The Journal of Clinical Pharmacology最新文献

{"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717341","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, 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}

{"title":"Patients in Clinical Trials are Sub-Optimally Protected for Drug–Drug Interactions: A Call for Action","authors":"David Burger PhD,&nbsp;Loek de Jong PhD,&nbsp;Daphne van Dijk MSc,&nbsp;Catherijne A. J. Knibbe PhD,&nbsp;Rob ter Heine PhD,&nbsp;Elise Smolders PhD,&nbsp;Munir Pirmohamed PhD","doi":"10.1002/jcph.6168","DOIUrl":"10.1002/jcph.6168","url":null,"abstract":"&lt;p&gt;It is essential that patients in clinical trials of investigational medicinal products are protected from harm. However, some of the advances made to improve medication safety in routine clinical care have only sparsely trickled down to clinical trials. For instance, in routine care, drug–drug interaction data from the approved product information&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; is incorporated in prescribing and dispensing software to generate an automatic alert when a drug–drug interaction may occur. In contrast, drug–drug interaction management with investigational medicinal products is performed manually by the study physician or pharmacist based on instructions in the study protocol.&lt;/p&gt;&lt;p&gt;In our experience, instructions for drug–drug interaction management in clinical studies with unlicensed investigational medicinal products are highly variable, often outdated, and/or incomplete. To our knowledge, this problem has not yet been investigated in a systematic manner. We decided to focus on investigational medicinal products with CYP3A-related drug–drug interaction management.&lt;/p&gt;&lt;p&gt;Between January 1, 2022, and March 1, 2023 we reviewed phase 2/3 study protocols of ongoing clinical trials in adults with unlicensed investigational medicinal products being small molecules, supported by the Pharmacy at RadboudUMC, Nijmegen, the Netherlands. Unlicensed investigational medicinal products not being small molecules (i.e., large proteins and antibodies) are usually not (or minimally) susceptible to drug interactions and were therefore not part of this investigation. Investigational medicinal products that were already licensed for other indications were also excluded.&lt;/p&gt;&lt;p&gt;For each unlicensed investigational medicinal product, we recorded the clinical development phase, the drug–drug interaction profile of the product known at the time of writing the study protocol (substrate/inhibitor/inducer), the list of prohibited medications when mentioned, and the relevant sources that were described. The unlicensed investigational medicinal product name/number and name of sponsor were not recorded in order to guarantee confidentiality.&lt;/p&gt;&lt;p&gt;In order to facilitate the analysis and interpretation of the data, we decided to focus on unlicensed orally administered investigational medicinal products with CYP3A-related drug–drug interaction management (n = 12) as this was by far the largest group of medications where drug–drug interaction management was described.&lt;/p&gt;&lt;p&gt;The 12 unlicensed investigational medicinal products were equally divided between clinical development phases 2 and 3. All were multinational studies. These included nine CYP3A substrates, three CYP3A inhibitors, and two CYP3A inducers.&lt;/p&gt;&lt;p&gt;Figure 1 shows the number of CYP3A inducers that were listed as prohibited co-medication in case the unlicensed investigational medicinal product was a CYP3A substrate (nine study protocols). This number varied between 0 and 26 agents per protocol, with the highe","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"654-657"},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683201","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":"Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia","authors":"Evan Bailey MD,&nbsp;Han Phan MD,&nbsp;Ayesha Ahmad MD,&nbsp;Janet Thomas MD,&nbsp;Elizabeth G. Ames MD,&nbsp;Amanda B. Pritchard MD,&nbsp;Shane C. Quinonez MD,&nbsp;Stella Wang MS, MPH,&nbsp;Caleb Dayley MS,&nbsp;Andrew Salt MS,&nbsp;Christina Pick MS,&nbsp;Abe Durrant MS,&nbsp;Samuel Johnson MS,&nbsp;Jessie Nicodemus-Johnson PhD,&nbsp;Samuel P. Dickson PhD,&nbsp;Riccardo Perfetti MD, PhD,&nbsp;Suzanne B. Hendrix PhD,&nbsp;Shoshana Shendelman PhD","doi":"10.1002/jcph.6170","DOIUrl":"10.1002/jcph.6170","url":null,"abstract":"<p>To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"575-587"},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683204","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":"In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers","authors":"Megumi Iwai PhD,&nbsp;Jace Nielsen Pharm D,&nbsp;Mayuko Miyagawa MS,&nbsp;Melanie Patton BSc,&nbsp;Peter L. Bonate PhD,&nbsp;Xuegong Wang MD, PhD,&nbsp;Tomasz Wojtkowski MS,&nbsp;Angela Sinn MD,&nbsp;Jiayin Huang PhD","doi":"10.1002/jcph.6157","DOIUrl":"10.1002/jcph.6157","url":null,"abstract":"<p>Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (C_max) and area under the curve from time of dosing extrapolated to infinity (AUC_inf) to 182% and 939%, respectively, while ES259564 C_max decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant C_max and AUC_inf decreased to 71.7% and 48.3%, respectively, while ES259564 C_max increased to 130.2% and AUC_inf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"508-519"},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668162","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":"Limited Sampling Strategy for Predicting the Area under Plasma Concentration–Time Curve of Nadolol in Healthy Subjects","authors":"Shingen Misaka PhD,&nbsp;Yuko Maejima PhD,&nbsp;Kenju Shimomura MD, PhD","doi":"10.1002/jcph.6164","DOIUrl":"10.1002/jcph.6164","url":null,"abstract":"<p>Nadolol is a hydrophilic β-adrenoceptor blocker with a relatively long half-life and negligible metabolism. It is a substrate of P-glycoprotein and organic anion transporting polypeptide 1A2, and may serve as an in vivo probe drug for the assessment of drug–drug and food–drug interactions mediated by these transporters. In the present study, we aimed to develop limited sampling strategy (LSS) models for predicting the area under the plasma concentration–time curve (AUC_0-∞) of nadolol. Plasma concentration data (C_t) in healthy volunteers reported in four previous studies were randomly divided into a training dataset for model development (n = 15) and a test dataset for model validation (n = 16). By multiple linear regression analysis, we confirmed that four out of the eight models using two time points and all models using three time points met the acceptable criteria. In particular, the three time point models using (C₃, C₆, and C₂₄) and (C₄, C₈, and C₂₄) showed better predictive performances with r² values of 0.983 and 0.980, respectively. In drug interaction studies of nadolol with itraconazole, rifampicin, grapefruit juice, and green tea extract, both LSS models accurately predicted the AUC_0-∞ with percent mean absolute error ≤11% and percent root mean square error ≤12%. In addition, using digitized pharmacokinetic data of nadolol, both LSS models were further validated by predicting the AUC_0-∞ in different doses. The results suggest that the LSS models using three time points allow a reliable prediction of AUC_0-∞ of nadolol in healthy individuals.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"621-627"},"PeriodicalIF":0.0,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649022","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":"Meta-Analysis of Exposure-Adverse Event Relationships for Antibody–Drug Conjugates","authors":"Cheng Wang PhD,&nbsp;Linda Irons PhD,&nbsp;Holly Kimko PhD,&nbsp;Dhaval K. Shah PhD","doi":"10.1002/jcph.6160","DOIUrl":"10.1002/jcph.6160","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities. Here, quantitative analysis was performed to correlate the incidence of clinical adverse events (AEs) with nine different commonly measured exposure parameters collected from study-level summary data. We considered ADC analytes for different classes of ADCs, to identify ADC analytes that are strongly associated with the AEs for ADCs. Published clinical exposure and safety data for any grade and grade ≥3 AEs from 40 publications across six ADCs and three payloads were collected and analyzed. Exposure-AE relationships were quantified using logit models, and the strength of the correlations and rank order were determined. The analysis suggests that deruxtecan ADC-related toxicities correlated most strongly with the exposure of the free payload; monomethyl auristatin E (MMAE) ADC-related toxicities correlated with the free MMAE area under the curve; and pyrrolobenzodiazepine ADC-related toxicities correlated with no specific analyte but the dose. These findings agree with the published literature and support the notion that AE profiles are often shared by ADCs that deliver the same cytotoxic payload. The exposure–AE relationships presented here, together with identification of the most informative ADC analytes, may facilitate more focused mechanistic studies on the drivers of clinical AEs and could support dosing decisions during clinical development of ADCs.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"486-498"},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630722","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}