Journal of clinical pharmacology最新文献

{"title":"Pregnancy-induced changes in the long-term pharmacokinetics of 1.1 mg vs. 5 mg folic acid: a randomized clinical trial.","authors":"Mahvash Shere,&nbsp;Patricia Nguyen,&nbsp;Carolyn Tam,&nbsp;Seth Stern,&nbsp;Bhushan Kapur,&nbsp;Deborah L O'Connor,&nbsp;Gideon Koren","doi":"10.1002/jcph.387","DOIUrl":"https://doi.org/10.1002/jcph.387","url":null,"abstract":"<p><p>The objective of this randomized clinical trial was to compare steady-state gestational RBC and plasma folate concentrations in pregnant women supplementing daily with 1.1 mg (regular dose) vs. 5 mg (high dose) folic acid. Thirty-seven pregnant women, who were not previously taking folic acid, were enrolled in this open-label, 2-arm, randomized clinical trial after informed consent. Participants were randomly assigned either 1.1 or 5 mg of folic acid-containing prenatals until gestational age (g.a.) 30 weeks. Plasma and RBC folate concentrations were measured at baseline, g.a.6 weeks, g.a.12 weeks, and g.a.30 weeks using a chemiluminescent immunoassay. Results showed sustained significant increase in RBC folate in the 5 mg group between g.a.6 weeks and g.a.30 weeks (P < 0.001), and between g.a.12 weeks and g.a.30 weeks (P < 0.01), whereas a significant increase in RBC folate concentrations was observed in the 1.1 mg group only between g.a.12 weeks to g.a.30 weeks (P < 0.05). Plasma folate increased in both groups from baseline to g.a.6 weeks, and then decreased between g.a.6 weeks and g.a.30 weeks, but this was not statistically significant. Plasma concentrations at g.a.30 weeks in both groups were comparable to their respective baseline concentrations. Thus, physiological changes in pregnancy alter long-term folate pharmacokinetics. Despite supplementation over an extended period of time, steady-state does not seem to be achieved in either dose group within our study. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 2","pages":"159-67"},"PeriodicalIF":2.9,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.387","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32622272","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, pharmacodynamics, and safety of peginterferon beta-1a in subjects with normal or impaired renal function.","authors":"Xiao Hu,&nbsp;Ali Seddighzadeh,&nbsp;Scott Stecher,&nbsp;Ying Zhu,&nbsp;Jaya Goyal,&nbsp;Mark Matson,&nbsp;Thomas Marbury,&nbsp;William Smith,&nbsp;Ivan Nestorov,&nbsp;Serena Hung","doi":"10.1002/jcph.390","DOIUrl":"https://doi.org/10.1002/jcph.390","url":null,"abstract":"<p><p>Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 μg (n = 5) or 125 μg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC [30-53%]) and peak serum concentration (Cmax [26-42%]) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 2","pages":"179-88"},"PeriodicalIF":2.9,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32639080","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":"Confirmatory population pharmacokinetic analysis for bapineuzumab phase 3 studies in patients with mild to moderate Alzheimer's disease.","authors":"Chuanpu Hu,&nbsp;Omoniyi Adedokun,&nbsp;Kaori Ito,&nbsp;Sangeeta Raje,&nbsp;Ming Lu","doi":"10.1002/jcph.393","DOIUrl":"https://doi.org/10.1002/jcph.393","url":null,"abstract":"<p><p>The population pharmacokinetics of bapineuzumab, a humanized monoclonal IgG1 antibody that was generated from a murine monoclonal antibody and binds specifically to amino acids 1 to 5 of the free N-terminus of human amyloid-beta peptide, were characterized in patients with mild-to-moderate alzheimer's disease in two Phase 3 studies (ELN115727-301 and ELN115727-302). A total of 8,040 serum concentration measurements were analyzed from 1,458 patients who received 6 doses of bapineuzumab intravenously once every 13 weeks. A confirmatory analysis was conducted using a prespecified two-compartment model with first-order elimination. After the primary covariate effect assessment, a reduced model was obtained. Based on the reduced model, the typical population values for clearance (CL) and volume (Vc ) from the central compartment in a Caucasian subject with a standardized body weight of 70 kg were 0.17 L/day and 3.13 L, respectively. Bapineuzumab CL and Vc increased with body weight. Furthermore, CL was 15% higher in non-Caucasian subjects; however, this was not considered clinically relevant. None of the other evaluated covariates had a meaningful impact on CL. The median terminal elimination half-life was estimated to be approximately 29 days. Sensitivity analyses and bootstrapping results supported model stability. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 2","pages":"221-9"},"PeriodicalIF":2.9,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.393","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32639315","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":"Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.","authors":"Claudia Kasserra,&nbsp;Mahmoud Assaf,&nbsp;Matthew Hoffmann,&nbsp;Yan Li,&nbsp;Liangang Liu,&nbsp;Xiaomin Wang,&nbsp;Gondi Kumar,&nbsp;Maria Palmisano","doi":"10.1002/jcph.384","DOIUrl":"https://doi.org/10.1002/jcph.384","url":null,"abstract":"<p><p>Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 2","pages":"168-78"},"PeriodicalIF":2.9,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.384","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32615861","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":"Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.","authors":"Paul Glue,&nbsp;Michelle Lockhart,&nbsp;Fred Lam,&nbsp;Noelyn Hung,&nbsp;Cheung-Tak Hung,&nbsp;Lawrence Friedhoff","doi":"10.1002/jcph.404","DOIUrl":"https://doi.org/10.1002/jcph.404","url":null,"abstract":"<p><p>Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 2","pages":"189-94"},"PeriodicalIF":2.9,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32716003","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":"Drug therapy yesterday, today and tomorrow, basic fundamentals for the non-scientist.","authors":"Krista L Levy","doi":"10.1002/jcph.420","DOIUrl":"10.1002/jcph.420","url":null,"abstract":"<p><strong>Description: </strong>This overview of the evolution of drug development and the tools utilized by pharmacologists to ensure drug safety and efficacy provides solid insight into the drug development process, the potential for drug interactions and the difference between drugs and non-drug \"natural\" products.</p><p><strong>Audience: </strong>This book is intended for the non-scientist, but is most applicable to the non-pharmacologist with a basic scientific background.</p><p><strong>Features: </strong>The book provides a basic history of medicinal agents and a good tutorial in the various terms and processes used in contemporary drug development to help the non-pharmacologist better understand all of the factors that must be considered when developing a therapeutic agent. It also explains in depth the effective use and potential perils of non-drug \"natural\" products. The material regarding the effect between the body and drugs may be difficult for an individual with no scientific background to understand; however, the awareness of drug interactions is an important one, the understanding of which would be beneficial for everyone.</p><p><strong>Assessment: </strong>This book in an excellent tutorial, well thought through and methodical in its presentation and could be used for teaching curriculum for the non-pharmacologist with a scientific background.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2014-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32784327","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":"The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics.","authors":"Antoni Ribas,&nbsp;Weijiang Zhang,&nbsp;Ilsung Chang,&nbsp;Keisuke Shirai,&nbsp;Marc S Ernstoff,&nbsp;Adil Daud,&nbsp;C Lance Cowey,&nbsp;Gregory Daniels,&nbsp;Elizabeth Seja,&nbsp;Elizabeth O'Laco,&nbsp;John A Glaspy,&nbsp;Bartosz Chmielowski,&nbsp;Todd Hill,&nbsp;Andrew K Joe,&nbsp;Joseph F Grippo","doi":"10.1002/jcph.255","DOIUrl":"https://doi.org/10.1002/jcph.255","url":null,"abstract":"<p><p>Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"54 4","pages":"368-74"},"PeriodicalIF":2.9,"publicationDate":"2014-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31986718","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":"Vemurafenib oral bioavailability: an insoluble problem.","authors":"Russell Z Szmulewitz,&nbsp;Mark J Ratain","doi":"10.1002/jcph.277","DOIUrl":"https://doi.org/10.1002/jcph.277","url":null,"abstract":"In the current issue of Journal of Clinical Pharmacology, Ribas et al have presented critical data with respect to vemurafenib clinical pharmacology, andwe applaud them for their efforts. Vemurafenib (PLX4032) is a small molecule kinase inhibitor selective for the BRAF V600 mutation that is currently FDA approved for the treatment of patients with unresectable or metastatic melanomawith the BRAF mutation at a dose of 960mg twice daily oral administration. Given exciting preliminary efficacy data, vemurafenib moved through phase I to phase III trials relatively quickly, with limited investigation of the clinical pharmacology of the currently manufactured product prior to FDA approval. Specifically, the current Ribas study is the first formal investigation of the effect of prandial state on vemurafenib bioavailability and clearance. Nonetheless, it should be noted, that the FDA label indicates that vemurafenib can be taken without regard to food intake. Ribas et al have now provided a crucial study that begins to fill in this fundamental knowledge gap in vemurafenib clinical pharmacology. Within this study, the investigators employed a twoperiod, randomized, open-label crossover study to evaluate the effect of food on the clearance of a single dose of 960mg vemurafenib. Fifteen patients with metastatic melanoma harboring the BRAF were allocated to into one of two treatment arms. In one arm, patients took a single 960mg vemurafenib dose after an overnight fast, followed by a 10-day wash out period, and then another single dose in the context of a high-fat/highcalorie meal. In the second arm, the sequence was reversed, with patients taking their first dose in the fed state and the second dose 10 days later after an overnight fast. Following the two single dose periods, patients were maintained on standard continuous dosing of 960mg vemurafenib twice daily. Of note, for the fed-state evaluation, the high fat ( 50% calorie from fat), high calorie (800–1000 calorie) meal was consumed within 30minutes, and drug was administered 30minutes after the initiation of the meal. No food was allowed in either arm for four hours post dose administration. Despite the small study size, the authors demonstrate a convincing and clinically relevant impact of prandial state on vemurafenib pharmacokinetics. Notably, although the absorption with food was slower (Tmax prolonged from 4 to 8 hours), the mean maximum vemurafenib concentration (Cmax) doubled and the AUC tripled. Similarly, the point estimate of the geometric mean ratios of fed/fasting for AUC and Cmax are 4.7and 2.5-fold, respectively. Not surprisingly, those patients with the lowest fasted AUC had the greatest increase in AUC with food. Consequently, interindividual variability was dramatically reduced with food (eg, AUC CV% fasting 93–95% vs. 49–54% in fed state). Although there were no major differences in safety after the single-dose portions, it should be noted that no report on QTc is reported, and one p","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"54 4","pages":"375-7"},"PeriodicalIF":2.9,"publicationDate":"2014-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32283337","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":"Effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate, an antiretroviral single-tablet regimen for the treatment of HIV infection.","authors":"Joseph M Custodio,&nbsp;Xiang Yin,&nbsp;Mischa Hepner,&nbsp;Kah Hiing J Ling,&nbsp;Andrew Cheng,&nbsp;Brian P Kearney,&nbsp;Srinivasan Ramanathan","doi":"10.1002/jcph.210","DOIUrl":"https://doi.org/10.1002/jcph.210","url":null,"abstract":"<p><p>The effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (STR) was evaluated in healthy subjects. Subjects (N = 24) received rilpivirine/emtricitabine/tenofovir disoproxil fumarate (25/200/300 mg) under fasted or fed conditions (light [390 kcal, 12 g fat]; standard [540 kcal, 21 g fat]) followed by pharmacokinetic (PK) sampling. The 90% confidence interval (CI) of the geometric mean ratio for rilpivirine, emtricitabine, tenofovir exposure was estimated for fed versus fasted dosing and light versus standard meal, with equivalence boundaries of 80 - 125%. Safety was assessed throughout study. Twenty-three subjects completed the study; one discontinued due to protocol violation. Adverse events were mild to moderate. Emtricitabine PK was unaffected. Tenofovir AUCinf was 38% and 28% higher, respectively, with standard and light meal versus fasted. Rilpivirine AUCinf and Cmax were 16% and 26% higher with a standard, and 9% and 34% with a light meal, respectively, versus fasted. Compared to standard meal, the lower limit of rilpivirine AUClast and AUCinf when taken with the light meal were narrowly below the equivalence bounds (79.9 and 79.2, respectively), rilpivirine Cmax was narrowly above (129). Rilpivirine/emtricitabine/tenofovir disoproxil fumarate should be administered with food, which can be a standard or light meal. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"54 4","pages":"378-85"},"PeriodicalIF":2.9,"publicationDate":"2014-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.210","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31821092","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":"Safety, tolerability and pharmacokinetic profile of single and multiple oral doses of arterolane (RBx11160) maleate in healthy subjects.","authors":"Nilanjan Saha,&nbsp;Joerg J Moehrle,&nbsp;Anita Zutshi,&nbsp;Pradeep Sharma,&nbsp;Pawandeep Kaur,&nbsp;Sunil S Iyer","doi":"10.1002/jcph.232","DOIUrl":"https://doi.org/10.1002/jcph.232","url":null,"abstract":"<p><p>Arterolane (RBx11160, OZ277) maleate is a rapidly acting synthetic trioxolane anti-malarial. This randomized, placebo controlled study was a phase I study to evaluate the clinical safety and tolerability as well as pharmacokinetics (PKs) of arterolane maleate including food effect. Eight single rising oral doses of arterolane (25, 50, 100, 150, 200, 300, 400, 600 mg), food effect under fed and fasting conditions at 100 mg dose and four multiple oral dose regimens (25, 50, 100, 200 mg) were administered once daily for 7 days in 64 healthy young males (Caucasian). A randomized, placebo-controlled study was also conducted in healthy elderly males and females (Caucasian) to investigate PKs, safety and tolerability of single oral dose (100 mg) of arterolane. All doses were well tolerated after oral administration. The initial peak of arterolane was apparent at 2-3 hours post-dose followed by a secondary peak at approximately 5 hours post-dose. Thereafter, plasma arterolane concentration declined with a geometric mean t1/2 of approximately 2-4 hours. The PKs of arterolane appeared to be time-invariant after repeated once-daily dosing. The incidence of adverse events was similar for placebo and active treatments. Arterolane had similar PKs and tolerability in elderly and younger subjects and between elderly males and females. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"54 4","pages":"386-93"},"PeriodicalIF":2.9,"publicationDate":"2014-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31874029","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}