Drugs in Research & Development最新文献

{"title":"Clinical Assessment of Breast Cancer Resistance Protein (BCRP)-Mediated Drug-Drug Interactions of Sepiapterin with Curcumin and Rosuvastatin in Healthy Volunteers.","authors":"Lan Gao, Diksha Kaushik, Kimberly Ingalls, Sarah Milner, Neil Smith, Ronald Kong","doi":"10.1007/s40268-024-00488-0","DOIUrl":"10.1007/s40268-024-00488-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Sepiapterin, also known as PTC923 and CNSA-001, is a synthetic form of endogenous sepiapterin being developed as a novel oral treatment for phenylketonuria. Sepiapterin is a natural precursor of tetrahydrobiopterin (BH<sub>4</sub>) and, when orally administered, is converted to BH<sub>4</sub> via the pterin salvage pathway. In vitro studies have demonstrated that both sepiapterin and BH<sub>4</sub> are both substrates and inhibitors of the breast cancer resistance protein (BCRP) transporter. This phase I study investigated BCRP-mediated drug-drug interactions of sepiapterin as a victim and as a perpetrator.</p><p><strong>Methods: </strong>An open-label, fixed-sequence, four-period, crossover, single-dose study was conducted in adult male and female healthy volunteers (18-55 years of age). In a given treatment period, subjects received a single oral dose of sepiapterin (20 mg/kg), sepiapterin (20 mg/kg) plus curcumin (2 g), rosuvastatin (10 mg), or rosuvastatin (10 mg) plus sepiapterin (60 mg/kg). The pharmacokinetics of sepiapterin, its metabolite BH<sub>4</sub>, and rosuvastatin were studied, and geometric mean ratios of exposures in the presence and absence of the BCRP inhibitor curcumin or sepiapterin were estimated. The presence of the BCRP c.421C>A polymorphism was evaluated in all subjects.</p><p><strong>Results: </strong>A total of 29 subjects were enrolled and included in the safety analysis. Among them, 26 subjects were included in the pharmacokinetic and drug-drug interaction analyses. Following oral administration 20 mg/kg sepiapterin, sepiapterin was rapidly and extensively converted to BH<sub>4</sub>, and BH<sub>4</sub> maximum observed concentration (415.0 ng/mL) was observed 4.95 h (time to maximum observed concentration) post-dose. Sepiapterin maximum observed concentration and area under the concentration-time curve from time 0 to time of the last quantifiable measurement or the last sample collection time (AUC<sub>last</sub>) were <1% of BH<sub>4</sub> values. Coadministration of the BCRP inhibitor curcumin (2 g) increased BH<sub>4</sub> maximum observed concentration, AUC<sub>last</sub>, and area under the concentration-time curve from time 0 extrapolated to infinity by 24%, 21%, and 20%, respectively. When sepiapterin was coadministered with the BCRP substrate rosuvastatin, there was no effect on the pharmacokinetics of rosuvastatin. BCRP c.421C/A carriers (n = 4) had higher plasma exposures of BH<sub>4</sub> (1.39 × for AUC<sub>last</sub>) and rosuvastatin (1.61 × for AUC<sub>last</sub>) than c.421C/C carriers (n = 22). Greater increases in BH<sub>4</sub> exposures (1.33 vs 1.18 for AUC<sub>last</sub>) were observed in c.421C/A carriers compared with c.421C/C carriers when sepiapterin was coadministered with curcumin. All treatments were well tolerated during the study.</p><p><strong>Conclusions: </strong>Oral coadministration of the BCRP inhibitor curcumin slightly increased the ","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"477-487"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308895","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 and Safety of Bilastine 20 mg Orodispersible Tablets and Conventional Tablets: A Randomized, Single-Dose, Two-Period Crossover Study in Healthy Volunteers Under Fasting Conditions.","authors":"Manuel Román, Dolores Ochoa, Samuel Martin, Sergio Luquero, Inmaculada Gilaberte, Paula Arranz, Carlos Sánchez","doi":"10.1007/s40268-024-00480-8","DOIUrl":"10.1007/s40268-024-00480-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Orodispersible tablets (ODT) rapidly dissolve in the oral cavity and can improve patient's convenience. This pharmacokinetic study assessed the bioequivalence of a novel 20 mg ODT formulation of bilastine compared with bilastine 20 mg tablets in healthy volunteers under fasting conditions.</p><p><strong>Methods: </strong>A phase I, single-center, open-label, two-period, two-sequence crossover randomized clinical trial was conducted. The study comprised two periods, in which participants were administered a single oral dose of bilastine 20 mg in the form of ODT as the test product, or conventional tablets as the reference product, and a washout of 7 days between each period. Blood samples were collected for up to 72 h. Bioequivalence was established if the 90% confidence intervals of the C_max and AUC_0-t were within the acceptance range (80-125%). Safety was evaluated at the follow-up visit (days 4-7 after the second dose) and throughout the study.</p><p><strong>Results: </strong>A total of 42 healthy volunteers were randomized, and 41 completed the study. Pharmacokinetic parameters were comparable for both formulations after a single dose of 20 mg. Bilastine ODT and conventional tablets were bioequivalent as the 90% confidence intervals of the test over reference ratios were within the predefined range (80-125%). Both formulations were well tolerated and showed a similar safety profile.</p><p><strong>Conclusions: </strong>Bilastine ODT was bioequivalent to the reference treatment formulated as conventional tablets when administered as a single oral dose of 20 mg under fasting conditions. Both formulations showed a similar tolerability and safety profile, with no serious adverse events or significant analytical alterations reported.</p><p><strong>Trial registration: </strong>2019-004071-39. Date of authorization: 10 December 2019.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"405-414"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861403","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, Mass Balance, and Biotransformation of [¹⁴C]tinengotinib, A Novel Multi-target Kinase Inhibitor, in Healthy Subjects.","authors":"Shumao Ni, Sheng Ma, Yingying Yu, Zhenwen Yu, Yujia Zhu, Xiaofen Sun, Lin Li, Caixia Sun, Hui Wang, Peng Peng, Zheming Gu, Hua Zhang, Frank Wu, Liyan Miao, Jean Fan","doi":"10.1007/s40268-024-00486-2","DOIUrl":"10.1007/s40268-024-00486-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [¹⁴C]tinengotinib following a single oral dose in healthy subjects.</p><p><strong>Methods: </strong>Six healthy male subjects received a single oral dose of [¹⁴C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism.</p><p><strong>Results: </strong>Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (T_max) of 1.0-4.0 h post-dose and a long terminal half-life (t_½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration-time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4.</p><p><strong>Conclusions: </strong>Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent.</p><p><strong>Registration: </strong>ChinadrugTrials.org.cn identifier: CTR20212852.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"465-476"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134212","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":"Damoctocog Alfa Pegol, a PEGylated B-domain Deleted Recombinant Extended Half-life Factor VIII for the Treatment of Hemophilia A: A Product Review.","authors":"Mark T Reding, Shadan Lalezari, Gili Kenet, Giovanni Di Minno, Jonathan Ducore, Alexander Solms, Anita Shah, Pål André Holme, Lone H Poulsen, Karina Meijer, Mindy Simpson, Maria Elisa Mancuso","doi":"10.1007/s40268-024-00481-7","DOIUrl":"10.1007/s40268-024-00481-7","url":null,"abstract":"<p><p>Damoctocog alfa pegol (BAY 94-9027, Jivi^®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate^®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta^®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate^®/Adynovi^®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate^®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"359-381"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005686","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":"Targeting Non-V600 Mutations in BRAF: A Single Institution Retrospective Analysis and Review of the Literature.","authors":"Hirra A Chaudhary, Timothy L Cannon, Arthur Winer","doi":"10.1007/s40268-024-00475-5","DOIUrl":"10.1007/s40268-024-00475-5","url":null,"abstract":"<p><strong>Background and objective: </strong>While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience.</p><p><strong>Methods: </strong>We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response.</p><p><strong>Results: </strong>Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease.</p><p><strong>Conclusions: </strong>This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will  expand our understanding.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"395-403"},"PeriodicalIF":2.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037514","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 Bioequivalence of Two Formulations of Azithromycin Tablets: A Randomized, Single-Dose, Three-Period, Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.","authors":"Yingrong Chen, Libing Ye, Jue Mei, Mengli Tian, Min Xu, Qiuyue Jin, Xiang Yu, Shuixin Yang, Jie Wang","doi":"10.1007/s40268-024-00464-8","DOIUrl":"10.1007/s40268-024-00464-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In a fasting state, the bioequivalence of maximum plasma concentration (C&lt;sub&gt;max&lt;/sub&gt;) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, S&lt;sub&gt;WR&lt;/sub&gt; &gt; 0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC&lt;sub&gt;0-t&lt;/sub&gt;) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC&lt;sub&gt;0-∞&lt;/sub&gt;) were evaluated by the average bioequivalence (ABE) method (S&lt;sub&gt;WR&lt;/sub&gt; &lt;  0.294). The geometric mean ratio (GMR) of T/R for C&lt;sub&gt;max&lt;/sub&gt; was 106.49%, while the 95% upper confidence bound was &lt;  0. The GMRs of AUC&lt;sub&gt;0-t&lt;/sub&gt; and AUC&lt;sub&gt;0-∞&lt;/sub&gt; were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of C&lt;sub&gt;max&lt;/sub&gt; (S&lt;sub&gt;WR&lt;/sub&gt; &gt;0.294), and the ABE approach was applied to estimate the bioequivalence of AUC&lt;sub&gt;0-t&lt;/sub&gt; and AUC&lt;sub&gt;0-∞&lt;/sub&gt; (S&lt;sub&gt;WR&lt;/sub&gt; &lt;  0.294). The GMR for C&lt;sub&gt;max&lt;/sub&gt; was 99.80%, while the 95% upper confidence bound value was &lt;  0. The GMRs of AUC&lt;sub&gt;0-t&lt;/sub&gt; and AUC&lt;sub&gt;0-∞&lt;/sub&gt; were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers und","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"201-209"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176726","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":"Efficacy of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: A Pooled Analysis of Data from Two Phase 3 Randomized Clinical Trials.","authors":"Richard Langford, Eugene R Viscusi, Adelaida Morte, Jesús Cebrecos, Mariano Sust, José María Giménez-Arnau, Oscar de Leon-Casasola","doi":"10.1007/s40268-024-00469-3","DOIUrl":"10.1007/s40268-024-00469-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>New acute pain medications are needed that provide effective analgesia while minimizing side effects and opioid exposure. Clinical trials of co-crystal of tramadol-celecoxib (CTC) have demonstrated an improved benefit/risk profile versus tramadol or celecoxib alone. We pooled data from two phase 3 clinical trials to evaluate the efficacy of CTC 200 mg twice daily (BID) in acute moderate-to-severe pain.</p><p><strong>Methods: </strong>Efficacy data were pooled from STARDOM1 [acute pain following oral surgery (NCT02982161)] and ESTEVE-SUSA-301 [acute pain following bunionectomy (NCT03108482)]. The primary efficacy outcome was sum of pain intensity difference from 0 to 48 h (SPID_0-48).</p><p><strong>Results: </strong>A total of 344 patients received CTC 200 mg BID, 342 received tramadol 50 or 100 mg four times a day, 181 received celecoxib 100 mg BID, and 172 received placebo. The least-squares mean difference in SPID_0-48 was -21.8 (p = 0.002) for CTC versus tramadol and -72.8 (p < 0.001) for CTC versus placebo. A similar pattern of SPID_0-48 was observed with CTC versus comparator whether patients had moderate or severe pain at baseline. Reduction in pain intensity was faster and reached mild intensity earlier with CTC versus comparators. Patients were significantly (p ≤ 0.005) less likely to receive rescue medication within 4 or 48 h with CTC compared with tramadol or placebo.</p><p><strong>Conclusions: </strong>This pooled analysis reinforces the efficacy profile of CTC versus tramadol and, given that CTC permits lower daily tramadol dosing and thereby reduces unnecessary opioid use, this highlights its improved benefit/risk profile and its potential for the management of moderate-to-severe pain.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"239-252"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318737","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 CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis.","authors":"Timothy J Turner, Pricilla Brun, Ross C Gruber, Dimitry Ofengeim","doi":"10.1007/s40268-024-00468-4","DOIUrl":"10.1007/s40268-024-00468-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Tolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS METHODS: We used in vitro kinase and cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS.</p><p><strong>Results: </strong>In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a K_i value of 4.7 nM and slow off-rate (1.54 x 10^-5 s^-1), also had an association rate 1760-fold slower (0.00245 μM^-1 * s^-1). Estimates of cellular potency were largely consistent with the in vitro kinase assays, with an estimated IC₅₀ of 0.7 nM for tolebrutinib against 33.5 nM for evobrutinib and 2.9 nM for fenebrutinib. We then observed that evobrutinib, fenebrutinib, and tolebrutinib achieved similar levels of exposure in non-human primate CSF after oral doses of 10 mg/kg. However, tolebrutinib CSF exposure (4.8 ng/mL) (k_p,uu CSF=0.40) exceeded the IC90 (the estimated concentration inhibiting 90% of kinase activity) value, while evobrutinib (3.2 ng/mL) (k_p,uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp,uu CSF=0.15) failed to reach the estimated IC₉₀ values.</p><p><strong>Conclusions: </strong>Tolebrutinib was the only candidate of the three that attained relevant CSF exposure in non-human primates.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"263-274"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535713","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":"Normalization of Hemoglobin, Lactate Dehydrogenase, and Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan.","authors":"Brian P Mulherin, Michael Yeh, Mohammed Al-Adhami, David Dingli","doi":"10.1007/s40268-024-00463-9","DOIUrl":"10.1007/s40268-024-00463-9","url":null,"abstract":"<p><strong>Background and objectives: </strong>We determined normalization rates for hemoglobin, lactate dehydrogenase (LDH), and fatigue in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan (PEG) in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) phase III trials.</p><p><strong>Methods: </strong>Enrolled patients had PNH and hemoglobin < 10.5 g/dL despite ≥ 3 months of eculizumab (ECU) [PEGASUS], or were complement component 5 (C5) inhibitor-naive, receiving supportive care only, with hemoglobin less than the lower limits of normal (LLN) [PRINCE]. Hematologic and fatigue normalization endpoints were hemoglobin greater than or equal to the LLN (females: 12 g/dL; males: 13.6 g/dL) in the absence of transfusion; LDH ≤226 U/L in the absence of transfusion; and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue ≥ 43.6, the general population norm. Safety was assessed by investigators using standardized terms and definitions for seriousness and severity.</p><p><strong>Results: </strong>Hemoglobin normalization occurred in 34.1% (14/41) of PEG-treated patients at Week 16 (randomized controlled period) in PEGASUS (vs. 0% [0/39] of ECU-treated patients) and in 45.7% (16/35) of PEG-treated patients at Week 26 in PRINCE (vs. 0% [0/18] of supportive care-treated patients). At Week 48 (open-label period) in PEGASUS, 24.4% of PEG-treated patients (PEG-to-PEG) and 30.8% of patients treated with ECU through Week 16 who switched to PEG through Week 48 (ECU-to-PEG) had hemoglobin normalization. Rates of LDH normalization in PEGASUS were 70.7% (PEG-treated patients) and 15.4% (ECU-treated patients) at Week 16, and 56.1% (PEG-to-PEG) and 51.3% (ECU-to-PEG) at Week 48. In PRINCE, 67.5% of PEG-treated patients at Week 26 had normalized LDH concentrations. Rates of FACIT-Fatigue score normalization in PEGASUS were 48.8% and 10.3% in PEG- and ECU-treated patients, respectively, at Week 16, and 34.1% and 51.3% in PEG-to-PEG- and ECU-to-PEG-treated patients, respectively, at Week 48. In PRINCE, 68.6% of PEG-treated patients and 11.1% of supportive care patients had FACIT-Fatigue score normalization at Week 26. PEG was safe and well tolerated. Injection site reactions, mostly mild, were the most common adverse event of special interest in PEG-treated patients in the PEGASUS randomized controlled period (36.6%) and in PRINCE (30.4%).</p><p><strong>Conclusion: </strong>PEG is superior to ECU and supportive care in hemoglobin, LDH, and FACIT-Fatigue score normalization for patients with PNH and persistent anemia despite ≥3 months of treatment with ECU, and in C5 inhibitor-naive patients.</p><p><strong>Clinical trial registration: </strong>The PEGASUS trial (NCT03500549) was registered on 18 August 2018, and the PRINCE trial (NCT04085601) was registered on 11 September 2019.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"169-177"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900037","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 Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.","authors":"Zhendong Chen, Max Taubert, Chunli Chen, Jana Boland, Qian Dong, Muhammad Bilal, Charalambos Dokos, Bertil Wachall, Manfred Wargenau, Bernhard Scheidel, Martin H J Wiesen, Elke Schaeffeler, Roman Tremmel, Matthias Schwab, Uwe Fuhr","doi":"10.1007/s40268-024-00466-6","DOIUrl":"10.1007/s40268-024-00466-6","url":null,"abstract":"<p><strong>Introduction: </strong>Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability.</p><p><strong>Objective: </strong>This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability.</p><p><strong>Methods: </strong>Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately.</p><p><strong>Results: </strong>Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3).</p><p><strong>Conclusion: </strong>The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at \"Deutsches Register Klinischer Studien\" under registration no. DRKS00017760.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"187-199"},"PeriodicalIF":2.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161910","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}