Journal of clinical pharmacology最新文献

{"title":"Brivaracetam: An Adjunctive Treatment for Partial-Onset Seizures.","authors":"John A Kappes,&nbsp;William J Hayes,&nbsp;Joe D Strain,&nbsp;Debra K Farver","doi":"10.1002/jcph.900","DOIUrl":"https://doi.org/10.1002/jcph.900","url":null,"abstract":"<p><p>Brivaracetam is an analogue of levetiracetam that is Food and Drug Administration-approved for adjunctive treatment of partial-onset seizures in patients 16 years and older. In placebo-controlled trials adjunct brivaracetam demonstrated efficacy in reducing the frequency of seizures. The most commonly reported adverse effects are somnolence, dizziness, and fatigue. Clinical trials have evaluated brivaracetam for safety and efficacy in adjunctive treatment of partial-onset seizures in patients 16 years and older for up to 16 weeks. Brivaracetam's mechanism is similar to that of levetiracetam but with greater receptor binding affinity on synaptic vesicle protein 2A and inhibitory effects on sodium channels. Clinically significant differences between these agents are undetermined. Brivaracetam is available as oral tablets, oral solution, and intravenous solution. The Food and Drug Administration-approved dose is 50 mg twice daily, and titration is not required. Brivaracetam does not need dose adjustment for renal impairment and has minimal drug-drug interactions. Current limitations of brivaracetam include lack of head-to-head trials, limited long-term safety and efficacy data, and cost. Overall, brivaracetam is a viable adjunct therapeutic option for refractory partial-onset seizures in those who have failed conventional therapies.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"811-817"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.900","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34899908","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":"Generic Docetaxel.","authors":"Dominique Levêque,&nbsp;Guillaume Becker","doi":"10.1002/jcph.893","DOIUrl":"https://doi.org/10.1002/jcph.893","url":null,"abstract":"We read with great interest the article by N. Al Faqeer et al on the retrospective comparison of generic and branded formulations of docetaxel in terms of incidence of febrile neutropenia resulting in hospital admission.1 The authors found a higher incidence of febrile neutropenia with generic formulations compared with branded docetaxel and stated that the lower cost of generics should be balanced with the expenditure relative to complications. This kind of study is rather uncommon because approved generics and branded drugs have the same clinical activity. The approval of intravenous generic drugs is based on pharmaceutical equivalence, and clinical trials are not required by drug regulatory agencies. In fact, they are useless because the active entity is the same. In short, comparing generic drugs and their branded reference is the same as comparing various batches of the branded drug.2 Suspicion about generic drugs is often related to case reports or isolated observations. We do not think that this study proves than docetaxel generics are clinically different from the branded reference because of the several limitations highlighted by the authors (retrospective design, no check of drug–drug interactions). Docetaxel is cleared by CYP3A-mediated metabolism, and huge variations of elimination have been found among patients.3,4 In addition, docetaxel clearance has been related to CYP3A activity5 and has also been found to be an independent predictor of febrile neutropenia.3 So the difference of febrile neutropenia might have been simply related to the variations of metabolic elimination and not to the source of the docetaxel. At last, if a higher incidence of severe neutropenia really exists between the different formulations of docetaxel, it suggests that the generic vials are overdosed. Consequently, the drug agencies and the manufacturers should be alerted and the vials checked and eventually withdrawn. Otherwise, what can we do with this information, apart from casting doubts on generics and fear among patients?","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"935"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.893","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34963645","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":"Use of Simvastatin and Risk of Acute Pancreatitis: A Nationwide Case-Control Study in Taiwan.","authors":"Chih-Ming Lin,&nbsp;Kuan-Fu Liao,&nbsp;Cheng-Li Lin,&nbsp;Shih-Wei Lai","doi":"10.1002/jcph.881","DOIUrl":"https://doi.org/10.1002/jcph.881","url":null,"abstract":"<p><p>The correlation between simvastatin use and acute pancreatitis is explored. A case-control study was conducted to analyze claim data from the Taiwan National Health Insurance Program. The case group comprising a total of 3882 subjects aged 20 to 84 years with their first acute pancreatitis episode occurring between 1998 and 2011 formed the case group, against 3790 randomly selected controls matched for sex, age, comorbidities, and index year of acute pancreatitis diagnosis. Recent use of simvastatin was defined as subjects whose last remaining simvastatin tablet was noted ≤7 days before the date of acute pancreatitis diagnosis. Remote use of simvastatin was defined as subjects whose last remaining 1 tablet for simvastatin was noted >7 days before the date of acute pancreatitis diagnosis. Never use of simvastatin was defined as subjects who had never been prescribed simvastatin. A multivariable unconditional logistic regression model was used to estimate the odds ratio and 95%CI to explore the correlation between simvastatin use and acute pancreatitis. After adjustment for confounders, multivariable logistic regression analysis revealed that the adjusted odds ratio of acute pancreatitis was 1.3 for subjects with recent use of simvastatin (95%CI 1.02, 1.73), when compared with those with never use of simvastatin. The crude odds ratio decreased to 1.1 for those with remote use of simvastatin (95%CI 0.93, 1.34) but without statistical significance. Recent use of simvastatin is associated with acute pancreatitis. Clinicians should consider the possibility of simvastatin-associated acute pancreatitis for patients presenting for acute pancreatitis without known cause.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"918-923"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.881","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34818084","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":"Generic and Branded Docetaxel.","authors":"Nour Al Faqeer,&nbsp;Lama Nazer","doi":"10.1002/jcph.914","DOIUrl":"https://doi.org/10.1002/jcph.914","url":null,"abstract":"We thank Leveque et al for their thoughtful comments regarding our study comparing generic and branded formulations of docetaxel. We agree that the generic formulations are expected to be comparable to the branded drugs in terms of quality and clinical activity. However, several studies have raised the concern about clinically significant differences between generic and branded formulations with both chemotherapy and nonchemotherapy products.1–4 Furthermore, the differences between brand and generic formulations of docetaxel were previously addressed and were attributed to insufficient active ingredients and/or high level of impurities that may affect the efficacy and safety of the drug.5,6 Poirier et al compared the adverse event profile of generic docetaxel to the branded product and reported results that were consistent with those reported in our study. The incidence of febrile neutropenia was more serious with generic docetaxel despite increased G-CSF use.5 We agree that the presence or absence of drug– drug interactions in the study patients may have had an impact on the findings, and we agree that the unavailability of this information for the patients included is a limitation to the study. However, we predict that the large sample size and the similarities between the groups in several patient-related characteristics may haveminimized the impact of this limitation on the final results. The findings of this study and other similar studies are important for clinicians when they switch patients from branded to generic formulations or vice versa. In fact, our study was conducted as a result of the clinical observations reported to the pharmacy after patients had been switched from the branded docetaxel to the generic. The studywas generated to answer the question of whether the change in docetaxel formulation was associated with the observed increased incidence of febrile neutropenia.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"936"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.914","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34962963","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":"Reply to Letter: Influence of Liver and Kidney Disease on Sofosbuvir Electrophysiological Effects.","authors":"Martina Vitrone,&nbsp;Antonio Parrella,&nbsp;Emanuele Durante-Mangoni","doi":"10.1002/jcph.915","DOIUrl":"https://doi.org/10.1002/jcph.915","url":null,"abstract":"We thank Drs Rossotti, Puoti, and colleagues for further reasoning on the electrophysiological effects of sofosbuvir for hepatitis C. Indeed, they analyze 2 important variables that we did not assess in our study,1 namely antiretroviral therapy for HIV coinfection and liver cirrhosis. None of our patients had HIV coinfection, but many had cirrhosis, a condition that can affect both cardiac electrical parameters and drug metabolism. A high frequency of mostly nonsignificant electrophysiological abnormalities occurs in patients with cirrhosis, including chronotropic incompetence, electromechanical uncoupling, and QT interval prolongation progressing from Child-Pugh-Turcotte (CPT) stage A to C.2 We therefore analyzed QTc duration in 18 cirrhotic and 8 noncirrhotic advanced fibrosis (F3) patients, all treated with sofosbuvir-based regimens. At week 1 of therapy, cirrhotic patients had no significant variation of QTc values compared with baseline (431.2 milliseconds vs 424.3 milliseconds, P = .480). Similar results were observed comparing QTc changes at week 4 (422.7 milliseconds vs 424.3 milliseconds at baseline, P = .554). When the same analysis was performed in CPT A patients (n = 15), the results were similar: 423.3 milliseconds at baseline, 429.9 milliseconds at week 1 and 421.5 milliseconds at week 4 (T0 to TW1 P = .575; T0 to TW4 P = .826). F3 patients similarly showed stable QTc values (424.4, 430.8, and 423.5 milliseconds at baseline, week 1, and week 4, respectively; T0 to TW1 P = .463; T0 to TW4 P = .161). Results confirm the overall conclusions of our study. We did not perform the same analysis in the CPT B group, due to the small number of patients (N = 3). The area under the concentration-time curve (AUC) of sofosbuvir given at 400 mg/day increased after 7 days of dosing by 126% and 143% in CPT B and CPT C patients, respectively, consistent with a potentially stronger electrophysiological effect. However, there are other conditions that can influence AUC. In patients with mild or moderate renal insufficiency, sofosbuvir AUC values were elevated by 61% and 107%, respectively, compared to controls.3 In this setting, sofosbuvir has demonstrated a favorable safety profile that did not appear to contribute any additional significant toxicity. Furthermore, no clinically significant electrocardiogram abnormalities and no meaningful changes in Fridericia-corrected QT intervals were observed in patients with a glomerular filtration rate &lt;30 mL/min, although AUC increased by 171%.4 In light of the common occurrence of renal functional impairment in HIV infection, results of Rossotti et al in this specific clinical setting could be explained by the double effect of liver and kidney impairment. Accordingly, we further assessed the influence of renal function on QTc duration. We divided sofosbuvirtreated patients in 2 groups according to the median value of the estimated glomerular filtration rate. Comparing patients with higher estimated glomerular ","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"933-934"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34963642","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 Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma.","authors":"Ahmed Hamed Salem,&nbsp;Suresh K Agarwal,&nbsp;Martin Dunbar,&nbsp;Sari L Heitner Enschede,&nbsp;Rod A Humerickhouse,&nbsp;Shekman L Wong","doi":"10.1002/jcph.821","DOIUrl":"https://doi.org/10.1002/jcph.821","url":null,"abstract":"<p><p>Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 4","pages":"484-492"},"PeriodicalIF":2.9,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.821","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34334471","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":"Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA.","authors":"Hisham Abdallah,&nbsp;Joy C Hsu,&nbsp;Peng Lu,&nbsp;Scott Fettner,&nbsp;Xiaoping Zhang,&nbsp;Wendy Douglass,&nbsp;Min Bao,&nbsp;Lucy Rowell,&nbsp;Gerd R Burmester,&nbsp;Alan Kivitz","doi":"10.1002/jcph.826","DOIUrl":"https://doi.org/10.1002/jcph.826","url":null,"abstract":"<p><p>Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 4","pages":"459-468"},"PeriodicalIF":2.9,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.826","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34366632","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":"Postmarketing Safety Events Relating to New Drugs Approved in Brazil Between 2003 and 2013: A Retrospective Cohort Study.","authors":"Stephanie Ferreira Botelho,&nbsp;Maria Auxiliadora Parreiras Martins,&nbsp;Liliana Batista Vieira,&nbsp;Adriano Max Moreira Reis","doi":"10.1002/jcph.822","DOIUrl":"https://doi.org/10.1002/jcph.822","url":null,"abstract":"<p><p>This study investigated postmarketing safety events (PMSEs) for new drugs approved in Brazil and evaluated whether a range of drug characteristics influenced the time between approval and the first PMSE. This retrospective study included new drugs registered between 2003 and 2013 by the National Health Surveillance Agency (ANVISA), which is responsible for medicines approval in Brazil. PMSEs were defined as any drug safety alert or drug withdrawal from the market. The existence of risk evaluation and mitigation strategies (REMS) by the US Food and Drug Administration (FDA) and Brazil were recorded. A Kaplan-Meier survival curve of the period between the date of ANVISA registration and the PMSE was calculated. We found a statistically significant difference between the time to PMSE for drugs with an FDA REMS compared with those without a REMS, with a log rank value (Mantel Cox) of 0.002. There was no association between the time to PMSE and the other drug characteristics investigated. This study demonstrated that the frequency of PMSEs for new drugs approved by ANVISA was statistically associated with the existence of an FDA REMS. The time between approval and first PMSE was shorter for drugs with an FDA REMS, and this finding may contribute to improved awareness of the risk/benefit balance required to ensure continued safe and effective use of new drugs.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 4","pages":"493-499"},"PeriodicalIF":2.9,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.822","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34395678","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":"Time Trends in Physician Visits for Gastroesophageal Reflux Disease Before and After the Rx-to-OTC Switch of Proton Pump Inhibitors.","authors":"Dong W Chang,&nbsp;Jonathan Grotts,&nbsp;Chi-Hong Tseng,&nbsp;Eric P Brass","doi":"10.1002/jcph.825","DOIUrl":"https://doi.org/10.1002/jcph.825","url":null,"abstract":"The availability of non-prescription or over-the-counter (OTC) medicines plays an important role in the United States (U.S.) healthcare system. Potential benefits to consumers of OTC drugs include increased access to effective medications, avoidance of unnecessary physician visits, as well as promoting increased patient autonomy and successful self-care.1 In addition, the availability of effective OTC medications for common conditions may be advantageous for the U.S. healthcare system by reducing the number of non-essential physician visits, while creating a more rational allocation of healthcare resources to manage more serious conditions and other healthcare priorities. Despite this theoretical benefit, the true impact of making medications available OTC on healthcare utilization is largely unknown. \u0000 \u0000This article is protected by copyright. All rights reserved","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 4","pages":"452-458"},"PeriodicalIF":2.9,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.825","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34366609","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 and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial","authors":"S. Shoaf, A. Chapman, V. Torres, J. Ouyang, F. Czerwiec","doi":"10.1002/jcph.880","DOIUrl":"https://doi.org/10.1002/jcph.880","url":null,"abstract":"In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2‐receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient‐reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split‐dose regimen: a single ascending‐dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split‐dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8‐week open‐label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to <300 mOsm/kg for 24 hours. The 45/15‐mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30‐mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 1","pages":"906 - 917"},"PeriodicalIF":2.9,"publicationDate":"2017-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.880","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48461665","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}