Journal of clinical pharmacology最新文献

{"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}

{"title":"Exodus of clinical pharmacologists and pharmacometricians from academia--Who is to blame? A policy statement from the American College of Clinical Pharmacology.","authors":"Vijay V Upreti","doi":"10.1002/jcph.542","DOIUrl":"https://doi.org/10.1002/jcph.542","url":null,"abstract":"Academic institutes are breeding grounds of innovation and the cradle of future clinical pharmacologists and pharmacometricians. However, there is a crisis looming over academic institutions; funding for research in clinical pharmacology is at an all-time low. This crisis of academic funding is no longer a well-kept secret. This crisis is at a national level and has far-reaching consequences. Federal funding for biomedical research in the United States doubled between 1998 and 2003 and fueled academic research nationally.This funding was considered key to maintaining the edge of the United States in the pharmaceutical and biotechnology industries. However, federal funding for biomedical research has been in decline since that time. Federal funding for biomedical research is estimated to be at least 25% less in inflationadjusted dollars than it was in 2003, whereas demand for research dollars has skyrocketed. The increased demand for research money in the face of dwindling federal support may be attributed to several factors. Universities were able to expand their facilities and hire more faculty during the years of surplus funding and now must maintain those facilities and retain key faculty in the face of ever-shrinking federal dollars. Adding to the problem, public universities face decreased funding at the state level, as state governments attempt to balance their budgets. Other sources of funding, such as the pharmaceutical industry, have also dried up, as the industry itself comes under pressure to control costs and faces close scrutiny of its funding of academic research. Finally, the rising cost of conducting biomedical research (both as actual costs and the ever-increasing regulatory burden to conduct those studies) contributes to the problem, as even phase 1 clinical studies may now cost upwards of $4 million. As dire as things are for the biomedical research community as a whole, the situation is even worse when it comes to attracting major federal funding for research in the field of clinical pharmacology and pharmacometrics. The key characteristic of being a universally applicable field of research has a considerable downside; clinical pharmacology is a field without the face of a disease that the public cares about. There is no 5K race for “getting the dose right,” in contrast to diseases like breast cancer, diabetes, and AIDS. The public in general does not know what clinical pharmacology is and does not understand its role in the development of new medicines for the diseases that affect loved ones in their families and communities. This is even reflected in federal funding, where the National Institutes of Health (NIH) has traditionally funded basic research while being slow in funding clinical pharmacology–based research. The funding crisis may affect what kind of research is performed in academic institutions, as “fundability” takes precedence over good science. More time is now spent by researchers worrying about how to bring in","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"955-6"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.542","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33304745","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":"Management of lipid disorders in patients living with HIV.","authors":"Merle Myerson,&nbsp;Carlos Malvestutto,&nbsp;Judith A Aberg","doi":"10.1002/jcph.473","DOIUrl":"https://doi.org/10.1002/jcph.473","url":null,"abstract":"<p><p>Since the discovery and development of antiretroviral therapy (ART), HIV has become a chronic disease with patients living longer lives and to ages where co-morbidities, such as cardiovascular disease (CVD) are prevalent. Diagnosis and management of risk factors for CVD, in particular dyslipidemia, have become an important part of the overall care for patients living with HIV infection. Existing guidelines and recommendations for the management of dyslipidemia for persons with HIV infection are largely based on guidelines for the general population. Clinical and epidemiologic research efforts are ongoing to provide information specific to patients living with HIV. This review offers a detailed guide for clinicians who manage dyslipidemia in patients infected with HIV. The first sections provide background information on dyslipidemia, risk stratification, and targets for lipid therapy. This is followed by a step-by-step approach for diagnosis and treatment with specific information on lipid drug use for patients with HIV. The recommendations presented here are based on existing guidelines for the general population, evidence from research in patients infected with HIV, and the clinical experience of the authors. Management issues for which little or no information is available specific to this patient population are noted and serve to highlight the many gaps in our knowledge that will need to be addressed. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"957-74"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.473","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33354032","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":"Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet(®)), sustained-release carbidopa-levodopa (Sinemet(®) CR), and carbidopa-levodopa-entacapone (Stalevo(®)).","authors":"Ann Hsu,&nbsp;Hsuan-Ming Yao,&nbsp;Suneel Gupta,&nbsp;Nishit B Modi","doi":"10.1002/jcph.514","DOIUrl":"https://doi.org/10.1002/jcph.514","url":null,"abstract":"<p><p>IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax ) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD---LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower (P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"995-1003"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33200159","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":"A dangerous lack of pharmacology education in medical and nursing schools: A policy statement from the American College of Clinical Pharmacology.","authors":"Peter H Wiernik","doi":"10.1002/jcph.539","DOIUrl":"https://doi.org/10.1002/jcph.539","url":null,"abstract":"Therapeutics in all subspecialties of medicine has become more complex in recent years for a variety of reasons. Newer pharmaceuticals with greater and potentially serious toxicities are commonly used today for a large number of serious illnesses. Such drugs often interact adversely with food and with many so-called “natural” medicines such as Saint. John’s wort. They may also interact with other drugs, such as those used to treat comorbidities that are outside of the realm of expertise of the physician treating the patient’s most serious problem. Many newer agents need to be given in precise doses based on the patient’s weight or body surface area, and somemust be taken in specific relationship to food intake. Drug dosing in many instances must take into account dietary components, administration of other drugs, and patient genetics. Consequently, correct prescribing of medicines today requires a complete knowledge of the pharmacokinetics, pharmacodynamics, drug–drug interactions, and other aspects of the agent to be prescribed. Unfortunately, there is abundant evidence in the form of prescription errors (paper and electronic) and increasing numbers of hospital admissions for drug toxicity in this country and many others that prescribers are not always sufficiently educated to properly administer and monitor present-day therapeutics. For physicians, nurses, and physician assistants, the lack of sufficient clinical pharmacologic training can often be traced all the way back to undergraduate school.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"953-4"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.539","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33300216","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 (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK.","authors":"Linh Nguyen,&nbsp;Jaymes Holland,&nbsp;Dale Miles,&nbsp;Caroline Engel,&nbsp;Natacha Benrimoh,&nbsp;Terry O'Reilly,&nbsp;Steven Lacy","doi":"10.1002/jcph.510","DOIUrl":"https://doi.org/10.1002/jcph.510","url":null,"abstract":"<p><p>Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0-inf , whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0-inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax , AUC0-24 , or AUC0-inf . In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"1012-23"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33202065","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":"Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.","authors":"Brian W Ogilvie,&nbsp;Rosarelis Torres,&nbsp;Marlene A Dressman,&nbsp;William G Kramer,&nbsp;Paolo Baroldi","doi":"10.1002/jcph.507","DOIUrl":"https://doi.org/10.1002/jcph.507","url":null,"abstract":"<p><p>Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"1004-11"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33197925","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":"Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens.","authors":"Daniel A Spyker,&nbsp;Robert A Riesenberg,&nbsp;James V Cassella","doi":"10.1002/jcph.502","DOIUrl":"https://doi.org/10.1002/jcph.502","url":null,"abstract":"<p><p>This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412. </p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"55 9","pages":"985-94"},"PeriodicalIF":2.9,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33160299","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}