A Fully Validated UHPLC–MS/MS Method for the Estimation of Pimavanserin in Human (K2EDTA) Plasma and its Application to a Clinical Pharmacokinetic Study

Aalapati, None Kiran Kumar; Singh, Amit; Patnaik, Ranjana

doi:10.1093/chromsci/bmab069

Cited by 2 publications

(2 citation statements)

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“…PK samples were analyzed using a method of liquid chromatography combined with tandem mass spectrometry that has been previously published 9 . After collection, samples were cooled to −70 °C and sent to a central facility to be analyzed.…”

Section: Methodsmentioning

confidence: 99%

“…PK samples were analyzed using a method of liquid chromatography combined with tandem mass spectrometry that has been previously published. 9 After collection, samples were cooled to −70 °C and sent to a central facility to be analyzed. All acceptable plasma samples from participants receiving pimavanserin were analyzed for the concentration of pimavanserin and its active metabolite (AC-260279).…”

Section: Study Design and Analysis Populationmentioning

confidence: 99%

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Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Darwish

Dirks

Passarell

et al. 2023

Clinical Pharm in Drug Dev

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In the 10-week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD-17) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure-response (E-R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population-pharmacokinetic empirical Bayesian estimates. E-R models were developed to describe exposure-efficacy (HAMD-17, SDS, and Clinical Global Impression-Improvement [CGI-I] scale) and exposure-safety relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD-17 scores), a sigmoid maximum-effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD-17 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (C max ) increased. At median pimavanserin C max (34-mg dose), the reduction from baseline in HAMD-17 scores was −11.1 and −13.5 at weeks 5 and 10, respectively. Relative to placebo, the model predicted comparable reductions in HAMD-17 scores at weeks 5 and 10. Similar improvements in favor of pimavanserin were detected with SDS, CGI-I, MGH-SFI, and KSS scores. No E-R relationship was found for AEs. E-R modeling predicted a relationship between higher pimavanserin exposure and improvement in HAMD-17 score and improvement across multiple secondary efficacy endpoints.

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Section: Methodsmentioning

confidence: 99%

Section: Study Design and Analysis Populationmentioning

confidence: 99%

Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Darwish

Dirks

Passarell

et al. 2023

Clinical Pharm in Drug Dev

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A novel Six Sigma approach and eco-friendly RP-HPLC technique for determination of pimavanserin and its degraded products: Application of Box–Behnken design

Nassef,

Ahmed,

Bashal

et al. 2024

Reviews in Analytical Chemistry

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A green analytical chemistry study attempts to generate environmentally friendly alternatives to dangerous compounds while reducing waste output. The study thoroughly analyzed eight green tools to determine their greenness. Given its importance in treating hallucinations and delusions produced by Parkinson’s disease psychosis, it is critical to have a reliable and precise method for identifying pimavanserin (PVS) in both pure form and pharmaceutical formulations. The current study used a straightforward approach to forced degradation experiments to establish a novel reversed-phase high-performance liquid chromatography method for evaluating stability. The method was executed on the Agilent Zorbax Eclipse Plus C18 column (100 × 4.6 mm, 3.5 μm particle size) with ultraviolet detection at 226 nm. The Box–Behnken design is the ultimate solution for identifying optimal chromatographic conditions in a timely and efficient manner, with minimal trials required. The study investigated the impact of three factors: acetonitrile ratio, column oven temperature, and flow rate on various responses, namely, retention time, tailing factor, and theoretical plates. Desirability and overlay plots were utilized to forecast the best mobile phase containing a buffer solution: acetonitrile: tetrahydrofuran in a ratio of (65: 20: 15, v/v/v), which proved highly effective in the experiments. Linearity was conducted for PVS in the 3–50 µg·mL−1 range with an R 2 coefficient of determination of 0.9997. PVS had detection and quantification limits of 1.1 and 3.5 µg·mL−1, respectively, indicating a highly significant correlation between the variables studied. PVS’s recovery percentage was determined to be 101.30%. We also used the Six Sigma lean technique to ensure precision and productivity. PVS was tested for acid, base, oxidative hydrolysis, photodegradation, and heat, as per International Council for Harmonisation guidelines. The highest degradation was obtained from oxidative hydrolysis and thermal degradation.

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A Fully Validated UHPLC–MS/MS Method for the Estimation of Pimavanserin in Human (K2EDTA) Plasma and its Application to a Clinical Pharmacokinetic Study

Cited by 2 publications

References 5 publications

Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

Exposure–response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder

A novel Six Sigma approach and eco-friendly RP-HPLC technique for determination of pimavanserin and its degraded products: Application of Box–Behnken design

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