The Journal of Clinical Pharmacology最新文献

{"title":"Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis","authors":"Jae Yoon Jeon PharmD, PhD,&nbsp;Vivaswath S. Ayyar PhD,&nbsp;Shohei Ouchi MPharm,&nbsp;Elisa Fabbrini MD, PhD,&nbsp;Anastasiya Koshkina PharmD,&nbsp;Jeffery J. Prusakiewicz PhD,&nbsp;Jed Dallas BS,&nbsp;Txheng Yang BA,&nbsp;Wenying Jian PhD,&nbsp;Lijuan Kang PhD,&nbsp;Korin Cofsky BS,&nbsp;Brian Rady PhD,&nbsp;Ryo Tamamura MS,&nbsp;Yuki Saito MEng,&nbsp;Aimi Yamashita MPH,&nbsp;Tamisha Vaughan PhD,&nbsp;Susan Wendel PhD,&nbsp;Hideo Makimura MD, PhD,&nbsp;Dénes Csonka PharmD, PhD,&nbsp;Navin Goyal PhD, FCP","doi":"10.1002/jcph.6174","DOIUrl":"10.1002/jcph.6174","url":null,"abstract":"<p>JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-<span>d</span>-galactosamine that targets the <i>PNPLA3</i> gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous <i>PNPLA3</i> I148M mutation in two phase 1 studies—a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses. JNJ-75220795 was predominantly distributed to the liver with peak liver concentrations reached at 4 h and still detectable at 672 and 336 h in rats and NHPs, respectively, with an apparent liver-to-plasma area under the curve (AUC) ratio of 2800 in rats. Consistent with the preclinical findings, clinical PK showed rapid systemic absorption and clearance in humans with median peak concentrations at 3.0-9.0 h and mean short half-life of 3.4-6.2 h. Plasma PK exposure parameters including C_max and AUC increased approximately dose proportionally. Kidney had the second highest tissue exposure following the liver in rats. Renal excretion was a significant but minor elimination pathway as approximately 15%-25% of the administered dose was recovered in urine. Based on the overall data, JNJ-75220795 was primarily localized to the liver and exhibited sustained hepatic exposures, which confer prolonged pharmacodynamic effects in the target organ. The favorable PK profiles of single subcutaneous doses observed in the phase 1 studies support continued clinical development of JNJ-75220795 for the treatment of MASH.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"644-653"},"PeriodicalIF":0.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Survival Benefit and Study Design on FDA Approval for Anticancer Drugs Over the Past Decades","authors":"Koji Ishizuka MSc, MBA,&nbsp;Shunsuke Ono PhD","doi":"10.1002/jcph.6172","DOIUrl":"10.1002/jcph.6172","url":null,"abstract":"<p>Despite the tremendous effort in the oncology community, the success rate of anticancer development remained low at 30% to 40% from the Phase 3 study to the regulatory approval. The factors associated with the regulatory approval for market authorization have gained interest in the community to improve the success rate of drug development. Using the data from 208 Phase 3 studies for anticancer drugs, we explored the possible factors associated with the US Food and Drug Administration's (FDA's) approval by multivariate logistic regression analysis. The model incorporated 21 factors from therapeutic context, study design, and outcomes. The hazard ratio (HR) for overall survival (OS) showed a significant association with FDA approval (coefficient: −29.907, <i>P</i> &lt; .001), and the age of control drugs in the market followed (coefficient: −2.581, <i>P</i> = .008). In the model, if the HR for OS changes from 0.75 to 0.85, the probability of FDA approval remarkably decreases from 79.6% to 16.4%. A 50% likelihood of FDA approval is predicted at HR 0.795 for OS. Furthermore, the <i>P</i>-value for the OS test and the width of the confidence interval on HR for OS showed a significant association with the probability of FDA approval. These findings consistently underscore the rigorous standard required for new anticancer drugs to obtain regulatory approval from the FDA.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"607-620"},"PeriodicalIF":0.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin–Tazobactam in Critically Ill Patients","authors":"Joshua A. Reeder BA,&nbsp;C. Buddy Creech MD,&nbsp;Roger L. Nation PhD,&nbsp;Kenan Gu PhD,&nbsp;Demet Nalbant PhD,&nbsp;Nan Wu PhD,&nbsp;Natalia Jimenez-Truque MD,&nbsp;William Fissell MD,&nbsp;Stephanie L. Rolsma MD, PhD,&nbsp;Nicholas Fishbane MS,&nbsp;Carl M. J. Kirkpatrick PhD,&nbsp;Pratish C. Patel PharmD,&nbsp;Amy Watanabe MS,&nbsp;Cornelia B. Landersdorfer PhD,&nbsp;Patricia Winokur MD,&nbsp;Guohua An MD, PhD","doi":"10.1002/jcph.6161","DOIUrl":"10.1002/jcph.6161","url":null,"abstract":"<p>Determining an effective dosing regimen for piperacillin–tazobactam in critically ill patients is challenging due to substantial pharmacokinetic variability caused by complex pathophysiological changes. To address this need, a prospective clinical study was conducted, which enrolled 112 critically ill patients and employed an opportunistic sampling strategy. Population modeling and simulation were performed to characterize the pharmacokinetics (PK) and probability of target attainment (PTA) of piperacillin–tazobactam under various dosing regimens. Both piperacillin and tazobactam final models were one-compartment models with zero-order input and first-order elimination. Significant covariates included lean body weight for piperacillin and creatinine clearance along with continuous renal replacement therapy (CRRT) for both drugs. Monte Carlo simulations demonstrated that continuous infusion can achieve higher PTA than intermittent and extended infusions. When considering the minimum inhibitory concentration (MIC) of 16 mg/L for <i>Pseudomonas aeruginosa</i> (a frequently encountered bacterial pathogen among critically ill patients) and a PK/PD target of 100% fT &gt;MIC, continuous infusion of 6 g/day is recommended for critically ill patients with a CLcr &lt;60 mL/min, 9 g/day for patients with CLcr in the range of 60 to 129 mL/min, and 12 g/day for patients with a CLcr ≥130 mL/min. In addition, extended infusion represents a good alternative, especially the 3 g q6h or 4 g q6h regimens which can achieve the designated European Committee on Antimicrobial Susceptibility Testing (EUCAST) non-species-related PK/PD breakpoint of 8 mg/L. Our study provided valuable insight into PTA outcomes, which, together with individual renal function of future patients and institution-specific piperacillin susceptibility patterns, may assist physicians when making dosing decisions.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"452-465"},"PeriodicalIF":0.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142773877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Meta-Analysis of the Safety and Immunogenicity of Pharmacokinetic Similarity Studies and Comparative Clinical Studies","authors":"Ping Ji PhD,&nbsp;Sarah J. Schrieber Pharm D,&nbsp;Rachel Glaser MD,&nbsp;Jianmeng Chen MD, PhD,&nbsp;Chinmay Shukla PhD,&nbsp;Suresh Doddapaneni PhD,&nbsp;Sahajwalla Chandrahas PhD","doi":"10.1002/jcph.6165","DOIUrl":"10.1002/jcph.6165","url":null,"abstract":"<p>A biosimilar clinical development program generally includes a pharmacokinetic similarity study and a comparative clinical study. Since both types of studies assess safety and immunogenicity, it is important to evaluate the role of each in determining whether there are any meaningful differences between the proposed biosimilar products and the reference products. We conducted a systematic review and meta-analysis of the safety and immunogenicity data from pharmacokinetic similarity studies and comparative clinical studies, using a database of approved monoclonal antibody and fusion protein biosimilars. Our analysis showed that pharmacokinetic similarity studies provided valuable information for comparing the immunogenicity and safety of the monoclonal antibody and fusion protein biosimilars with their respective reference products. This work underscores the evolving understanding of these biologics and offers insights into the clinical development of biosimilars.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"499-507"},"PeriodicalIF":0.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ritonavir May Prolong Sedation but is Unlikely to Increase the Risk of Respiratory Arrest in Patients Requiring Intravenous Midazolam for Procedural Sedation","authors":"Jason Arsanious BMedSci,&nbsp;Angela Rowland MD,&nbsp;Michael J. Sorich PhD,&nbsp;Ashley M. Hopkins PhD,&nbsp;Sam Alfred MD,&nbsp;Andrew Rowland PhD","doi":"10.1002/jcph.6171","DOIUrl":"10.1002/jcph.6171","url":null,"abstract":"<p>Intravenous midazolam is frequently used for procedural sedation. Use of ritonavir containing antivirals in patients requiring procedural sedation with intravenous midazolam is postulated to increase the risk or prolong the consequences of exposure related adverse events. The primary objective of this study was to characterize interaction of ritonavir with IV midazolam. The secondary objective was to define the time course over with the interaction of ritonavir with IV midazolam resolves following cessation of ritonavir. Physiologically based pharmacokinetic modeling was used to conduct clinical trials with a parallel group design defining exposure to a single 5 mg IV dose of midazolam in the presence and absence of nirmatrelvir/ritonavir dosed twice daily for 5 days. Simulations comprised 50 virtual healthy subjects aged 20 to 50 years (50% female). Based on FDA criteria, a moderate/strong interaction between nirmatrelvir/ritonavir and intravenous midazolam (area under the curve [AUC] ratio &gt;2) was observed when intravenous midazolam was administered up to 72 h following cessation of nirmatrelvir/ritonavir. The geometric mean (90% CI) midazolam AUC ratio was 9.21 (5.44 to 16.43) when coadministered on the final day of nirmatrelvir/ritonavir dosing. Importantly, there was no change in peak exposure; the geometric mean (90% CI) midazolam maximum concentration ratio was 0.99 (0.99 to 1.00). Use of ritonavir containing antivirals is unlikely to increase a patient's risk of experiencing an exposure related adverse event following administration of intravenous midazolam but may prolong complications in patients who experience an event. A meaningful interaction persists for 72 h following cessation of nirmatrelvir/ritonavir.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"637-643"},"PeriodicalIF":0.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Atorvastatin and Metformin after Coadministration with Islatravir in Healthy Adults","authors":"Jacqueline B. McCrea PharmD,&nbsp;Munjal Patel PhD,&nbsp;Yang Liu PhD,&nbsp;Ryan Vargo PhD,&nbsp;Rose Witter BS,&nbsp;Andrew Litovsky PharmD, MBA,&nbsp;S. Aubrey Stoch MD,&nbsp;Marian Iwamoto MD, PhD,&nbsp;Randolph P. Matthews MD, PhD","doi":"10.1002/jcph.6169","DOIUrl":"10.1002/jcph.6169","url":null,"abstract":"<p>Islatravir, a deoxyadenosine analog that inhibits HIV-1 replication by multiple mechanisms of action, including reverse transcriptase translocation inhibition, is being developed for use in HIV-1 treatment. People living with HIV often have comorbidities, such as dyslipidemia or type 2 diabetes mellitus, necessitating long-term concomitant drug therapy. This nonrandomized, two-period, fixed-sequence, open-label, phase 1, drug-drug interaction study was conducted to evaluate the effects of islatravir coadministration on atorvastatin and metformin pharmacokinetics (PK) in healthy adults. In period 1, participants received a single dose of atorvastatin 20 mg and metformin 1000 mg. After a 5-day washout, participants received atorvastatin 20 mg and metformin 1000 mg coadministered with a single oral dose of islatravir 60 mg (period 2). In both periods, blood samples were collected up to 72 h post dose to characterize the plasma PK of atorvastatin and metformin. Safety was monitored throughout the study. Fourteen participants were enrolled and completed the study. Atorvastatin and metformin plasma PK were similar after administration of atorvastatin and metformin with or without islatravir. The geometric mean ratio and 90% confidence interval of the area under the concentration-time curve from time zero to infinity (AUC_0-∞) for atorvastatin and metformin with or without a single oral dose of islatravir were 1.04 (1.00-1.10) and 0.87 (0.79-0.96), respectively. Coadministration of islatravir with atorvastatin and metformin was well tolerated. Overall, coadministration of atorvastatin and metformin with a single oral dose of islatravir did not have a clinically meaningful effect on the PK profiles of either drug.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"628-636"},"PeriodicalIF":0.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaginal Misoprostol Pharmacokinetic Changes in Obese Parturient Women Who Presented Labor Induction Failure","authors":"Gabriela Campos de Oliveira Filgueira PhD,&nbsp;Jhohann Richard de Lima Benzi PhD,&nbsp;Grazielle de Fátima Pinto Rodrigues PhD,&nbsp;Maria Paula Marques PhD,&nbsp;Matheus De Lucca Thomaz MA,&nbsp;Geraldo Duarte PhD, MD,&nbsp;Vera Lucia Lanchote PhD,&nbsp;Ricardo Carvalho Cavalli PhD, MD","doi":"10.1002/jcph.6166","DOIUrl":"10.1002/jcph.6166","url":null,"abstract":"<p>Clinical experience shows an increased duration of labor in obese parturient women. It is unclear if this population should receive the same dose of vaginal misoprostol for induction of labor as non-obese parturient women. We investigate the influence of obesity on the pharmacokinetics and placental transfer of the metabolite misoprostol acid in parturient women. Parturient women (n = 40) were enrolled and received misoprostol 25 µg/6 h vaginally and were allocated into two groups according to the pre-pregnancy body mass index (BMI &lt;30 kg/m² non-obese, n = 18 or BMI &gt;30 kg/m² obese, n = 22) or according to the labor induction outcome (failure [n = 10] or success [n = 30]). Blood collection for pharmacokinetic study occurred after the first misoprostol dose. The pharmacokinetic parameters obtained in non-obese parturient women were not statistically different from those obtained in obese group (<i>P</i> Value &gt;  .05). However, when the parturient women were grouped by the labor induction outcome, the failed labor induction group presented a higher (median [interquartile range]) BMI (44.4 [34.6-47.9] vs 33.7 [28.9-36.5] kg/m²) (<i>P</i> Value =  .0017), lower C_max (11.5 [4.82-22.2] vs 22.8 [14.2-30.8] pg/mL) (<i>P</i> Value =  .0308) and not statistically different AUC_0-6 (31.8 [13.4-61.5] vs 53.4 [35.4-77.7]) pg•h/mL) (<i>P</i> Value =  .0580) and t_max (2.50 [1.19-4.25] vs 3.00 (1.88-5.00) h (<i>P</i> Value =  .3198) when compared with parturient women who presented successful labor induction. This data suggests a higher loading dose (higher volume of distribution) and unchanged maintenance dose (unchanged AUC_0-6) of misoprostol for this population. Further studies are required to investigate the efficacy and safety of higher misoprostol loading doses for this population.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"403-410"},"PeriodicalIF":0.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults","authors":"Fiona Glassman PhD,&nbsp;John-Philip Lawo PhD,&nbsp;Mihai Alexandru Bica MD, MPH,&nbsp;Anthony Roberts PhD,&nbsp;Dipti Pawaskar PhD,&nbsp;Hideto Akama MD, PhD,&nbsp;Meena Jain MD,&nbsp;Summer Goodson PhD","doi":"10.1002/jcph.6162","DOIUrl":"10.1002/jcph.6162","url":null,"abstract":"<p>Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10 mg/kg IV doses in Japanese participants. Follow-up for safety was over 84 days post-dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow-up. Following SC administration, time to maximum plasma concentration (t_max) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC), increased less than 3-fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for C_max and AUC close to 100%. Following IV administration, t_max occurred at the end of infusion, and garadacimab exposure increased in a dose-proportional manner. Inhibition of FXIIa-mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti-drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"466-477"},"PeriodicalIF":0.0,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sentinel Dosing—Time for a Risk-Based Approach?","authors":"Peter L. Bonate PhD, FCP, FAAPS, FISoP,&nbsp;Mark Rogge PhD, FCP,&nbsp;Jean-Michel Gries PharmD, PhD, FCP,&nbsp;Alexander J. Prokopienko PharmD, PhD,&nbsp;Sudhakar M. Pai PhD, FCP,&nbsp;ACCP Public Policy Committee","doi":"10.1002/jcph.6167","DOIUrl":"10.1002/jcph.6167","url":null,"abstract":"","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"267-271"},"PeriodicalIF":0.0,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relative Bioavailability of Dordaviprone (ONC201) is Not Affected by Co-Administration of the Proton-Pump Inhibitor Rabeprazole","authors":"Shamia L. Faison PhD, PMP,&nbsp;Joelle Batonga Msc,&nbsp;Thangam Arumugham PhD,&nbsp;Angela Bartkus MBA, BSN RN,&nbsp;Marion Morrison MD,&nbsp;Mark J. Mullin BS,&nbsp;Tim Tippin PhD,&nbsp;Odin Naderer PharmD","doi":"10.1002/jcph.6163","DOIUrl":"10.1002/jcph.6163","url":null,"abstract":"<p>Dordaviprone (ONC201) is a novel, orally administered, anti-cancer, small molecule imipridone with demonstrated antitumor effects in patients with glioma. Dordaviprone in vitro solubility is significantly reduced at pH &gt;4.5. Concomitant use of acid reducing agents (ARAs) may therefore impact dordaviprone solubility and bioavailability. This open-label, single-sequence, three-period crossover study evaluated the effect of proton-pump inhibitor rabeprazole on dordaviprone pharmacokinetics (PK). Periods were consecutive and comprised of period 1 (days 1-3), period 2 (days 4-9), and period 3 (days 10-13). In period 1, participants received a single oral 625 mg dose of dordaviprone on day 1. In period 2, participants received six consecutive days of QD 20 mg rabeprazole alone. In period 3, patients received one oral dose of 20 mg rabeprazole (the seventh consecutive daily dose), followed 2 h later by a single 625 mg dordaviprone oral dose. PK blood samples were collected and analyzed from pre-dose 72 h following dordaviprone administration in periods 1 and 3. Dordaviprone exposure PK parameters were similar following administration of dordaviprone alone or with rabeprazole. Geometric mean ratios and 90% CIs for dordaviprone exposure parameters with and without rabeprazole following dordaviprone administration fell within bioequivalence limits of 80.00%-125.00% for Cmax (97.19% [86.43-109.28]), AUClast (102.21% [95.19-109.75]), and AUCinf (102.27% [95.21-109.86]), indicating no effect of multiple oral doses of rabeprazole on dordaviprone relative bioavailability. Six of the 16 participants reported treatment-emergent adverse events (TEAEs); dordaviprone-related TEAEs were reported by three participants and were limited to mild nausea and dizziness. No dordaviprone dose adjustment or ARA treatment modification is warranted.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"520-526"},"PeriodicalIF":0.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}