed during either fasting or fed conditions. Trazodone has proven to have an acceptable safety profile in the Chinese population, with bioequivalence successfully established under both fasting and fed conditions.

Rozanolixizumab is an anti-human neonatal Fc receptor humanized immunoglobulin (Ig) G4 monoclonal antibody that reduces IgG, including pathogenic IgG autoantibodies. Rozanolixizumab safety and tolerability have been assessed in previous clinical studies with predominantly White participants. We assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of rozanolixizumab in healthy Japanese and Chinese participants compared with White participants. This double-blind, single-center, UK-based, Phase 1 study randomized 65 participants to rozanolixizumab 4 mg/kg (Japanese and White participants only), 7  mg/kg, or 10 mg/kg. All treatment-emergent adverse events (TEAEs) were mild to moderate in severity; no severe TEAEs, serious TEAEs, or TEAEs leading to discontinuation occurred. Incidences of TEAEs in Japanese and Chinese participants were comparable to those in White participants. Japanese and Chinese participants had lower systemic rozanolixizumab exposure relative to Caucasian participants, attributable to lower actual doses administered due to lower body weight in Chinese and Japanese participants, indicating that body weight is not a relevant predictor of rozanolixizumab pharmacokinetics. All 3 ethnicities demonstrated dose-dependent IgG reductions, with IgG nadir achieved around Day 10 and gradual return to baseline levels by Day 56. These data support the applicability of safety data from previous clinical studies of rozanolixizumab to individuals of Japanese and Chinese ethnicity.

Hydroxysafflor yellow A (HSYA), an active ingredient extracted from Carthami flos, shows potential for treating ischemic stroke. This phase 1 study assessed the safety, tolerability, and pharmacokinetic (PK) properties of HSYA in healthy Chinese volunteers who received intravenous infusions of pure HSYA powder. The study comprised 2 parts. Part A was a randomized, double-blind, placebo-controlled dose-escalation study that evaluated safety and tolerability. This included a single-dose study with 7 dose levels of HSYA (6.25, 12.5, 25, 50, 75, 100, and 125 mg) in 52 volunteers, and a multidose study (100 and 125 mg) in 16 volunteers. Part B was an open-label study where 12 volunteers received 75 mg of HSYA once daily for 14 consecutive days to examine PKs. There were no adverse events (AEs) leading to treatment discontinuation by HSYA throughout the treatment period. All reported AEs were mild and did not require special treatment. PK analysis revealed rapid absorption (median T_max of 1.1 hours) and elimination (median t_1/2 4.0 and 4.7 hours) of HSYA. Total body clearance on the 1st and 14th days was 1.7 and 1.6 L/h, respectively.

Montelukast sodium is a leukotriene type 1 receptor antagonist that can be used for the prophylaxis and treatment of asthma. However, the pharmacokinetics of montelukast sodium tablets (10 mg) remain unclear in healthy Chinese subjects. Here, a single-dose randomized, open-label, 2-sequence, and 2-period crossover (7-day washout period between treatments) study was performed to compare the pharmacokinetics and bioequivalence between the test products and the reference at a single dose of 10 mg among healthy Chinese subjects under fasting and fed conditions. Blood samples were collected at specified time points to analyze the plasma concentrations of montelukast by a validated liquid chromatography-tandem mass spectrometry method. The results showed that the 90% confidence interval values of the geometric mean ratio of test/reference for the maximum plasma drug concentration, area under the concentration-time curve from time 0 to the end, and area under the concentration-time curve from time 0 to infinity were within the range of 80%-125%. Moreover, both the test and reference formulations were safe and well tolerated, with no occurrence of severe adverse events. These results demonstrate that both the test montelukast sodium tablets and the reference showed similar bioequivalence, safety, and tolerability among healthy Chinese subjects under fasting and fed conditions.

This study compared the safety and efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with those of other TKIs and its use alongside bevacizumab in patients with EGFR mutation-positive advanced non–small-cell lung cancer. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were used to conduct extensive searches for relevant randomized controlled trials until January 30, 2024. Osimertinib monotherapy favored disease control rate, whereas the comparator treatment arm favored overall survival. Using subgroup analysis, the objective response rate and progression-free survival (PFS) were significantly elevated by Osimertinib monotherapy compared with pemetrexed combined with carboplatin or cisplatin. The comparator treatment arm receiving gefitinib or erlotinib significantly favored progression-free survival and overall survival compared with osimertinib monotherapy. In patients treated with osimertinib monotherapy, the incidence of all adverse events (AEs) decreased compared with comparator treatment arm. Anemia was the only AE associated with osimertinib monotherapy. Pemetrexed combined with carboplatin or cisplatin resulted in greater loss of appetite than osimertinib monotherapy. The most associated AE of osimertinib monotherapy was diarrhea, according to network analysis. Although its efficacy is not consistent with other EGFR TKIs, osimertinib was associated with a decrease in AEs in patients with EGFR mutation-positive advanced non–small-cell lung cancer.

Pyruvate kinase (PK) deficiency is a rare, hereditary, hemolytic anemia caused by mutations in the PKLR gene encoding the PK enzyme. Mitapivat (previously designated AG-348) is a first-in-class, oral, allosteric activator of PK. We report results from 5 Phase 1 trials in healthy adults to characterize and compare mitapivat pharmacokinetics across different formulations and analyze food effects on mitapivat bioavailability (Studies 1-5). Pharmacokinetic assessments were peak exposure, total exposure, time to maximum plasma concentration of mitapivat, and relative bioavailability (where appropriate). Plasma total exposure of mitapivat was similar in the fasted and fed (high-fat meal or different soft foods) states after capsule, tablet, and pediatric granule formulations. Although mitapivat administration with food reduced the rate of mitapivat absorption (delay in time to maximum plasma concentration; reduction in maximum concentration) versus dosing under fasted conditions, this was not considered clinically relevant, given the lack of effect on total mitapivat exposure. Consequently, the administration instructions for mitapivat relating to food state that “patients may take mitapivat tablets with or without food.” These findings will continue to inform clinical studies and development of mitapivat in adult and pediatric patients with hemolytic anemias and may help inform healthcare professionals on mitapivat dosing/administration recommendations in clinical practice.

A randomized, open-label, 2-period, 2-sequence crossover study was conducted to evaluate the pharmacokinetics and bioequivalence of 2 oral formulations of vildagliptin tablets under both fasting and fed conditions in healthy Chinese subjects. A total of 56 healthy subjects were randomized to receive a single 50-mg dose of either a generic vildagliptin tablet (T) or the reference formulation (R). The washout period was 3 days. Blood samples were collected up to 24 hours postdosing during each period and analyzed for vildagliptin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time 0 to the last measurable concentration, and area under the serum concentration-time curve from time 0 to infinity were all within the predefined bioequivalence range of 80%-125%. This indicates that the generic and reference formulations are bioequivalent under both fasting and fed states. All adverse events reported were mild and transient. High-fat meals delayed absorption and reduced the maximum peak concentration of both formulations; however, they did not affect the overall exposure. Therefore, vildagliptin can be taken without regard to meals.

This was a single-center, randomized, open-label, 2-formulation, and 2-cycle crossover trial conducted in 48 healthy Chinese volunteers, under fasting and fed conditions. The participants received oral doses of the test formulation (regorafenib) and reference formulation (40 mg) during each study period. Blood samples were collected before and up to 144 hours 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 of maximum blood concentration, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration_, and area under the plasma concentration-time curve from time 0 to infinity for regorafenib were as follows: 94.7%, 91.4%, and 91.7%, respectively, under fasting conditions; and 94.6%, 97.7%, and 98.8%, respectively, under fed conditions. The 90% confidence intervals for the geometric mean ratios were within the 80%-125% equivalence interval for both the fasting and fed tests. Ingesting high-fat and high-calorie foods increases exposure to regorafenib, leading to slower rates of absorption. The safety profiles of the 2 preparations were similar.

Azilsartan is an angiotensin II receptor blocker used for treating adult hypertension. It significantly improves cardiovascular outcomes in patients with high-risk hypertension, heart failure, and diabetic nephropathy. A single-center, randomized, open-label, single-dose, dual-cycle, dual-crossover clinical trial was conducted to evaluate the bioequivalence of azilsartan under fasting and postprandial conditions in 60 Chinese healthy volunteers. Thirty healthy subjects were enrolled in each test group, with random cross-administration for fasting and postprandial tests. The concentration of azilsartan in human plasma was evaluated using liquid chromatography-tandem mass spectrometry after a single oral administration of test and reference preparations, each at a dose of 20 mg (1 tablet). Pharmacokinetic parameters were determined using WinNonlin8.2 software, and bioequivalence was evaluated using SAS 9.4 software. The geometric mean ratios and 90% confidence intervals for maximum concentration, area under the plasma concentration-time curve from time 0 to the time of last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity of the test and reference preparations in the fasting and postprandial test groups were in the range of 80%-125%. The incidence of adverse events in the fasting and postprandial test groups was 30% (9/30) and 33.3% (10/30), respectively. No serious adverse events or unexpected adverse drug reactions were observed. In conclusion, the test and reference preparations of azilsartan tablets demonstrate bioequivalence and good safety in healthy Chinese subjects under fasting and postprandial conditions.