Extended-release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate-release formulations

ABSTRACTBenznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentrationin vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease.

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Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy

Epilepsy Currents ◽

10.5698/1535-7597.18.4.269 ◽

2018 ◽

Vol 18 (4) ◽

pp. 269-278 ◽

Cited By ~ 5

Author(s):

Andres M. Kanner ◽

Eric Ashman ◽

David Gloss ◽

Cynthia Harden ◽

Blaise Bourgeois ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Seizure Frequency ◽

Extended Release ◽

Focal Epilepsy ◽

Immediate Release ◽

Juvenile Myoclonic Epilepsy ◽

Review Literature ◽

Treatment Resistant ◽

New Antiepileptic Drugs ◽

Frequency Level

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods: 2004 criteria were used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Forty-two articles were included. Recommendations: The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment; rufinamide for Lennox–Gastuat syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic–clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month to 16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month to 4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

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A pharmacokinetic evaluation of single and multiple doses of extended-release hydrocodone bitartrate in subjects experiencing surgical or osteoarthritic pain

Journal of Opioid Management ◽

10.5055/jom.2015.0290 ◽

2015 ◽

Vol 11 (5) ◽

pp. 405 ◽

Cited By ~ 3

Author(s):

Cynthia Y. Robinson, PhD ◽

Christopher M. Rubino, PharmD ◽

Stephen J. Farr, PhD

Keyword(s):

Single Dose ◽

Steady State ◽

Extended Release ◽

Venous Blood ◽

Plasma Concentrations ◽

Immediate Release ◽

Pharmacokinetic Parameters ◽

Single Dose Study ◽

Dosing Interval ◽

Osteoarthritic Pain

Objectives: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies.Setting: Both studies were multicenter clinical studies.Subjects and interventions: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone-ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites.Main outcome measures: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods.Results: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steady-state mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies.Conclusions: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.

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QbD based Eudragit coated Meclizine HCl immediate and extended release multiparticulates: formulation, characterization and pharmacokinetic evaluation using HPLC-Fluorescence detection method

Scientific Reports ◽

10.1038/s41598-020-71751-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Faaiza Qazi ◽

Muhammad Harris Shoaib ◽

Rabia Ismail Yousuf ◽

Fahad Siddiqui ◽

Muhammad Iqbal Nasiri ◽

...

Keyword(s):

Extended Release ◽

Geometric Mean ◽

Compartmental Analysis ◽

Immediate Release ◽

Drug Analysis ◽

Fluorescence Method ◽

Pharmacokinetic Parameters ◽

Comparative Pharmacokinetic ◽

Time Period ◽

Pharmacokinetic Evaluation

Abstract This study is based on the QbD development of extended-release (ER) extruded-spheronized pellets of Meclizine HCl and its comparative pharmacokinetic evaluation with immediate-release (IR) pellets. HPLC-fluorescence method was developed and validated for plasma drug analysis. IR drug cores were prepared from lactose, MCC, and PVP using water as granulating fluid. Three-level, three-factor CCRD was applied for modeling and optimization to study the influence of Eudragit (RL100-RS100), TEC, and talc on drug release and sphericity of coated pellets. HPLC-fluorescence method was sensitive with LLOQ 1 ng/ml and linearity between 10 and 200 ng/ml with R2 > 0.999. Pharmacokinetic parameters were obtained by non-compartmental analysis and results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with a 90% CI limit of 0.8–1.25. The AUC0–t and AUC0–∞ of ER pellets were not significantly different with geometric mean ratio 1.0096 and 1.0093, respectively. The Cmax of IR pellets (98.051 ng/ml) was higher than the ER pellets (84.052 ng/ml) and the Tmax of ER pellets (5.116 h) was higher than the IR pellets (3.029 h). No significant food effect was observed on key pharmacokinetic parameters of ER pellets. Eudragit RL100 (6%) coated Meclizine HCl pellets have a potential therapeutic effect for an extended time period.

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Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy

Neurology ◽

10.1212/wnl.0000000000005756 ◽

2018 ◽

Vol 91 (2) ◽

pp. 82-90 ◽

Cited By ~ 27

Author(s):

Andres M. Kanner ◽

Eric Ashman ◽

David Gloss ◽

Cynthia Harden ◽

Blaise Bourgeois ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Seizure Frequency ◽

Extended Release ◽

Focal Epilepsy ◽

Immediate Release ◽

Juvenile Myoclonic Epilepsy ◽

Review Literature ◽

Treatment Resistant ◽

New Antiepileptic Drugs ◽

Frequency Level

ObjectiveTo update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs).Methods2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.ResultsForty-two articles were included.RecommendationsThe following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month–16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month–4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

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Effects of CPY3A5 Genetic Polymorphisms on the Pharmacokinetics of Extended-release and Immediate-release Tacrolimus Formulations in Renal Transplant Recipients: a Systematic Review and Meta-analysis

Current Drug Metabolism ◽

10.2174/1389200222666210825160021 ◽

2021 ◽

Vol 22 ◽

Author(s):

Qiufen Xie ◽

Qian Xiang ◽

Zhiyan Liu ◽

Guangyan Mu ◽

Shuang Zhou ◽

...

Keyword(s):

Renal Transplant ◽

Extended Release ◽

Immediate Release ◽

Cochrane Library ◽

Pharmacokinetic Parameters ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Post Transplantation ◽

Subgroup Analyses ◽

Daily Dose

Background : Although the pharmacokinetic variability of Tacrolimus (Tac) metabolism is primarily influenced by CYP3A5 genotypes, the potential effect according to CYP3A5 polymorphisms in Tac extended-release (Tac-ER) and immediate-release (Tac-IR) and between these formulations’ conversion needs further investigation. The purpose of this study was to clarify the association of CYP3A5 genotypes and pharmacokinetics of different Tac formulations in renal transplant recipients. Methods : PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies (protocol registration No. CRD 42019133790 in PROSPERO network). The summary weighted mean difference with 95% confidence intervals was calculated for pharmacokinetic parameters using the random-effects model according to post-transplantation periods, genotypes and formulations. Sensitivity analysis, publication bias, and subgroup analyses were conducted. Results : A total of 27 studies involving 2,713 renal transplant recipients were adopted. Whether patients treated with Tac-ER or Tac-IR, CYP3A5 non-expressors (*3/*3) had a decreased daily dose and CL/F, an increased Ctrough, Ctrough/D, AUC0-24h/D and Cmax/D than expressors (*1/*1 or *1/*3) at most post-transplantation periods. Furthermore, when 1:1 dose conversion from Tac-IR to Tac-ER (all at ≥12 months post-transplantation), Ctrough and Cmax were decreased in both CYP3A5 non-expressors and expressors, while daily dose was only decreased in CYP3A5 non-expressors and AUC0-24h was only decreased in CYP3A5 expressors. Finally, subgroup analyses indicated that ethnicity, mean age, and male percentage influenced daily dose and Ctrough of Tac, especially for Tac-IR. Conclusion: The results indicated that CYP3A5 genotypes affect the pharmacokinetics of Tac in renal transplant recipients in both formulations and between formulations’ conversion. Future studies should be exploring more other associations of CYP3A5 genotypes and the pharmacodynamics of Tac.

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