scholarly journals Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat

2015 ◽  
Vol 44 (2) ◽  
pp. 189-210 ◽  
Author(s):  
Nicolas Darville ◽  
Marjolein van Heerden ◽  
Tim Erkens ◽  
Sandra De Jonghe ◽  
An Vynckier ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Time Course ◽  
Drug Exposure ◽  
Critical Time ◽  
Granulomatous Inflammation ◽  
Mechanistic Modeling ◽  
Paliperidone Palmitate ◽  
Therapeutic Drug ◽  
Monocyte Chemoattractant Protein 1 ◽  
Long Acting

Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1β, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation–physiology interplay regulating the drug absorption from LAIs.

scholarly journals Long-acting antiretrovirals: a new era for the management and prevention of HIV infection

2021 ◽  
Author(s):  
Paul Thoueille ◽  
Eva Choong ◽  
Matthias Cavassini ◽  
Thierry Buclin ◽  
Laurent A Decosterd
Keyword(s):  
Hiv Infection ◽  
Drug Exposure ◽  
Real Life ◽  
Effective Vaccine ◽  
Therapeutic Drug ◽  
People Living With Hiv ◽  
Medical Procedure ◽  
Clinical Pharmacokinetics ◽  
Long Acting ◽  
Prevention Of Hiv

Abstract The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA and Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing the 365 daily pill burden to only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, is intended to be formulated as an implant with a dosing interval of 1 year or more. At present, long-acting antiretroviral therapies (LA-ARTs) are given at fixed standard doses, irrespectively of the patient’s weight and BMI, and without consideration for host genetic and non-genetic factors likely influencing their systemic disposition. Despite a few remaining challenges related to administration (e.g. pain, dedicated medical procedure), the development and implementation of LA-ARTs can overcome long-term adherence issues by improving patients’ privacy and reducing social stigma associated with the daily oral intake of anti-HIV treatments. Yet, the current ‘one-size-fits-all’ approach does not account for the recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic drug monitoring (TDM), an important tool for precision medicine, may provide physicians with valuable information on actual drug exposure in patients, contributing to improve their management in real life. The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.

VP51 Hospitalizations And Costs In Schizophrenia Patients Initiating Long-acting Injectable Antipsychotics

2017 ◽  
Vol 33 (S1) ◽  
pp. 171-171
Author(s):  
Mallik Greene ◽  
Tingjian Yan ◽  
Eunice Chang ◽  
Ann Hartry ◽  
Michael Broder
Keyword(s):  
Index Date ◽  
Reference Group ◽  
Cohort Analysis ◽  
Paliperidone Palmitate ◽  
Linear Regression Models ◽  
Inpatient Hospitalization ◽  
Retrospective Cohort Analysis ◽  
Inpatient Hospitalizations ◽  
Medicaid Population ◽  
Long Acting

INTRODUCTION:Existing evidence on clinical and economic effectiveness of one long-acting injectable antipsychotic (LAI) versus another in successful management of schizophrenia is scarce. The study was conducted to compare all-cause inpatient healthcare utilization and associated costs among Medicaid patients with schizophrenia who initiated LAIs.METHODS:This retrospective cohort analysis used the Truven Health Analytics MarketScan® Medicaid claims database. Schizophrenia patients >18 years with at least one claim for one of the following LAI were identified between 1 January 2013 and 30 June 2014 (identification period): aripiprazole, fluphenazine, haloperidol, paliperidone palmitate, and risperidone. The first day of initiating an LAI was considered the index date. Patients were followed for 1 year from index date. Logistic and general linear regression models were used to estimate risk of inpatient hospitalization and associated costs during follow up.RESULTS:Of the identified Medicaid patients with schizophrenia, 1,672 (36.7 percent) initiated an LAI: 44.0 percent received paliperidone, 26.4 percent haloperidol, 13.8 percent risperidone, 9.2 percent aripiprazole, and 6.6 percent fluphenazine. With the aripiprazole cohort as the reference group, the odds of having any inpatient hospitalizations were significantly higher in haloperidol [Odds Ratio, OR (95 percent Confidence Interval, CI): 1.51 (1.05 - 2.16)] and risperidone [OR (95 percent CI): 1.58 (1.07 - 2.33)] cohorts. Fluphenazine and paliperidone palmitate cohorts also had higher risk of having any inpatient hospitalizations compared with aripiprazole, but the differences were not statistically significant (p>.05). Among LAI initiators with any inpatient hospitalizations, the adjusted mean inpatient costs were lowest in the aripiprazole cohort (USD25,616), followed by haloperidol (USD30,811), paliperidone (USD30,833), risperidone (USD31,584), and fluphenazine (USD37,338), although differences were not statistically significant.CONCLUSIONS:Our study findings highlight the value of aripiprazole in reducing inpatient hospitalizations and associated costs among patients with schizophrenia. However, our study is limited as our results are reflective of a multi-state Medicaid population. Future studies are warranted to confirm the results in non-Medicaid patient populations.

Discontinuation and relapse with paliperidone palmitate three-monthly for maintenance of schizophrenia: Two year follow-up of use in clinical practice

2021 ◽  
pp. 026988112110097
Author(s):  
Phoebe Wallman ◽  
Ivana Clark ◽  
David Taylor
Keyword(s):  
Clinical Practice ◽  
Treatment Duration ◽  
Maintenance Treatment ◽  
Clinical Care ◽  
Paliperidone Palmitate ◽  
Reduce Risk ◽  
Patient Refusal ◽  
Long Acting ◽  
Post Hoc

Background: The use of antipsychotic long-acting injections (LAI) aims to reduce risk of relapse and hospitalisation in patients with schizophrenia compared with oral medication. Paliperidone palmitate is currently the only LAI that can be administered at three-monthly intervals for maintenance treatment of schizophrenia. Aim: This prospective study aimed to evaluate relapse and continuation in licensed use of paliperidone palmitate three-monthly (PP3M) over a 2-year follow-up in clinical practice. Method: Non-interventional, observational study of patients treated in the South London and The Maudsley NHS Foundation Trust. Results: A total of 166 patients initiated on PP3M, 55 were excluded from the study (non-F20 diagnosis ( n = 43); F20 >65 years old ( n = 12)). Of the 111 patients included, 67 (60%) continued PP3M for 2 years. Overall 102 patients received more than one dose of PP3M and 92 (90%) remained on the same dose of PP3M for the whole of their treatment duration. Relapse (defined as a step-up in clinical care) occurred in eight patients (7%) while on PP3M. The most common reason for discontinuation was patient refusal and the most frequent medication prescribed after discontinuation was paliperidone palmitate one-monthly (PP1M). Post hoc, we analysed outcome in those continuing any form of PPLAI (those continuing with PP3M and those switching back to PP1M). Continuation over 2 years with any PPLAI formulation was 73% (81/111) and relapse was recorded in 9% (10/111). Conclusion: Overall, PP3M was an effective maintenance treatment for schizophrenia after stabilisation on PP1M in a clinical setting.

scholarly journals Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

2006 ◽  
Vol 50 (6) ◽  
pp. 2079-2086 ◽  
Author(s):  
Déborah Hirt ◽  
Jean-Marc Treluyer ◽  
Vincent Jullien ◽  
Ghislaine Firtion ◽  
Hélène Chappuy ◽  
...  
Keyword(s):  
Population Study ◽  
Time Course ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Concomitant Administration ◽  
Individual Characteristics ◽  
Individual Treatment ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Linear Absorption

ABSTRACT A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h−1; absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL10/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL1M/F), 0.65 liters/h (69%); and M8 elimination rate constant (k M0), 3.3 h−1 (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h−1) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

P.7.d.012 Paliperidone palmitate long-acting injection in adolescents: report of two cases

2013 ◽  
Vol 23 ◽  
pp. S606-S607 ◽  
Author(s):  
M. Fabrega Ribera ◽  
S. Garcia Chulbi ◽  
G. Sugranyes Ernest ◽  
I. Baeza Pertegaz
Keyword(s):  
Paliperidone Palmitate ◽  
Long Acting

Effectiveness of paliperidone palmitate one-month long-acting injection in obese vs. non-obese patients

2021 ◽  
pp. 152269
Author(s):  
Charles Dorflinger ◽  
Colleen LeHew ◽  
Heather Carey ◽  
Jennifer Roche-Desilets ◽  
Christopher J. Burant
Keyword(s):  
Paliperidone Palmitate ◽  
Obese Patients ◽  
Long Acting

Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Susanne Weber ◽  
Sara Tombelli ◽  
Ambra Giannetti ◽  
Cosimo Trono ◽  
Mark O’Connell ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Real Time ◽  
Drug Monitoring ◽  
Time Course ◽  
Drug Dosage ◽  
Immunosuppressive Drug ◽  
Therapeutic Drug ◽  
Continuous Sampling ◽  
Real Time Analysis ◽  
Drug Concentrations

AbstractObjectivesTherapeutic drug monitoring (TDM) plays a crucial role in personalized medicine. It helps clinicians to tailor drug dosage for optimized therapy through understanding the underlying complex pharmacokinetics and pharmacodynamics. Conventional, non-continuous TDM fails to provide real-time information, which is particularly important for the initial phase of immunosuppressant therapy, e.g., with cyclosporine (CsA) and mycophenolic acid (MPA).MethodsWe analyzed the time course over 8 h of total and free of immunosuppressive drug (CsA and MPA) concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 16 kidney transplant patients. Besides repeated blood sampling, intravenous microdialysis was used for continuous sampling. Free drug concentrations were determined from ultracentrifuged EDTA-plasma (UC) and compared with the drug concentrations in the respective microdialysate (µD). µDs were additionally analyzed for free CsA using a novel immunosensor chip integrated into a fluorescence detection platform. The potential of microdialysis coupled with an optical immunosensor for the TDM of immunosuppressants was assessed.ResultsUsing LC-MS/MS, the free concentrations of CsA (fCsA) and MPA (fMPA) were detectable and the time courses of total and free CsA comparable. fCsA and fMPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, fCsA in µDs measured with the immunosensor correlated clearly with those determined by LC-MS/MS (r=0.82).ConclusionsThe new microdialysis-supported immunosensor allows real-time analysis of immunosuppressants and tailor-made dosing according to the AUC concept. It readily lends itself to future applications as minimally invasive and continuous near-patient TDM.

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