scholarly journals Comparison of the Impact of Pharmacogenetic Variability on the PK of Slow Release and Immediate Release Tacrolimus Formulations

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1205
Author(s):  
Teun van Gelder ◽  
Oumaima Etsouli ◽  
Dirk Jan Moes ◽  
Jesse J. Swen
Keyword(s):  
Drug Exposure ◽  
Immediate Release ◽  
Current Data ◽  
Modified Release ◽  
Release Formulation ◽  
Once Daily ◽  
Drug Concentrations ◽  
Presystemic Metabolism ◽  
And Function ◽  
The Impact

Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme (CYP3A5 *1/*3 or *1/*1) compared to nonexpressers (CYP3A5*3/*3). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the CYP3A5 expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected.

scholarly journals Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology

2022 ◽  
Author(s):  
Debra Tompson ◽  
Mark Whitaker ◽  
Rennan Pan ◽  
Geoffrey Johnson ◽  
Teresa Fuller ◽  
...  
Keyword(s):  
Half Life ◽  
Immediate Release ◽  
Modified Release ◽  
Release Formulation ◽  
Interacting Protein ◽  
Once Daily ◽  
The Matrix ◽  
Monolithic Formulation ◽  
H Formulation

Abstract Purpose GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology. Methods Part A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states. Results Pharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing. Conclusions The DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).

scholarly journals Application of the Gastrointestinal Simulator (GIS) Coupled with In Silico Modeling to Measure the Impact of Coca-Cola® on the Luminal and Systemic Behavior of Loratadine (BCS Class 2b)

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 566 ◽  
Author(s):  
Bart Hens ◽  
Marival Bermejo ◽  
Patrick Augustijns ◽  
Rodrigo Cristofoletti ◽  
Gregory Amidon ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
Buffer Capacity ◽  
Drug Product ◽  
Tap Water ◽  
Systemic Exposure ◽  
Immediate Release ◽  
Release Formulation ◽  
Gastric Emptying Rate ◽  
Physiological Variables ◽  
The Impact

In the present work, we explored if Coca-Cola® had a beneficial impact on the systemic outcome of the weakly basic drug loratadine (Wal-itin®, immediate-release formulation, 10 mg, generic drug product). To map the contribution of underlying physiological variables that may positively impact the intestinal absorption of loratadine, a multi-compartmental and dynamic dissolution device was built, namely the Gastrointestinal Simulator (GIS). The luminal behavior of one immediate-release (IR) tablet of 10 mg of loratadine was tested under four different fasted state test conditions in the GIS: (i) with 250 mL of water and applying a predetermined gastric half-life (t1/2,G) of 15 min; (ii) with 250 mL of water and applying a t1/2,G of 30 min; (iii) with 250 mL of Coca-Cola® and a t1/2,G of 15 min; (iv) with 250 mL of Coca-Cola® and a t1/2,G of 30 min. After initiating the experiments, solution concentrations and solubility were measured in the withdrawn samples, and pH was monitored. To address the impact of the present CO2 in Coca-Cola® on the disintegration time of the tablet, additional disintegration experiments were performed in a single-vessel applying tap water and sparkling water as dissolution media. These experiments demonstrated the faster disintegration of the tablet in the presence of sparkling water, as the present CO2 facilitates the release of the drug. The buffer capacity of Coca-Cola® in the presence of FaSSGF was 4-fold higher than the buffer capacity of tap water in the presence of FaSSGF. After performing the in vitro experiments, the obtained results were used as input for a two-compartmental pharmacokinetic (PK) modeling approach to predict the systemic concentrations. These simulations pointed out that (i) the present CO2 in Coca-Cola® is responsible for the enhancement in drug release and dissolution and that (ii) a delay in gastric emptying rate will sustain the supersaturated concentrations of loratadine in the intestinal regions of the GI tract, resulting in an enhanced driving force for intestinal absorption. Therefore, co-administration of loratadine with Coca-Cola® will highly likely result in an increased systemic exposure compared to co-administration of loratadine with tap water. The mechanistic insights that were obtained from this work will serve as a scientific basis to evaluate the impact of Coca-Cola® on the systemic exposure of weakly basic drugs for patients on acid-reducing agents in future work.

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats

2010 ◽  
Vol 25 (2) ◽  
pp. 92-100 ◽  
Author(s):  
G. Marchese ◽  
B. Pittau ◽  
G. Casu ◽  
G. Peddio ◽  
G.P. Spada ◽  
...  
Keyword(s):  
Motor Impairment ◽  
Receptor Occupancy ◽  
Immediate Release ◽  
Pharmacokinetic Profile ◽  
Continuous Administration ◽  
Release Formulation ◽  
Antipsychotic Efficacy ◽  
Drug Concentrations ◽  
Oral Antipsychotic ◽  
Novel Antipsychotic

AbstractIt is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D2-receptor occupancy by antipsychotics within the striatum must exceed 60−65%. However, at high levels of D2-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D2-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak−trough fluctuations and consistent D2-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

scholarly journals Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Pooja Manchandani ◽  
Jian Zhou ◽  
Jessica T. Babic ◽  
Kimberly R. Ledesma ◽  
Luan D. Truong ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Drug Exposure ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Renal Tissue ◽  
Sprague Dawley ◽  
Electron Microscopic ◽  
Drug Concentrations ◽  
The Impact

ABSTRACT Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity.

scholarly journals Levetiracetam Extended Release as Adjuvant Therapy for the Control of Partial-onset Seizures

2011 ◽  
Vol 3 ◽  
pp. JCNSD.S4126
Author(s):  
Hasan H. Sonmezturk ◽  
Nabil J. Azar
Keyword(s):  
Animal Studies ◽  
Extended Release ◽  
Immediate Release ◽  
Brand Name ◽  
First Line ◽  
Release Formulation ◽  
Once Daily ◽  
Seizure Reduction ◽  
Extended Release Formulation ◽  
Clonic Seizures

Extended release (XR) formulation of levetiracetam (LEV) is approved by the Food and Drug Administration as an add-on to other antiepileptic drugs (AEDs) for adults with partial onset seizures. This is based on class-I evidence demonstrating significant seizure reduction in once daily dosing. Keppra-XR is marketed with the brand name of Keppra XR since 2008 (UCB Pharma). Its original immediate release (IR) formulation has been in the market since 2000. LEV has a unique molecular structure which is chemically unrelated to existing AEDs. The precise mechanism of action is unknown. Animal studies showed binding to synaptic vesicle protein SV2A, thought to be involved in modulating synaptic neurotransmitter release. LEV-IR is proven effective as adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures and myoclonic seizures. It was shown to be equivalent to carbamazepine as first-line treatment for partial-onset seizures. The extended release formulation added advantages such as better tolerance and increased compliance.

Comparative Efficacy of a Once-Daily Controlled-Release Formulation of Glipizide and Immediate-Release Glipizide in Patients With NIDDM

Diabetes Care ◽  
1994 ◽  
Vol 17 (12) ◽  
pp. 1460-1464 ◽  
Author(s):  
M. Berelowitz ◽  
C. Fischette ◽  
W. Cefalu ◽  
D. S. Schade ◽  
T. Sutfin ◽  
...  
Keyword(s):  
Controlled Release ◽  
Immediate Release ◽  
Comparative Efficacy ◽  
Release Formulation ◽  
Once Daily ◽  
Controlled Release Formulation

Modified Release Tizanidine in the Treatment of Spasticity

1988 ◽  
Vol 16 (6) ◽  
pp. 459-465 ◽  
Author(s):  
A. Chantraine ◽  
C. Van Ouwenaller
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Body Weight ◽  
Side Effects ◽  
Modified Release ◽  
Cerebral Lesions ◽  
Release Formulation ◽  
Once Daily ◽  
End Of Treatment ◽  
Severe Spasticity

A 6-week study of a modified release formulation of tizanidine designed for once daily administration was performed in 27 patients with spasticity due to cerebral lesions. The dosage of tizanidine used ranged from 6 to 18 mg/day. At the start of the study all patients had at least moderate spasticity and 20 (74%) patients had severe or very severe spasticity. All had a decrease in muscle strength. After 1 week of treatment 22 (81%) patients showed improvement in overall spastic state and, after 6 weeks, all 27 patients had improved. At the end of treatment 25 (93%) patients showed an improvement in overall disability. The drug was well tolerated. Side-effects were reported in only four patients, and these were minor and mostly mild. Tizanidine had no clinically important effects on blood pressure, heart rate, body weight or laboratory values. Overall, once daily treatment with modified release tizanidine is well tolerated and gives good clinical efficacy in patients with spasticity.

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