Search

Terence Fullerton,1 Glenn Pixton2 1Internal Medicine and Infectious Disease, Pfizer Research and Development, Pfizer Inc., Groton, CT, USA; 2Statistics, Pfizer Inc., Groton, CT, USACorrespondence: Terence Fullerton, Internal Medicine and Infectious Disease, Pfizer Research and Development, Pfizer Inc., 445 Eastern Point Road, Groton, CT, 06355, USA, Tel +1 860-441-6548, Email Terence.Fullerton@pfizer.comPurpose: To examine use of concomitant analgesics and antiemetics during treatment with rimegepant in adults with migraine.Patients and Methods: This was a post hoc analysis of a long-term, open-label, safety study in adults with a history of 2– 14 moderate or severe migraine attacks per month. Participants self-administered rimegepant 75 mg (1) up to once daily as needed (PRN) for 52 weeks or (2) every other day plus PRN (EOD+PRN) for 12 weeks. The PRN cohort was further divided based on baseline attack frequency, with PRN (2– 8) and PRN (9– 14) cohorts having a history of 2– 8 or 9– 14 attacks per month, respectively. Use of select analgesics and antiemetics was analyzed during a 30-day pre-treatment observation period (OP) and during rimegepant treatment.Results: Overall, 1800 rimegepant-treated participants (PRN n = 1514, EOD+PRN n = 286) were included in the analysis. Select analgesics or antiemetics were used by 80.1% of participants during the OP. Among 1441 participants using analgesics or antiemetics during the OP, the proportion who did not use any analgesics or antiemetics following initiation of rimegepant treatment increased during weeks 1– 4 (36.9%), 5– 8 (52.6%), and 9– 12 (56.5%). The mean number of days per month using analgesics or antiemetics was also significantly reduced over time in all cohorts beginning at weeks 1– 4 (P < 0.001 vs OP). This pattern of reduced analgesic or antiemetic use was consistent for all rimegepant cohorts, but was most pronounced in the EOD+PRN cohort in which 74.8% of participants reported ≥ 50% reduction in analgesic/antiemetic days at weeks 9– 12. Reduction in use was maintained over time, with 61.3% of participants not using any analgesics or antiemetics during weeks 49– 52 of PRN treatment.Conclusion: Long-term treatment with oral rimegepant was associated with reduced analgesic and antiemetic use. Clinicaltrials.gov: NCT03266588.Keywords: rimegepant, migraine, analgesics, antiemetics, clinical trial

Varenicline is a novel selective alpha4beta2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (> or = 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance > or = 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone. [ABSTRACT FROM AUTHOR]

Background: CP-X is an opioid antagonist evaluated in a thorough QT (TQT) study to investigate the potential effect of CP-X concentration on the QTc interval following repeated oral administration.Methods: This was a multiple-dose, randomized, 4-period crossover, double-blind study investigating 10 mg and 40 mg QD of CP-X and placebo on Days 1 through 7, and open-label moxifloxacin 400 mg single dose on Day 7 in 64 healthy volunteers. Plasma samples were analyzed for CP-X using solid phase extraction followed by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) analysis. Time-matched ECG measurements and pharmacokinetic data were analyzed using NONMEM V, Level 1.1.Results: The QTcF-concentration relationship was characterized with a linear model that accounted for effects of placebo, sex, and study day on intercept and the effect of study day on slope. The mean (95% CI) slope describing the QTcF-concentration relationship was 0.0866 (0.0476, 0.126) msec/(ng/mL) on Day 1, which translates to mean prolongations of 1.33 msec and 6.51 msec at mean Cmax following the initial 10 mg and 40 mg doses, respectively. The mean (95% CI) slope on Day 7 was 0.0480 (0.0300, 0.0670) msec/(ng/mL), producing expected prolongations of 1.80 msec and 7.49 msec at mean steady state Cmax following multiple 10 mg and 40 mg doses.Conclusions: Exposure-response modeling allowed for quantification of concentration and time-dependent changes in the QTcF interval-concentration relationship in a TQT study.Clinical Pharmacology & Therapeutics (2005) 79, P29–P29; doi: 10.1016/j.clpt.2005.12.109 [ABSTRACT FROM AUTHOR]

Background: Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year., Methods: This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks., Results: Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal., Conclusions: One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated. Trial registration: Clinicaltrials.gov: NCT04408794., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KM serves as a consultant, advisory board member, or has received honoraria from Amgen, Teva, Theranica, Vorso, Biohaven, electroCore, and Eli Lilly.RC was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd, was an employee of Pfizer, has received research payments from Pfizer, and provides services to Collima LLC which has had consulting agreements with Pfizer, Actio Biosciences, Inc., Aptose Biosciences Inc., Manistee Therapeutics, and Vida Ventures Management Co., LLC.LM and TF are employed by Pfizer Inc. JM was employed by Biohaven Pharmaceuticals at the time the study was conducted. JM and LM own stock in Biohaven Pharmaceuticals. LM owns stock in Pfizer Inc.RBL serves on the editorial board of Neurology and as senior advisor to Headache but is not paid for his roles on these journals. He has received research support from the NIH. He also receives support from the National Headache Foundation. He receives research grants from Allergan/AbbVie, Amgen, Dr. Reddy's Laboratories, and Novartis. He has reviewed for the NIA and NINDS and serves as consultant, advisory board member, or has received honoraria from Allergan/AbbVie, Amgen, Biohaven, Dr. Reddy's Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta. He receives royalties from Wolff's Headache (8th Edition, Oxford University Press, 2009) and Informa. He holds stock options in Biohaven Pharmaceuticals and Manistee.

PF-05212377 (SAM760) is a potent and selective 5-HT 6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (C bu /C pu ) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT 6 receptor occupancy (%RO). The NHP C pu EC 50 of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 K i : 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT 6 RO; maximal 5-HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC 50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding K i 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate. Clinical trial number: NCT01258751., (© 2023 John Wiley & Sons Ltd.)

γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere deemed not drug related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PK/PD model well described the tendency of observed CSF Aβ data and the steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials., (© 2019 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Symptomatic benefits have been reported for 5-HT 6 receptor antagonists in Alzheimer's disease (AD) trials. SAM-760 is a potent and selective 5-HT 6 receptor antagonist that has demonstrated central 5-HT 6 receptor saturation in humans at a dose of 30 mg., Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10-24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data., Results: At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment)., Conclusions: SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT 6 receptor antagonists., Trial Registration: Clinicaltrials.gov, NCT01712074 . Registered 19 October 2012.

This analysis looks at the application of a robust process improvement methodology to achieve a sustained organizational change. The implementation took place in a safety net hospital's operating suites that had a problem with relatively long, nonproductive turnover times between surgical procedures. Organizational leadership empowered stakeholders to use Lean and Six-Sigma tools to develop more efficient organizational processes. These processes were then implemented in a phased approach with careful attention to the organization's culture. The result was a significant reduction in turnover times leading to greater operational efficiency., Competing Interests: The authors have declared that no competing interests exist.

This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

Background: A mathematical model was developed to describe the longitudinal response in Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) obtained from the Alzheimer's Disease Neuroimaging Initiative., Methods: The model was fit to the longitudinal ADAS-cog scores from 817 patients. Risk factors (age, apolipoprotein ɛ4 [APOE ɛ4] genotype, gender, family history of AD, years of education) and baseline severity were tested as covariates., Results: Rate of disease progression increased with baseline severity. Age, APOE ɛ4 genotype, and gender were identified as potential covariates influencing disease progression. The rate of disease progression in patients with mild to moderate AD was estimated as approximately 5.5 points/yr., Conclusions: A disease progression model adequately described the natural decline of ADAS-cog observed in Alzheimer's Disease Neuroimaging Initiative. Baseline severity is an important covariate to predict a curvilinear rate of disease progression in normal elderly, mild cognitive impairment, and AD patients. Age, APOE ɛ4 genotype, and gender also influence the rate of disease progression., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)