Clinical Pharmacology in Drug Development最新文献

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.

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_max and AUC_0-∞, 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.

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_max, AUC_0-t, and AUC_0-∞ 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_max 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.

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_max, AUC_0-t, and AUC_0-∞ 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_max, AUC_0-t, and AUC_0-∞ of both ibuprofen and phenylephrine fell within 80%-125% in both nutritional states, with RSABE applied to phenylephrine C_max 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.

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.

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.

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.