Clinical Pharmacology in Drug Development最新文献

{"title":"Effects of High- and Low-Fat Meals on the Bioavailability and Pharmacokinetics of Votoplam, a HTT Gene Splicing Modifier","authors":"Lucy Lee,&nbsp;Amy-Lee Richards,&nbsp;Nageswara Reddy,&nbsp;Brian Beers,&nbsp;Lee Golden,&nbsp;Ronald Kong","doi":"10.1002/cpdd.1626","DOIUrl":"10.1002/cpdd.1626","url":null,"abstract":"<p>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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Bioequivalence and Safety Evaluation of Ibuprofen/Phenylephrine Hydrochloride Fixed-Dose Combination Tablets in Healthy Chinese Volunteers","authors":"Menghan Ye,&nbsp;Rui Zhang,&nbsp;Jing Wan,&nbsp;Jinping Zhou,&nbsp;Pengpeng Guo,&nbsp;Dianwen Yu,&nbsp;Peixia Li,&nbsp;Yani Liu,&nbsp;Shaojun Shi","doi":"10.1002/cpdd.1625","DOIUrl":"10.1002/cpdd.1625","url":null,"abstract":"<p>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 &lt;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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Dose Pharmacokinetic Assessment of TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets): Results From Randomized, Open-Label Studies in Healthy Volunteers","authors":"Bruce L Daugherty,&nbsp;Bernd Meibohm,&nbsp;Gregory M Sullivan,&nbsp;Errol M Gould,&nbsp;Seth Lederman","doi":"10.1002/cpdd.70034","DOIUrl":"10.1002/cpdd.70034","url":null,"abstract":"<p>Daily oral cyclobenzaprine hydrochloride (HCl) has provided transient benefits in fibromyalgia, a chronic pain condition. To improve this effect, we evaluated sublingual formulations designed to drive transmucosal absorption. Two open-label studies evaluated the pharmacokinetics (PK), tolerability, and relative bioavailability of sublingual cyclobenzaprine HCl in healthy adults. In Study 1 (n = 24), three 2.8 mg sublingual formulations of cyclobenzaprine HCl containing potassium phosphate dibasic (A), sodium phosphate dibasic (B), or trisodium citrate (C) were compared to immediate release (IR) cyclobenzaprine HCl 5 mg. All sublingual formulations showed increased bioavailability (154% [A], 126% [B], and 125% [C]) and rapid absorption. Formulation A demonstrated the most favorable PK, with a ∼3 min absorption lag versus ∼37 min for oral IR, and a 783% higher dose-normalized AUC_0-1. Formulation A was designated TNX-102 SL for further development. In Study 2 (n = 16), TNX-102 SL 2.8 and 5.6 mg exhibited dose proportionality and no food effect. Furthermore, this is the first report describing the active metabolite norcyclobenzaprine in clinical studies, showing an elimination half-life of ∼60 h. Oral hypoesthesia and abnormal taste were the most common adverse events. These findings support TNX-102 SL as a rapidly absorbed and efficient sublingual tablet formulation of cyclobenzaprine HCl, providing effective transmucosal delivery.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1, Randomized, Placebo-Controlled, Multiple-Dose, Double-Blind Study to Evaluate and Compare the Pharmacokinetics and Safety of Rimegepant in Healthy Adult Japanese and Caucasian Individuals","authors":"Rajinder Bhardwaj,&nbsp;Chay Ngee Lim,&nbsp;Yinhua Li,&nbsp;Kyle T. Matschke,&nbsp;Richard Bertz,&nbsp;Robert Croop,&nbsp;Jing Liu","doi":"10.1002/cpdd.1630","DOIUrl":"10.1002/cpdd.1630","url":null,"abstract":"<p>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 &lt;20% following a single dose (Day 1) and &lt;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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical assessment of mocravimod as a victim of drug–drug interactions via CYP3A4 metabolism and transporters","authors":"Dymphy R. Huntjens,&nbsp;Stephan Oehen,&nbsp;Elisabeth Kueenburg","doi":"10.1002/cpdd.1622","DOIUrl":"10.1002/cpdd.1622","url":null,"abstract":"<p>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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12933224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145387575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Safety of VV116 in Subjects With Mild or Moderate Hepatic Impairment Compared With Healthy Controls: A Phase I, Open-Label Study","authors":"Xi Tan,&nbsp;Tong Lu,&nbsp;Shijuan Kuang,&nbsp;Qin Meng,&nbsp;Ge Yu,&nbsp;Jianjun Zou,&nbsp;Yuya Wang","doi":"10.1002/cpdd.70037","DOIUrl":"10.1002/cpdd.70037","url":null,"abstract":"<p>VV116 (Mindvy, JT001) is a deuterated oral derivative of remdesivir hydrobromide developed for the treatment of COVID-19. Because hepatic dysfunction may influence drug exposure, this Phase 1, open-label, parallel-group study characterized the pharmacokinetics and safety of VV116 in adults with mild or moderate hepatic impairment (classified by the Child–Pugh method) compared with matched healthy controls. Each participant received a single oral 0.3-g dose of VV116 under fasting conditions, and serial plasma samples were collected through 72 h to quantify VV116 and its active metabolite, 116-N1, by validated LC-MS/MS. Overall exposure (AUC) in mild and moderate impairment was comparable to controls (AUC_0-t GMRs 94.10% [90% CI 71.59%-123.68%] and 97.72% [74.34%-128.44%]), with similar median T_max and t_1/2; C_max was lower in both impairment cohorts. Treatment-emergent adverse events occurred in 12.5% (mild), 37.5% (moderate), and 12.5% (control) groups; all were mild or moderate, transient, and resolved without treatment. The higher incidence in the moderate group was not considered clinically meaningful, as events were isolated and not related to VV116 exposure. No serious adverse events, deaths, or discontinuations occurred. Overall, hepatic impairment had no clinically relevant effect on VV116 pharmacokinetics, and dose adjustment appears unnecessary for patients with mild or moderate hepatic impairment.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Aztreonam–Avibactam After Single- and Multiple-Dose Administration: A Phase 1, Open-Label Study in Healthy Chinese Participants and Ethnic Comparison with Non-Chinese Participants","authors":"Jingjing Wang,&nbsp;Jinjie He,&nbsp;Jufang Wu,&nbsp;Jing Zhang,&nbsp;Ying Ma,&nbsp;Xiaoqing Ren,&nbsp;Hua Wei,&nbsp;Chunye Zhang,&nbsp;Hua Zhu,&nbsp;Susan R. Raber,&nbsp;Shuangchen Cong","doi":"10.1002/cpdd.70040","DOIUrl":"10.1002/cpdd.70040","url":null,"abstract":"<p>Combined treatment with aztreonam (an established intravenous antibiotic) and avibactam (a β-lactamase inhibitor) has the potential to address the unmet need for safe and effective agents to combat infections caused by Gram-negative bacteria producing metallo β-lactamases (MBLs). Aztreonam–avibactam may also address other problematic β-lactamases, such as extended-spectrum β-lactamases and serine carbapenemases, which may be co-expressed with MBLs and contribute to a multidrug-resistant phenotype. Based on completion of two Phase 3 trials, aztreonam–avibactam was approved in Europe (2024), the United States and China (2025). This Phase 1 open-label study assessed the pharmacokinetics, safety, and tolerability of aztreonam–avibactam in healthy Chinese participants after single- and multiple-dose administration (doses equivalent to those evaluated in Phase 3 aztreonam–avibactam trials), with a fixed 3:1 ratio. Pharmacokinetics, safety, and tolerability characteristics of aztreonam and avibactam were consistent with previous knowledge, with no clinically significant differences in exposures between Chinese and non-Chinese participants. Based on population pharmacokinetic modeling which incorporated data from the aztreonam–avibactam Phase 1–3 trials, predicted aztreonam and avibactam exposures at steady state for Phase 3 participants in China and non-China (rest-of-world) regions were numerically similar. These findings indicate that aztreonam–avibactam is well tolerated in healthy Chinese adults and support the use of the approved dose regimen by EMA for Chinese patient populations.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12919684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioequivalence Between a Gantenerumab Disposable Syringe and an Autoinjector: A Randomized Controlled Trial in Healthy Volunteers","authors":"Dietmar Schwab,&nbsp;Carsten Hofmann,&nbsp;Nicole Justies,&nbsp;Daniel S. Dickerson,&nbsp;Ali Keshavarz,&nbsp;Thijs van Iersel,&nbsp;Kimberly Martens,&nbsp;Beate Bittner","doi":"10.1002/cpdd.70038","DOIUrl":"10.1002/cpdd.70038","url":null,"abstract":"<p>Gantenerumab, a monoclonal antibody targeting amyloid beta plaques in the brain, reduces plaque accumulation and was developed to slow Alzheimer's disease progression. Results from the pivotal GRADUATE I and II studies evaluating gantenerumab in people with early Alzheimer's disease were announced in 2022. The studies did not meet their primary endpoint of slowing clinical decline. This study evaluated the pharmacokinetics, immunogenicity, and safety of a high concentration liquid formulation of gantenerumab administered subcutaneously as a single dose using an autoinjector (AI) or a disposable syringe (DS). The DS was employed in pivotal clinical trials, while the AI was developed in parallel to ease SC administration. The study aimed to demonstrate bioequivalence (BE) between AI and DS administration in healthy participants, defined by 90% confidence intervals (CIs) for geometric least square (LS) mean ratios being within the 0.80-1.25 range for maximum observed plasma concentration (C_max) and area under the plasma concentration–time curve (AUC). Among the 266 healthy participants, 135 received 255 mg gantenerumab via AI and 131 received 255 mg via DS in a parallel group design. BE between AI and DS SC administration was demonstrated with geometric LS mean ratios (90% CIs) for C_max, AUC_0-inf, and AUC_0-last of 1.078 (1.006, 1.155), 1.053 (0.986, 1.124), and 1.054 (0.992, 1.121), respectively, all within the 0.80-1.25 BE range. Safety findings were consistent with the known safety profile of gantenerumab.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12919677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Phase 1 Study of Firsekibart in Chinese Healthy Participants","authors":"Xiaolan Yong,&nbsp;Xiaolin Du,&nbsp;Xiao Li,&nbsp;Yushi Chen,&nbsp;Xiaoyan Zhu,&nbsp;Tianhong Luo,&nbsp;Qian Xu","doi":"10.1002/cpdd.70030","DOIUrl":"10.1002/cpdd.70030","url":null,"abstract":"<p>Firsekibart is an anti-IL-1β monoclonal antibody for treating acute gout flares in adults. This randomized, double-blind, placebo-controlled study assessed the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of multiple ascending doses of firsekibart in healthy Chinese adults. Participants were assigned to one of the two firsekibart cohorts (120 or 200 mg) every 4 weeks for three doses and randomized in a 5:1 ratio to receive firsekibart or placebo. Twenty-four participants completed the study. After a single dose, the median T_max was 7.0 days for both firsekibart groups. Mean C_max was 16.0 and 29.2 µg/mL; AUC_0–t was 350.6 and 600.0 d·µg/mL for the 120 and 200 mg groups. Following multiple doses, the median T_max,ss was 4.0 days and 5.5 days, C_max,ss was 31.5 and 54.1 µg/mL, AUC_0–t,ss was 1213.3 and 1975.8 d·µg/mL, and AUC_0–∞,ss was 1445.3 and 2355.4 d·µg/mL. Accumulation ratios for C_max and AUC were &lt;2 in both groups. Serum total IL-1β levels showed no dose-related trends and immunogenicity was low. Treatment-emergent adverse events (TEAEs) occurred in 65.0% of firsekibart-treated participants and 75.0% of placebo-treated participants. TEAEs were mostly grade 1 or 2. Firsekibart was safe, well tolerated after multiple administrations in healthy participants, with dose-proportional exposure and modest accumulation.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12907776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1 Study Evaluating the Effects of Single-Dose Frespaciguat, an Inhaled Soluble Guanylate Cyclase Stimulator, Co-administered with Multiple-Dose Sildenafil on Systemic Hemodynamics","authors":"Ednan K. Bajwa,&nbsp;Dawn Cislak,&nbsp;John Palcza,&nbsp;Tom Reynders,&nbsp;Jenny Barthson,&nbsp;Sylvie Rottey,&nbsp;Eseng Lai,&nbsp;S. Aubrey Stoch","doi":"10.1002/cpdd.70035","DOIUrl":"10.1002/cpdd.70035","url":null,"abstract":"<p>Co-administration of oral phosphodiesterase 5 inhibitors with oral soluble guanylate cyclase (sGC) stimulators is contraindicated due to the risk of systemic side effects. Frespaciguat, an inhaled sGC stimulator, has been studied in pulmonary hypertension (PH)-related conditions such as pulmonary arterial hypertension (PAH) and PH associated with chronic obstructive pulmonary disease (PH-COPD), and may allow combined use with oral PDE5i due to low systemic exposure. To evaluate a potential interaction between inhaled frespaciguat and oral sildenafil, 19 healthy participants were randomized to two treatment sequences (two periods separated by a 36-h washout). Treatment involved 3 days of dosing with open-label oral sildenafil (20 mg, three times per day) and a single inhaled dose of frespaciguat 240 µg or placebo on Day 3. Primary endpoints included safety assessed by adverse events (AEs) and change from baseline in systolic and diastolic blood pressure, and heart rate. Incidence of AEs was comparable across groups with no serious AEs, discontinuations due to AEs, or deaths. In conclusion, inhaled frespaciguat was well tolerated when administered on background sildenafil, without negative effects on systemic hemodynamics, versus placebo. The lack of additive systemic effects on blood pressure further documents pulmonary selectivity of inhaled frespaciguat, including when co-administered with sildenafil (EudraCT number 2019-001224-35).</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}