Journal of clinical pharmacology最新文献

{"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}

{"title":"Pharmacokinetics and Safety Assessment of l-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study.","authors":"Hazem E Hassan,&nbsp;Deanna Kelly,&nbsp;Moshe Honick,&nbsp;Sagar Shukla,&nbsp;Ahmed Ibrahim,&nbsp;David A Gorelick,&nbsp;Matthew Glassman,&nbsp;Robert P McMahon,&nbsp;Heidi J Wehring,&nbsp;Ann Marie Kearns,&nbsp;Stephanie Feldman,&nbsp;Mingming Yu,&nbsp;Ken Bauer,&nbsp;Jia Bei Wang","doi":"10.1002/jcph.789","DOIUrl":"https://doi.org/10.1002/jcph.789","url":null,"abstract":"<p><p>Cocaine use disorder (CUD) remains a significant public health challenge. l-Tetrahydropalmatine (l-THP), a well-tolerated and nonaddictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of l-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive l-THP (30 mg twice a day orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, ECG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for l-THP and cocaine using highly sensitive and specific ultraperformance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of l-THP was safe and well tolerated and did not affect cocaine's PK or its acute cardiovascular effects. The cocaine AUC_0→∞ was 211.5 and 261.4 h·ng/mL, and the C_max was 83.3 and 104.5 ng/mL for the l-THP and placebo groups, respectively. In addition there were no significant differences in the number of side effects reported in each group (l-THP group 22 [48%], placebo group 24 [52%]) or vital signs including, heart rate, blood pressure, complete blood count, or ECG. These findings suggest that oral THP has promise for further development as a treatment for CUD.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"151-160"},"PeriodicalIF":2.9,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.789","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34623824","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":"Pharmacokinetic, Pharmacodynamic, and Safety Profile of a Novel Anti-CD28 Domain Antibody Antagonist in Healthy Subjects.","authors":"Rong Shi,&nbsp;Marek Honczarenko,&nbsp;Sean Zhang,&nbsp;Catherine Fleener,&nbsp;Johanna Mora,&nbsp;Sun Ku Lee,&nbsp;Reena Wang,&nbsp;Xiaoni Liu,&nbsp;Diane E Shevell,&nbsp;Zheng Yang,&nbsp;Haiqing Wang,&nbsp;Bindu Murthy","doi":"10.1002/jcph.791","DOIUrl":"https://doi.org/10.1002/jcph.791","url":null,"abstract":"We report pharmacokinetics, pharmacodynamics, and safety of a novel anti‐CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single‐ or multiple‐dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single‐ascending‐dose (SAD), double‐blind, first‐in‐human study. Part 1 included 9 intravenous (IV; 0.01‐100 mg) and 3 subcutaneous (SC; 9‐50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9‐100 mg) or placebo. In a double‐blind, multiple‐ascending‐dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9‐mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"161-172"},"PeriodicalIF":2.9,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.791","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34721207","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":"Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Minireview.","authors":"Guohua An","doi":"10.1002/jcph.804","DOIUrl":"https://doi.org/10.1002/jcph.804","url":null,"abstract":"<p><p>Nonlinearities are commonplace in pharmacokinetics, and 1 special source is the saturable binding of the drug to a high-affinity, low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Compared with large-molecule compounds undergoing TMDD, which has been well recognized due to its high prevalence, TMDD in small-molecule compounds is more counterintuitive and has not been well appreciated. With more and more potent small-molecule drugs acting on highly specific targets being developed as well as increasingly sensitive analytical techniques becoming available, many small-molecule compounds have recently been reported to have nonlinear pharmacokinetics imparted by TMDD. To expand our current knowledge of TMDD in small-molecule compounds and increase the awareness of this clinically important phenomenon, this minireview provides an overview of the small-molecule compounds that demonstrate nonlinear pharmacokinetics imparted by TMDD. The present review also summarizes the general features of TMDD in small-molecule compounds and highlights the differences between TMDD in small-molecule compounds and large-molecule compounds.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"137-150"},"PeriodicalIF":2.9,"publicationDate":"2017-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.804","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34633604","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":"Oral Human Abuse Potential of Oxycodone DETERx® (Xtampza® ER)","authors":"E. Kopecky, A. Fleming, N. Levy‐Cooperman, M. O’Connor, Edward M. Sellers","doi":"10.1002/jcph.833","DOIUrl":"https://doi.org/10.1002/jcph.833","url":null,"abstract":"Oxycodone DETERx® (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended‐release, microsphere‐in‐capsule, abuse‐deterrent formulation designed to retain its extended‐release properties after tampering (eg, chewing/crushing). This randomized, double‐blind, placebo‐controlled, triple‐dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate‐release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high‐fat, high‐calorie meal and fasted), chewed oxycodone DETERx (high‐fat, high‐calorie meal and fasted), crushed immediate‐release oxycodone (fasted), and placebo (high‐fat, high‐calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty‐eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate‐release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (Emax) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate‐release oxycodone (P < .01). The time to Emax was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate‐release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate‐release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate‐release oxycodone.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 1","pages":"500 - 512"},"PeriodicalIF":2.9,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.833","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50907423","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":"Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment","authors":"J. Gibbs, J. G. Slatter, O. Egbuna, M. Geller, L. Hamilton, C. Dias, Ren Y. Xu, Jessica Johnson, S. Wasserman, M. Emery","doi":"10.1002/jcph.832","DOIUrl":"https://doi.org/10.1002/jcph.832","url":null,"abstract":"Evolocumab binds PCSK9, increasing low‐density lipoprotein cholesterol (LDL‐C) receptors and lowering LDL‐C. Target‐mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL‐C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open‐label, parallel‐group study evaluated the pharmacokinetics of evolocumab in hepatic‐impaired (Child‐Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140‐mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL‐C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere‐Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration –34%; mean area under the concentration‐time curve (AUC) –47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL‐C reductions in the healthy, mild, and moderate groups were –57% (–64% to –48%), –70% (–75% to –63%), and –53% (–61% to –43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 1","pages":"513 - 523"},"PeriodicalIF":2.9,"publicationDate":"2016-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.832","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50907412","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":"Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.","authors":"Zhongping Lily Mao, Nishit B Modi","doi":"10.1002/jcph.683","DOIUrl":"10.1002/jcph.683","url":null,"abstract":"<p><p>Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"56 1","pages":"974-82"},"PeriodicalIF":2.9,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50907322","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}