scholarly journals Pharmacokinetics and safety of deltoid or gluteal injection of aripiprazole lauroxil NanoCrystal® Dispersion used for initiation of the long-acting antipsychotic aripiprazole lauroxil

2019 ◽  
Vol 9 ◽  
pp. 204512531985996 ◽  
Author(s):  
Marjie L. Hard ◽  
Angela Wehr ◽  
Lisa von Moltke ◽  
Yangchun Du ◽  
Sarah Farwick ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase I Study ◽  
Single Injection ◽  
Area Under The Curve ◽  
Maximum Plasma ◽  
Plasma Samples ◽  
Gluteal Muscle ◽  
Intramuscular Dose ◽  
Long Acting ◽  
To Receive

Background: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia in adults, can be started with either 21 days of daily oral aripiprazole supplementation or a 1-day initiation regimen consisting of a single injection of a NanoCrystal® Dispersion formulation of AL (ALNCD) and a single dose of 30 mg oral aripiprazole. This phase I study assessed the pharmacokinetics and safety of deltoid versus gluteal ALNCD injections. Methods: Patients with schizophrenia or schizoaffective disorder ( N = 47) were randomized 1:1 to receive a single intramuscular dose of ALNCD in the deltoid or gluteal muscle. Plasma samples were collected over 85 days to measure ALNCD concentration by injection site. Relative aripiprazole bioavailability for deltoid versus gluteal injection was assessed based on area under the curve (AUC∞ and AUClast) and maximum concentration (Cmax) values. Adverse events were monitored throughout the study. Results: Plasma aripiprazole concentrations after a single ALNCD injection were comparable between deltoid and gluteal administration. Mean maximum plasma aripiprazole concentrations were 196.1 ng/ml (deltoid) and 175.0 ng/ml (gluteal). Exposure to aripiprazole was similar, with mean AUC∞ values of 6591 day × ng/ml for deltoid and 6437 day × ng/ml for gluteal. Aripiprazole bioavailability was not significantly different between injection sites. ALNCD administration in the deltoid or gluteal muscle was well tolerated, with similar safety profiles at both sites. Conclusion: ALNCD demonstrated similar exposure and safety profiles between the two administration sites, suggesting that ALNCD can be given in either the gluteal or the deltoid muscles as a component of the 1-day initiation regimen for AL.

scholarly journals Single-Dose Phase I Study To Evaluate the Pharmacokinetics of Posaconazole in New Tablet and Capsule Formulations Relative to Oral Suspension

2012 ◽  
Vol 56 (8) ◽  
pp. 4196-4201 ◽  
Author(s):  
Gopal Krishna ◽  
Lei Ma ◽  
Monika Martinho ◽  
Edward O'Mara
Keyword(s):  
Single Dose ◽  
Phase I ◽  
Coefficient Of Variation ◽  
Phase I Study ◽  
Area Under The Curve ◽  
Oral Suspension ◽  
High Fat ◽  
Open Label ◽  
Proven Efficacy ◽  
Fat Meal

ABSTRACTPosaconazole oral suspension, a marketed extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis, should be taken with food to maximize absorption. New tablet and capsule formulations have been developed in an attempt to optimize absorption and bioavailability. The aims of this exploratory open-label, partially randomized, 2-part, 4-way, single-dose crossover study in 16 healthy adults were to characterize pharmacokinetics for posaconazole tablet and capsule formulations relative to those for posaconazole oral suspension under fasted and fed conditions and to assess safety and tolerability. Under fasted conditions, posaconazole exposures (area under the curve [AUC]) for the tablet and capsule formulations were similar (mean AUC from time zero to infinity [AUC0–∞], tablet A, 11,700 ng · h/ml [coefficient of variation {CV}, 26%]; tablet B, 11,300 ng · h/ml [CV, 22%]; capsule, 11,000 ng · h/ml [CV, 25%]) and were substantially higher than the exposure for the oral suspension (mean AUC0–∞, 3,420 ng · h/ml [CV, 44%]). Tablets and capsule showed less variability in exposure than the oral suspension. In fed subjects, tablets and capsule resulted in similar AUC values (mean AUC0–∞, tablet A, 11,900 ng · h/ml [23%]; tablet B, 12,400 ng · h/ml [CV, 25%]; capsule, 12,300 ng · h/ml [CV, 28%]) and slightly higher exposure than the oral suspension (mean AUC0–∞, 8,750 [CV, 24%]). Median times to the maximum concentration of drug in plasma were 4 to 5 h (fasted conditions) and 6 to 8 h (fed conditions). Mean half-lives values were similar for all formulations under fed and fasted conditions (23.1 to 29.2 h). Consistent with previous data, exposure for the oral suspension increased 2.5- to 3-fold when it was given with a high-fat meal. Conversely, exposures for tablets and capsule were not markedly affected by food. All formulations of posaconazole at 100 mg were safe and well tolerated.

scholarly journals Safety, tolerability, and pharmacokinetics of a single dose of pasireotide long-acting release in healthy volunteers: a single-center Phase I study

2012 ◽  
Vol 166 (5) ◽  
pp. 821-828 ◽  
Author(s):  
H. Dietrich ◽  
K. Hu ◽  
M. Ruffin ◽  
D. Song ◽  
E. Bouillaud ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase I ◽  
Healthy Volunteers ◽  
Phase I Study ◽  
Single Center ◽  
Long Acting

scholarly journals Influence of Resveratrol on the Pharmacokinetics and Pharmacodynamics of Naproxen: Involvement of CYP1A2 Inhibition

2018 ◽  
Vol 1 (1) ◽  
pp. 01-03
Author(s):  
Prasad Neerati
Keyword(s):  
Single Dose ◽  
Area Under The Curve ◽  
Treatment Phase ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Maximum Plasma ◽  
Time Intervals ◽  
Novel Approach ◽  
Gastrointestinal Side Effects ◽  
Apparent Volume Of Distribution

The purpose of the present study was to assess the effect of resveratrol (RSV) on the pharmacokinetics of naproxen (NAP) in rats. A single dose of RSV 30mg/kg was administered once during treatment phase. A single dose of NAP 25mg/kg was administered after RSV treatment. The blood samples were collected after NAP dosing at predetermined time intervals and analyzed by HPLC. In comparison with the control, RSV pretreatment significantly enhanced maximum plasma concentration (Cmax), area under the curve (AUC), and half life (t1/2) and significantly decreased apparent oral clearance (CL/F) and apparent volume of distribution (Vd/F), while there was no significant change observed in time to reach maximum concentration (tmax) of NAP. The results suggest that the altered pharmacokinetics of NAP might be attributed to RSV-mediated inhibition of CYP1A2 enzyme. Therefore, combination therapy of NAP along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of NAP.

scholarly journals The relative bioavailability of two formulations containing 10 mg Dapagliflozin assessed under fasting conditions in a randomized crossover study in healthy Caucasian subjects

2020 ◽  
Vol 66 (1) ◽  
pp. 30-34
Author(s):  
Monica Oroian ◽  
Diana Ioana Pop ◽  
Ana-Maria Gheldiu ◽  
Sandeep Bhardwaj ◽  
Adriana Marcovici ◽  
...  
Keyword(s):  
Single Dose ◽  
Reference Product ◽  
Area Under The Curve ◽  
Immediate Release ◽  
Relative Bioavailability ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Pharmaceutical Industries

AbstractObjective: The aim of the present study was to evaluate the relative bioavailability of two formulations containing 10 mg dapagliflozin in healthy Caucasian subjects under fasting conditions.Materials and Methods: Forty-eight healthy Caucasian subjects were enrolled in a single-dose, crossover, balanced, open label, randomized clinical trial, with two treatment, two periods and two sequences. The wash-out period was of 7 days and thirty-eight subjects completed both study periods. Each subject received a single dose of 10 mg dapagliflozin as the reference product Farxiga® (AstraZeneca Pharmaceuticals LP, USA) and the test product developed by Sun Pharmaceutical Industries, India. Dapagliflozin plasma levels were determined from blood samples collected in both study periods before and after dosing until 48 hours by using a validated LC-MS/MS method. For pharmacokinetic analysis of data, the non-compartmental method was used (Phoenix® WinNonlin 6.3). The statistical analysis was performed by SAS software 9.1.3 for the logarithmically transformed values of maximum plasma concentration and area under the curve.Results: The 90% confidence intervals for the evaluated pharmacokinetic parameters were found to be in the accepted interval for bioequivalence (80.00-125.00%).Conclusion: The 10 mg dapagliflozin immediate release tablet newly developed by Sun Pharmaceutical Industries, India, is bioequivalent with the reference product Farxiga® under fasted state of the subjects.

Safety and Pharmacokinetics of Ruxolitinib (INC424) in Healthy Japanese Volunteers: Placebo-Controlled, Double-Blind, Dose-Escalation Phase 1 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5162-5162
Author(s):  
Yoichiro Ogama ◽  
Tomoko Mineyame ◽  
Asuka Yamamoto ◽  
Naomi Shimada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Half Life ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Maximum Plasma ◽  
Post Dose ◽  
To Receive ◽  
Dose Reductions

Abstract Abstract 5162 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been evaluated in non-Asian healthy subjects. However, its ethnic sensitivity has not been investigated. This is the first study in Japan to evaluate the safety, tolerability, and PK of ruxolitinib in healthy Japanese volunteers. Methods: There were 4 dose cohorts with 10 male subjects in each, 8 randomized to receive ruxolitinib and 2 randomized to receive placebo. In cohort 1 (10 mg) and cohort 2 (25 mg), each subject received a single dose (QD) of ruxolitinib or placebo on day 1 and received twice daily (bid) doses on days 4 through 10. In cohorts 3 and 4, subjects received a single dose of ruxolitinib (50 and 100 mg, respectively) or placebo on day 1. Serial blood samples for PK analysis were collected up to 48 hours post-dose, and ruxolitinib concentrations were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters were derived from individual plasma concentration time data using non-compartmental analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Results: The median age of the 40 enrolled healthy subjects was 27 years. Ruxolitinib was rapidly absorbed (Cmax achieved 0.5 hours after dosing), and exposure increased dose proportionally between 10 and 100 mg (Table). Consistent with the half-life of 2–3 hours and a 12-hour dosing interval, drug accumulation was not observed after repeated dosing. These results are similar to those obtained in non-Japanese healthy volunteers (Shi JG, et al. J Clin Pharmacol, May 20, 2011 [epub ahead of print]). AUC(0–¥), area under the curve from zero to infinity; Cmax, maximum plasma concentration; t1/2, half-life; CL/F, apparent total body clearance. Consistent with ruxolitinib's inhibition of the JAK pathway, grade 2 decreases in absolute neutrophil counts were observed in 5 subjects (3 in the 10-mg bid cohort, 1 in the 25-mg bid cohort, and 1 in the 100-mg QD cohort). However, these neutrophil decreases were managed with dose reductions in 2 subjects (1 each in the 10- and 25-mg bid cohorts) or without dose reductions in 3 subjects and rapidly recovered after the last administration of the study drug. Laboratory values showed that a similar decrease in neutrophils was also observed in subjects randomized to placebo. One subject (25-mg bid cohort) experienced a grade 1 increase in alanine aminotransferase 3 days following the last dose. All AEs resolved during the study without any treatment and were not dose dependent. Conclusions: Orally administered ruxolitinib has a predictable PK and is well tolerated in healthy Japanese volunteers. There are no apparent ethnic differences in the PK of ruxolitinib between Japanese and non-Japanese subjects. Disclosures: Shimada: Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Natsume:Novartis Pharma K.K.: Employment.

STUDIES ON THE MECHANISM OF DECIDUALIZATION. I.

1963 ◽  
Vol 42 (2) ◽  
pp. 225-232 ◽  
Author(s):  
M. C. Shelesnyak ◽  
Peretz F. Kraicer ◽  
Gerard H. Zeilmaker
Keyword(s):  
Single Dose ◽  
Single Injection

ABSTRACT The concept of an oestrogen surge as a prerequisite for successful decidualization of the progravid uterus and consequently nidation in the rat was tested. Experiments were designed to see whether administration of an oestrogen antagonist at specific times would block decidualization (and nidation); whether the ovary was the source of the oestrogen, and whether a single dose of oestrogen, in the absence of the ovary (if the ovary is the source) would allow the uterus to respond to a decidualizing stimulus. It was found that when given prior to the surge, the oestrogen antagonist prevented decidualization and interfered with nidation. The ovary is thus the source of the oestrogen; and a single injection of oestradiol can act as a substitute for the surge.

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

scholarly journals PK/PD Analysis of Marbofloxacin by Monte Carlo Simulation against Mycoplasma agalactiae in Plasma and Milk of Lactating Goats after IV, SC and SC-Long Acting Formulations Administration

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1104
Author(s):  
Emilio Fernández-Varón ◽  
Edgar García-Romero ◽  
Juan M. Serrano-Rodríguez ◽  
Carlos M. Cárceles ◽  
Ana García-Galán ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
High Performance ◽  
Small Ruminants ◽  
Area Under The Curve ◽  
Hplc Method ◽  
Surrogate Markers ◽  
Contagious Agalactia ◽  
Lactating Goats ◽  
Long Acting

Contagious agalactia is a mycoplasmosis affecting small ruminants that have become an important issue in many countries. However, PK/PD studies of antibiotics to treat this problem in lactating goats affected by Mycoplasma (M.) agalactiae, the main CA-causing mycoplasma are almost non-existent. The aims of this study were to evaluate the plasma and milk disposition of marbofloxacin in lactating goats after intravenous (IV), subcutaneous (SC) and subcutaneous poloxamer P407 formulations with and without carboxy-methylcellulose (SC-P407-CMC and SC-P407) administration. Marbofloxacin concentrations were analysed by the High Performance Liquid Chromatography (HPLC) method. Minimum inhibitory concentrations (MIC) of M. agalactiae field isolates from mastitic goat’s milk were used to calculate surrogate markers of efficacy. Terminal half-lives of marbofloxacin after IV, SC, SC-P407 and SC-P407-CMC administration were 7.12, 6.57, 13.92 and 12.19 h in plasma, and the half-lives of elimination of marbofloxacin in milk were 7.22, 7.16, 9.30 and 7.74 h after IV, SC, SC-P407 and SC-P407-CMC administration, respectively. Marbofloxacin penetration from the blood into the milk was extensive, with Area Under the Curve (AUCmilk/AUCplasma) ratios ranged 1.04–1.23, and maximum concentrations (Cmax-milk/Cmax-plasma) ratios ranged 0.72–1.20. The PK/PD surrogate markers of efficacy fAUC24/MIC and the Monte Carlo simulation show that marbofloxacin ratio (fAUC24/MIC > 125) using a 90% of target attainment rate (TAR) need a dose regimen between 8.4 mg/kg (SC) and 11.57 mg/kg (P407CMC) and should be adequate to treat contagious agalactia in lactating goats.

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