Multidrug-resistant Enterobacteriaceae are a primary cause of complicated urinary tract infections (cUTIs) worldwide. This study compared pharmacokinetic (PK) parameters of plazomicin among Indian versus non-India participants. This was a post hoc analysis of PK data from the Phase 2 study (ACHN-490-002), a multicenter, double-blind, randomized, comparator-controlled study. Eligible participants (aged 18-85 years, body weight ≤100 kg) with documented/suspected cUTI or acute pyelonephritis received either 10 or 15 mg/kg plazomicin. Among 91 participants, 70 were non-Indian and 21 were Indian. For the 15 mg/kg dose, plazomicin demonstrated a higher area under the plasma time-concentration curve from time 0 to 24 h (AUC) and maximum concentration (C) compared to the 10 mg/kg dose, which showed greater variability. At the 10 mg/kg dose, Indian participants had a mean AUC of 163.0 mg•h/L, while non-Indian participants had a mean AUC of 185.0 mg•h/L. The estimated mean plazomicin AUC values were comparable between Indian and non-Indian participants. The mean C for Indian participants was 17.2 mg•h/L, and for non-Indian participants it was 15.7 mg•h/L. Dose-normalized AUC and C point estimates were 110% and 103%, respectively. This showed comparable plazomicin exposure in Indian and non-Indian patients.

Glucagon-like peptide-1 (GLP-1) receptor agonists have become frontline agents in obesity treatment due to their efficacy. However, there is considerable inter-individual variability in treatment response. Although these agents are primarily degraded by proteolytic enzymes rather than cytochrome P450 (CYP) pathways, pharmacogenomic factors may indirectly influence therapeutic outcomes. This review investigates the role of CYP2D6 polymorphisms in optimizing GLP-1 receptor agonist therapy in obesity. It explores genetic influences on treatment variability and highlights the importance of personalized dosing strategies. A systematic search of PubMed, Embase, and Web of Science (1990-2025) was conducted using terms such as "CYP2D6 polymorphisms," "GLP-1 receptor agonists," "pharmacogenomics," and "personalized medicine." Emphasis was placed on primary experimental studies. While GLP-1RAs are not CYP2D6 substrates, pharmacogenomic factors play a key role through indirect mechanisms. ARRB1 (rs140226575 and Thr370Met) and GLP1R (rs6923761 and Gly168Ser) variants affect glycemic response. CYP2D6 polymorphisms significantly influence metabolism of concomitant medications (e.g., antidepressants and beta-blockers), affecting efficacy and safety. Ethnic variability in CYP2D6 allele frequencies further underscores the need for tailored approaches. Integrating pharmacogenomic data, including CYP2D6 status, can support personalized obesity management and improve clinical outcomes. The primary metabolizers of GLP-1 receptor agonists are proteolytic enzymes; nevertheless, pharmacogenomic heterogeneity influences treatment results via both direct and indirect mechanisms. Variants in CYP2D6 polymorphisms have an indirect impact on treatment outcomes through changed metabolism of concurrent drugs including beta-blockers and antidepressants, while variations in GLP1R and ARRB1 directly affect receptor signaling and weight loss effectiveness.

This single-center, randomized, open-label bioequivalence program compared two fixed-dose combination (FDC) tablets containing ibuprofen (200 mg) and phenylephrine hydrochloride (10 mg) from different manufacturers in healthy Chinese adults under fasting and fed conditions. A three-period, partially replicated crossover design was used for the fasting study and a four-period, fully replicated crossover design for the fed study. Serial plasma samples were collected up to 16 h post-dose, and pharmacokinetic parameters included C, AUC, and AUC for both analytes. Bioequivalence was assessed using average bioequivalence (ABE) when the within-subject standard deviation of the reference was <0.294 and reference-scaled ABE (RSABE) otherwise. The geometric mean ratios (90% CIs) for C, AUC, and AUC of both ibuprofen and phenylephrine fell within 80%-125% in both nutritional states, with RSABE applied to phenylephrine C where variability was high. Both products were well tolerated; adverse events were mild, comparable between test and reference, and no subject discontinued due to adverse events. These findings demonstrate bioequivalence of the two ibuprofen/phenylephrine FDC and support their similar safety profiles in healthy Chinese volunteers.

Olopatadine hydrochloride, a second-generation selective histamine H1 receptor antagonist, is an effective anti-allergic agent. This study evaluated the pharmacokinetics and bioequivalence of two olopatadine hydrochloride tablet formulations in healthy Chinese subjects under fasting (n = 24) and fed (n = 24) conditions. A single-center, randomized, open-label, single-dose, two-way crossover study was conducted, in which 48 subjects were randomized to receive 5 mg of the test or reference formulation, followed by a 7-day washout period. Blood samples were collected at predefined intervals up to 24 h post-dose, and olopatadine plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. The results demonstrated no significant differences in the pharmacokinetic profiles between the test and reference formulations under fasting or fed conditions. The 90% confidence intervals (CIs) for the ratio of geometric means of C, AUC, and AUC of olopatadine hydrochloride under both conditions were within the bioequivalence range of 0.80-1.25. A high-fat diet delayed olopatadine hydrochloride absorption, leading to a reduction in C to approximately 60% of the fasting value and a decrease in AUC to 85%-90%. No serious adverse events occurred, and safety profiles were comparable between formulations. This research confirmed the bioequivalence and similar safety of the generic olopatadine hydrochloride tablets to the reference formulation.

Fipaxalparant, a small molecule and negative allosteric modulator of lysophosphatidic acid receptor 1, is being evaluated in phase 2 clinical trials of idiopathic pulmonary fibrosis (IPF) and diffuse cutaneous systemic sclerosis. This phase 1, open-label, crossover, 3-cohort study in healthy adults evaluated mutual drug-drug interactions (DDIs) between fipaxalparant and the IPF medications pirfenidone and nintedanib, as well as the effects of itraconazole (P-glycoprotein inhibitor) and rifampin (potent organic anion transporting polypeptide [OATP] inhibitor) on fipaxalparant. Participants received a single oral dose of fipaxalparant 300 mg. Overall, 16, 20, and 15 participants completed the study in cohorts 1, 2, and 3, respectively. The study demonstrated no relevant mutual DDIs between fipaxalparant and pirfenidone/nintedanib at clinical doses. There was no effect of itraconazole 400 mg on fipaxalparant exposure. A single rifampin 600 mg dose caused 1.48-fold and 1.86-fold increases in fipaxalparant C and AUC, respectively. Treatment-emergent adverse events were mild/moderate with fipaxalparant alone or with the other study drugs. Overall, fipaxalparant absorption in vivo occurs independently of the P-glycoprotein-mediated gut efflux pathway, and fipaxalparant is a clinically relevant OATP substrate. Results of this DDI study will inform the management of concomitant medications of ongoing/future trials of fipaxalparant.

Omadacycline is a novel aminomethylcycline antibiotic that shows non-inferior efficacy to moxifloxacin in adults with community-acquired pneumonia (CAP), but lacking clinical evidence in elderly patients with CAP. This randomized, controlled study aimed to investigate the efficacy and safety of omadacycline in elderly patients with CAP. Eligible elderly patients with CAP were randomized at a 1:1 ratio to the omadacycline group (n = 48) and moxifloxacin group (n = 49) to receive the corresponding agent. The primary endpoint was clinical response. The most common pathogens in the omadacycline and moxifloxacin groups were viridans streptococci (16.7%, 16.3%), Klebsiella pneumoniae (14.6%, 14.3%), and Neisseria sicca (14.6%, 14.3%). Clinical response rate was greater in the omadacycline group compared to the moxifloxacin group (54.2% vs 26.5%, P =  .032). The omadacycline group showed higher significant improvement rate (41.7% vs 16.3%, P =  .02), but similar complete recovery (12.5% vs 10.2%, P =  .737), effective improvement (37.5% vs 59.2%, P =  .125), and ineffectiveness (8.3% vs 14.3%, P =  .384) rates compared to the moxifloxacin group. Results of C-reactive protein, procalcitonin, and interleukin-6 at baseline and after treatment, as well as their changes did not vary between the omadacycline and moxifloxacin groups (all P >  .05). No difference was observed in liver, kidney, and coagulation function parameters between the two groups (all P >  .05). Omadacycline indicates greater treatment efficacy and comparable safety profiles versus moxifloxacin in elderly patients with CAP.

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) and 1.22-1.48 for area under the concentration-time curve to one dosing interval (AUC) 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 and 1.10-1.38 for AUC 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 and AUC 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.

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, AUC, and C 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.

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, AUC, and AUC 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.

Bepirovirsen, an antisense oligonucleotide in development for the treatment of chronic hepatitis B virus (HBV) infection, is administered from glass vials as a subcutaneous (SC) injection by healthcare professionals (HCPs). A ready-to-use prefilled syringe (PFS) assembled with a safety syringe device (SSD) has been developed to make administration more convenient and facilitate patient self-administration. This Phase 1, open-label, randomized, parallel-group study evaluated the relative bioavailability of bepirovirsen delivered from a vial or PFS SSD, assessed the viability of PFS SSD self-administration, and evaluated the safety and tolerability of SC bepirovirsen in healthy participants. Participants (N = 159) received a single 300 mg SC dose of bepirovirsen administered by a HCP (vial [n = 46] or PFS SSD [n = 49]), or self-administered (PFS SSD, with [n = 32] or without [n = 32] training from a HCP). Relative bioavailability (primary endpoint) of HCP-administered bepirovirsen delivered by vial versus PFS SSD was assessed using maximum observed plasma concentration (C) and area under the concentration-time curve from time zero extrapolated to infinity (AUC). Participants were monitored for adverse events. Bepirovirsen exposure was bioequivalent when HCP-administered either by vial or PFS SSD; the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) were within the standard bioequivalence reference range, 0.80-1.25, for both C (1.02 [0.91-1.14]) and AUC (1.05 [0.96-1.15]). Self-administration using PFS SSD achieved bioequivalence for bepirovirsen exposure compared with HCP administration. No new safety concerns were identified. These findings confirm that PFS SSD is a viable alternative to vials for bepirovirsen administration, when HCP- or self-administered, for the treatment of chronic HBV. Clinical trial identifier: NCT06058390.

Fezolinetant is a non-hormonal, selective neurokinin-3 receptor antagonist that blocks neurokinin B activation of kisspeptin/neurokinin B/dynorphin neurons to thereby modulate neuronal activity in the thermoregulatory center. Fezolinetant has been approved in many regions, including North America, Europe, Asia, and Australia for the treatment of vasomotor symptoms associated with menopause at a dose of 45 mg once daily (QD). The risk of potential QT prolongation for fezolinetant was assessed prior to the initiation of the phase 3 trials. A concentration-QTc (C-QTc) analysis was performed in accordance with recommendations from ICH E14 Guideline and utilized data from a phase 1 single and multiple ascending dose study, which tested single doses up to 900 mg and multiple daily doses up to 720 mg in healthy male and female participants. The fezolinetant C-QTc relationship indicated no clinically relevant QT prolongation at therapeutic or supra-therapeutic doses of fezolinetant. Based on these modeling results as well as data from other clinical and non-clinical studies, no thorough QT/QTc (TQT) study was required for fezolinetant.

This study aimed to assess the bioequivalence of a newly developed generic formulation of empagliflozin in comparison with the reference product. A total of 32 healthy adult volunteers participated in an open-label, randomized, balanced, two-treatment, two-sequence, two-period crossover study. Following an overnight fast, each participant received a 25 mg single oral dose of either the test or the reference empagliflozin with a 1-week washout period between treatments. Safety was monitored throughout the study, and 21 blood samples were collected at pre-dose and at multiple time points from 0.5 to 48 h post-dose. Plasma concentrations of empagliflozin were quantified using a validated LCMS/MS method following liquid-liquid extraction. Pharmacokinetic parameters were calculated using non-compartmental analysis and statistically compared between formulations using multivariate analysis of variance. The test formulation was well tolerated under fasting conditions, with no serious adverse events reported. The pharmacokinetic parameters, including C and AUC , were not significantly different between the test and reference products. The 90% confidence intervals of the Ln-transformed pharmacokinetic parameters fell within the bioequivalence acceptance range of 80.00% to 125.00%. In conclusion, the test and reference formulations of empagliflozin 25 mg are bioequivalent under fasting conditions in healthy individuals.

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). Secondary parameters included time to C (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.

Asciminib is the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) in patients with chronic myeloid leukemia. This phase 1, two-treatment-period, drug-drug interaction study evaluated the effect of steady-state asciminib on the pharmacokinetics of atorvastatin. A single dose of atorvastatin (20 mg) was administered on day 1 (period 1: days 1-4). On days 5-11 (period 2: days 5-12), 80 mg asciminib was administered once daily, with a single dose of atorvastatin co-administered on day 9. Pharmacokinetic sampling for atorvastatin was performed on days 1-4 in period 1 and days 9-12 in period 2. Twenty-two healthy participants were enrolled. Twenty participants completed the study, and two discontinued due to adverse events (AEs). Asciminib increased the adjusted geometric mean (G) of maximum plasma concentration (C), the area under the curve (AUC) from zero to the last quantifiable concentration (AUC), and the AUC from zero to infinity (AUC) of atorvastatin by 24%, 16%, and 14%, respectively, and did not affect these parameters for its active metabolites, o-hydroxy-atorvastatin and p-hydroxy-atorvastatin. Plasma concentrations of coproporphyrin-1 (CP-1), an endogenous substrate of the atorvastatin transporter OATP1B, were not affected by asciminib. Thirteen participants reported at least one AE, all being grade 1/2, except for one grade 3 AE (increased alanine aminotransferase). No serious AEs were reported. In conclusion, concomitant administration of steady-state asciminib and atorvastatin resulted in a small, clinically irrelevant increase in atorvastatin exposure and no change in CP-1 concentrations. Both drugs were well tolerated. These data support co-administration of asciminib and atorvastatin.

The oral, small molecule inhibitor of activin receptor-like kinase-2, zilurgisertib (INCB000928), is under evaluation in fibrodysplasia ossificans progressiva. Cardiac safety was assessed using electrocardiogram (ECG) parameters and a plasma concentration-heart rate-corrected QT (C-QTc) interval analysis of pooled data from single ascending dose (SAD) and multiple ascending dose (MAD) studies of zilurgisertib in healthy adult participants (SAD: 10-500 mg; INCB00928-102: 50-400 mg QD, 300 mg BID). Overall, 91 (SAD) and 79 (MAD) participants provided at least one pair of PK/ECG data. As both studies indicated a dose-dependent effect of zilurgisertib on heart rate, individualized QT correction (QTcI) was used as the primary endpoint for QTc analysis. Estimated population slope of the individualized C-ΔQTc (C-ΔQTcI) relationship was shallow (0.02 ms per µm [90% CI, -0.60, 0.65]) and not statistically significantly different from 0; treatment effect-specific intercept was small and not significant (-0.83 ms [90% CI, -2.26, 0.61]). No significant relationship between zilurgisertib plasma concentration and change in QTcI was identified; zilurgisertib did not have a clinically relevant effect on QTc prolongation. QT effect >10 ms could therefore be excluded within the dose range studied (up to 300 mg BID). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. These data support further clinical development of zilurgisertib.

N-acetylcysteine (NAC) is a derivative of cysteine with potent mucolytic and antioxidant properties. However, the pharmacokinetics of NAC tablets remain unclear in healthy Chinese subjects. This study aimed to assess the pharmacokinetics, bioequivalence, and safety of a domestically manufactured NAC tablet (600 mg) compared with the reference formulation in healthy Chinese volunteers under both fasting and fed conditions. A single-dose, randomized, open-label, two-formulation, crossover bioequivalence study was conducted, using a two-period, two-sequence design under fasting conditions and a four-period, fully replicated crossover design under fed conditions. Blood samples were collected at predetermined time points and analyzed using a validated liquid chromatography-tandem mass spectrometry method. The 90% confidence intervals for the geometric mean ratios (test/reference) of the maximum plasma concentration, the area under the concentration-time curve from time zero to the last measurable concentration, and from time zero to infinity were all within the accepted bioequivalence range of 80%-125%. Furthermore, both the test and reference formulations were well tolerated, and no serious adverse events were reported. These results demonstrate that the test and reference NAC tablets are bioequivalent and exhibit similar pharmacokinetic profiles and safety in healthy Chinese subjects under both fasting and fed conditions.

This randomized, open-label, single-dose crossover study evaluated the bioequivalence of a Chinese-manufactured oseltamivir phosphate oral suspension (7.5 mg/12.5 mL) against Tamiflu under fasting and fed conditions. A total of 42 healthy Chinese adults were enrolled in each group, with 39 completing the fasting group (3 withdrew) and 40 completing the fed group (1 withdrew in washout, 1 lost to follow-up). Plasma concentrations of oseltamivir and its active metabolite oseltamivir carboxylate were measured via LC-MS/MS, and pharmacokinetic parameters were calculated using non-compartmental models. The 90% confidence intervals of key parameters fell within the 80.00-125.00% range, confirming bioequivalence. No serious adverse events occurred, indicating similar safety profiles. The test formulation is bioequivalent to Tamiflu under both fasting and fed conditions.

Mocravimod, a novel immunomodulator targeting sphingosine-1-phosphate receptor (S1PR), is being developed as a maintenance treatment for patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Preclinical data suggested that cytochrome (CYP) 3A4 is the primary enzyme involved in mocravimod metabolism. In vitro data showed that both mocravimod and its active metabolite mocravimod-phosphate are substrates for breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) but not for organic-anion-transporting polypeptides (OATP1B1 and OATP1B3). As mocravimod is co-administered with CYP3A4 inhibitors such as azoles or cyclosporin, the potential for drug-drug interactions (DDIs) was evaluated. In addition, the effect of BCRP, P-gp, and OATP via cyclosporin co-administration was assessed. Two open-label, two-period, fixed-sequence studies were conducted in healthy subjects to evaluate the DDI potential of mocravimod and 1) itraconazole, a dual CYP3A4/P-gP inhibitor, or 2) cyclosporin, a moderate inhibitor of CYP3A4 and P-gp, BCRP, OATP1B1, and OATP1B3. Safety and tolerability were also monitored. The PK of mocravimod and mocravimod-phosphate were bioequivalent with or without co-administration of multiple doses of itraconazole and a moderate interaction is observed when co-administered with cyclosporin. The most commonly-reported treatment-emergent adverse events were bradycardia and decreased lymphocyte count, which are expected side effects for S1PR modulators.