Multiple Dose Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers

2000 ◽  
Vol 92 (3) ◽  
pp. 665-673 ◽  
Author(s):  
Talmage D. Egan ◽  
Amarnath Sharma ◽  
Michael A. Ashburn ◽  
Jur Kievit ◽  
Nathan L. Pace ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Maximum Concentration ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Multiple Dosing ◽  
Fentanyl Citrate ◽  
Minimum Concentration ◽  
Intravenous Fentanyl ◽  
Oral Transmucosal Fentanyl Citrate

Background Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. Methods Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. Results The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. Conclusions The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.

scholarly journals The Pharmacokinetic Study of Progesterone and Allopregnanolone in Refractory Epilepsy : Phase II Study

2021 ◽  
Author(s):  
Marisa Senngam ◽  
Juthathip Suphanklang ◽  
Wichai santimaleeworagun ◽  
Piradee Suwanpakdee ◽  
Pornsawan Mekhasingharrak ◽  
...  
Keyword(s):  
Seizure Frequency ◽  
Maximum Concentration ◽  
Refractory Epilepsy ◽  
Serum Levels ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Serum Progesterone ◽  
Minimum Concentration ◽  
Clinical Trials Registry ◽  
The Relationship

Abstract Background: Progesterone belongs to a class of neurosteroids used for the reduction of seizure frequency in patients with refractory epilepsy. However, the pharmacokinetics of progesterone and its active derivative, allopregnanolone, have never been studied in these patients. Objectives: This study was aim to explore the pharmacokinetic parameters of progesterone 400 mg every 12 h, for 3 months, in patients with refractory epilepsy as an add-on therapy to control seizures. Phoenix® WinNonlin® was used to analyse the pharmacokinetic parameters. Results: Twelve patients were recruited. From a therapeutic drug monitoring, the serum progesterone and allopregnanolone levels after taking the first dose of progesterone were characterised by a time to maximum concentration (Tmax) median of 1 and 2.5 h, a maximum concentration (Cmax) median of 274.97 and 3.81 ng/mL, and a minimum concentration (Cmin) median of 56.93 and 1.06 ng/mL, respectively. The median values of the pharmacokinetic parameters of progesterone and allopregnanolone during the steady state were as follows: t1/2 of 2.4 and 2.0 h, Cmax of 964.35 and 8.92 ng/mL, and Cmin of 64.67 and 1.86 ng/mL, respectively. By examining the relationship between the progesterone or allopregnanolone concentrations with seizure-controlling ability, we could identify a responder patient group with 6- to 7-fold higher serum concentrations of progesterone and allopregnanolone than the non-responders. Conclusions: We could establish higher serum levels of both progesterone and allopregnanolone, which could consequently relate to lowering the seizure frequency in patients with refractory epilepsy. The suggested progesterone dose was 400 mg orally every 12 h against refractory epilepsy Trial registration: This study has been registered on the Thai Clinical Trials Registry (No. TCTR20200710005, 10 July 2020)

scholarly journals Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan

2021 ◽  
Vol 12 ◽  
Author(s):  
Muhammad Muaaz Munir ◽  
Huma Rasheed ◽  
Muhammad Imran Khokhar ◽  
Rizwan Rasul Khan ◽  
Hafiz Asad Saeed ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Goodness Of Fit ◽  
Volume Of Distribution ◽  
Surgical Patients ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Concentration Data ◽  
Population Pharmacokinetic Modeling

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan.Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration–time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks.Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively.Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

Influence of Age on the Pharmacokinetics and Pharmacodynamics of Oral Transmucosal Fentanyl Citrate

2004 ◽  
Vol 101 (3) ◽  
pp. 738-743 ◽  
Author(s):  
Evan D. Kharasch ◽  
Christine Hoffer ◽  
Dale Whittington
Keyword(s):  
Cancer Pain ◽  
Pupil Diameter ◽  
The Elderly ◽  
Pharmacokinetic Parameters ◽  
Clinical Effects ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Fentanyl Citrate ◽  
Oral Transmucosal Fentanyl Citrate ◽  
Older Volunteers ◽  
Older Subjects

Background Cancer pain is primarily a problem of older persons. Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is the first drug specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa but a considerable portion is swallowed and absorbed enterally. The effects of age on OTF pharmacokinetics and pharmacodynamics are unknown. This investigation evaluated OTF disposition and clinical effects in older (60-75 yr) compared with younger (18-40 yr) volunteers. Methods Healthy young (26 +/- 6 yr) and older (67 +/- 6 yr) volunteers (n = 12 each) were studied in an Institutional Review Board approved protocol. They received OTF (10 microg/kg). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and by subjective self-assessments using visual analog scales. Results Plasma fentanyl and norfentanyl concentrations and pharmacokinetic parameters did not differ between younger and older subjects. Maximum pupil diameter change from baseline was significantly less in older (3.1 +/- 0.7 mm) compared with younger (4.5 +/- 1.1 mm) subjects (P < 0.05). OTF-dependent subjective assessments of alertness/sedation, energy level, confusion, clumsiness, anxiety, and nausea did not differ in the older subjects. Discussion The pharmacokinetics of OTF were not altered in older volunteers. In contrast, there was a somewhat diminished response to the miotic effects of fentanyl in older subjects. No change in OTF dosing in the elderly would appear necessary because of altered pharmacokinetics. If the response to OTF in older patients is similar to that in older volunteers and miosis is representative of analgesia and respiratory depression, then changes in OTF dosing with age alone do not appear indicated.

scholarly journals Pharmacokinetics of Ciprofloxacin in Broiler Chickens After Single Intravenous and Intraingluvial Administration

2017 ◽  
Vol 40 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Sofiya Ivanova ◽  
Dimitrichka Dimitrova ◽  
Metodi Petrichev
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Infectious Diseases ◽  
Crossover Study ◽  
Intravenous Injection ◽  
Broiler Chickens ◽  
Bolus Injection ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Pharmacokinetic Models

Abstract The trial was performed on 10 clinically healthy Ross hybrid chickens, 5 from each gender, weighing 2.75-2.84 kg. The tested quinolone was applied at the same dose for both routes of application - 10 mg/kg of body weight. Ciprofloxacin hydrochloridum 5% solution for i.v. and 1% solution for intraingluvial treatment were prepared. In a crossover study design, ciprofloxacin hydrochloridum was administered as 5 % solution for i.v. bolus injection to broiler chickens and after 14 days as 1 % solution for intraingluvial administration into a crop to the same birds. Serum ciprofloxacin concentrations were assayed by HPLC with UV detection at a wavelength of 279 nm. After intravenous injection the following pharmacokinetic parameters were determined: t1/2β = 9.07 h; t1/2α= 0.36 h; MRT = 10.20 h and MRT = 10.75 h; AUC0→∞ = 19.560 μg.h/mL and AUC0→∞ = 19.843 μg.h/mL. After intraingluvial application parameters determined by the two pharmacokinetic models were as: t1/2α= 0.86 h; t1/2β = 7,20 h and t1/2β = 7.89 h; MRT = 12.67 h and MRT = 12.93 h; AUC0→∞ = 11.340 μg.h/mL and AUC0→24 h = 11.973 μg.h/mL; Cmax = 2.841 μg/mL and Cmax = 2.638 μg/mL; Tmax = 0.48 h and Tmax = 0.39 h; t1/2abs. = 0.146 h; MAT = 2.47 h and MAT = 2.18 h; F = 57.91% and F = 63.89%. These results suggested that a dose of 10 mg/kg of body weight provides maximum plasma concentration ater intraingluvial administration and is effective in the control of many infectious diseases of poultry.

DO WE HAVE A CONSENSUS TO APPLY MODEL-BASED AMINOGLYCOSIDE THERAPY: A REVIEW OF POPULATION PHARMACOKINETIC MODELS

2015 ◽  
Vol 101 (1) ◽  
pp. e1.51-e1
Author(s):  
Guo-Xiang Hao ◽  
Sophie Teng ◽  
Evelyne Jacqz-Aigrain ◽  
Wei Zhao
Keyword(s):  
Meta Analysis ◽  
Pharmacokinetic Modeling ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Related Factors ◽  
Model Based ◽  
Aminoglycoside Therapy ◽  
Bibliographic Search ◽  
Adults And Children

Background and ObjectiveAminoglycosides remain the standard antibiotic therapy for Gram-negative infections in both adults and children. The pharmacokinetic modeling approach has been widely used to evaluate aminoglycosides therapy. The aim of the present study is to review the published population pharmacokinetic models of commonly used aminoglycosides (gentamycin, amikacin and tobramycin), in order to determine if there was a consensus to apply model-based personalized aminoglycoside therapy in routine clinical practice.MethodsThe bibliographic search was performed electronically using PubMed on 30th January 2015, following the search strategy: “((population Pharmacokinetics) OR (Pharmacokinetic modeling)) AND (gentamycin OR gentamicin OR amikacin OR tobramycin)”.ResultsA total of 49 articles were identified. Persistent variabilities exist in terms of structure model; typical pharmacokinetic parameters and identified covariates.ConclusionA pharmacokinetic meta-analysis is required to evaluate the study-related factors influencing the pharmacokinetics of aminoglycosides. A clinical evaluation of pharmacokinetic model of aminoglycosides is required to demonstrate its clinical utility.

scholarly journals Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1244
Author(s):  
Silvia Marquez-Megias ◽  
Amelia Ramon-Lopez ◽  
Patricio Más-Serrano ◽  
Marcos Diaz-Gonzalez ◽  
Maria Remedios Candela-Boix ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Predictive Performance ◽  
Stochastic Simulations ◽  
University Hospital ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Inflammatory Bowel ◽  
The Individual

Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.

Pharmacokinetics of sternal intraossesous atropine administration in normovolemic and hypovolemic swine

2016 ◽  
Vol 11 (4) ◽  
pp. 233-236
Author(s):  
Mark Cornell, MSN, CRNA ◽  
Jaime Kelbaugh, MSN, CRNA ◽  
Brian Todd, MSN, CRNA ◽  
Krista Christianson, MSN, CRNA ◽  
Kevin Grayson, DVM, PhD ◽  
...  
Keyword(s):  
Experimental Study ◽  
Plasma Concentration ◽  
Maximum Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Pharmacokinetic Parameters ◽  
Blood Samples ◽  
Absorption Phase ◽  
Distribution Phase ◽  
Study Setting

Objective: Characterize and compare the pharmacokinetics of atropine administered via the sternal intraosseous (IO) route in a normovolemic and hypovolemic swine model.Design: Prospective, experimental study. Setting: Vivarium.Subjects: Yorkshire-cross swine (N = 12).Intervention: Atropine was administered via the sternal IO route to normovolemic and hypovolemic swine. Blood samples were drawn at regular intervals after atropine administration and analyzed for plasma atropine concentration. Pharmacokinetic parameters were obtained from modeling the plasma concentrations.Main Outcome Measurements: Pharmacokinetic parameters, maximum concentration (Cmax), and time to maximum concentration (Tmax).Results: The normovolemic and hypovolemic models reached peak plasma concentration immediately and had a very rapid distribution phase with no apparent absorption phase for the IO groups. The hypovolemic group had slower clearance and longer half-life compared to the normovolemic group.Conclusion: The sternal IO route is an effective method of administering atropine and is comparable to the previously reported tibial IO and intravenous data even under conditions of significant hemorrhage.

Some Pitfalls in Selecting Descriptive Pharmacokinetic Models

1984 ◽  
Vol 18 (9) ◽  
pp. 708-713 ◽  
Author(s):  
Tom B. Vree ◽  
Yechiel A. Hekster ◽  
Marijn J.M. Oosterbaan ◽  
Emiel F.S. Termond
Keyword(s):  
Plasma Concentration ◽  
Renal Excretion ◽  
Parent Drug ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Models ◽  
Time Curve ◽  
Concentration Time ◽  
Two Compartment Model ◽  
Plasma Concentration Time Curve

Some pitfalls in selecting pharmacokinetic models are enumerated. To calculate the pharmacokinetic parameters of a drug that exhibits a biphasic convex plasma concentration-time curve, a two-compartment model does not automatically have to be applied. When only the parent drug in plasma is considered, a two-compartment model seems to be most appropriate. However, when the kinetic behavior of the metabolite has to be taken into account, and when a metabolic equilibrium underlies the metabolic elimination, the two-compartment model may not be appropriate. Also, when calculating the kinetic parameters of a drug with a concave biphasic plasma concentration-time curve, a capacity-limited metabolic conversion is not the automatic explanation for this observation. Limitations in renal excretion and bioavailability may be the reasons for this behavior. Convex and concave biphasic plasma concentration-time curves are illustrated, using sulfonamides as test compounds.

Dose Proportionality and Pharmacokinetics of Oral Transmucosal Fentanyl Citrate 

1998 ◽  
Vol 88 (2) ◽  
pp. 305-309 ◽  
Author(s):  
James B. Streisand ◽  
Michael A. Busch ◽  
Talmage D. Egan ◽  
Barbara Gaylord Smith ◽  
Mason Gay ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
Half Life ◽  
Maximum Concentration ◽  
Area Under The Curve ◽  
Supplemental Oxygen ◽  
Fentanyl Citrate ◽  
Oral Transmucosal Fentanyl Citrate ◽  
Concentration Time ◽  
Elimination Half ◽  
Dose Proportional

Background The pharmacokinetics of a single dose (15 microg/kg) of oral transmucosal fentanyl citrate (OTFC) have been characterized. A range of doses may eventually be used in clinical practice. The goal of this study was to determine if the pharmacokinetics of OTFC are dose proportional for doses ranging from 200 to 1,600 microg. Methods Twelve healthy male volunteers were studied on four different occasions, receiving 200, 400, 800, and 1,600 microg OTFC in a double-blind, randomized protocol. Venous blood samples were collected at selected times during and after dosing for a 24-h period and assayed for fentanyl using a radioimmunoassay. Maximum concentration, time to maximum concentration, area under the curve, and elimination half-life were determined for each dose administered. In addition, respiratory rate, need for verbal prompting to breathe, and supplemental oxygen requirements were noted. Results Mean fentanyl concentration time curves were similarly shaped with increasing doses. Both peak concentrations and area under the curve increased linearly with an increase in dose, whereas time to reach peak serum concentrations did not vary significantly between doses. Except for the 200-microg dose, the apparent elimination half-life remained relatively constant (358-386 min). The incidence of low respiratory rate, supplemental oxygen requirement, and number of breathing prompts significantly increased with increasing doses. Conclusions Oral transmucosal fentanyl citrate exhibits dose-proportional pharmacokinetics over the dose range of 200-1,600 microg.

scholarly journals A Rapid and Sensitive UHPLC-MS/MS Method for Determination of 2, 3, 8-Trimethylellagic, a Potent Active Compound from Sanguisorba officinalis L., and Its Application in the Pharmacokinetic Study within Thrombocytopenia Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yuqing Wang ◽  
Jianming Wu ◽  
Yunxia Li ◽  
Jing Yang ◽  
Long Wang ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Maximum Concentration ◽  
High Performance ◽  
Internal Standard ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Relative Standard ◽  
Plasma Concentration Time Curve

To investigate the pharmacokinetics of 2, 3, 8-trimethylellagic (TMEA) in rats in vivo and determine the possible effects of the pathological conditions and compatibility, a rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantitative determination was developed. TMEA and Artemetin (internal standard, IS) were separated on an Acquity Shim-pack GIST column with a total running time of 7 min using gradient elution at a flow rate of 0.3 mL/min. The intraday and interday relative standard deviations were <9.50%, and the relative error of accuracy was between −5.70% and 2.96%. The calibration curve of TMEA demonstrated good linearity with r2 = 0.9996, with the average recovery changing from 94.77% to 102.47% and the matrix effect from 93.16% to 100.15%. Compared with the normal group, the area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration (AUC(0 − t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0 − ∞)), and the maximum concentration (Cmax) of TMEA increased, whereas the time of maximum concentration (Tmax) and apparent clearance (CL/F) remarkably decreased in the TMEA group. With significantly reduced CL/F, AUC(0 − t), AUC(0 − ∞), and Cmax for TMEA were increased approximately one time after combining with 3, 7-Di-O-methylducheside A (DOMA). AUC(0 − t) and Cmax for TMEA in the 2, 3, 8-trimethylellagic-3, 8-dimethoxyellagic acid-2-oxyglucoside (TMEA-DMAG) group were significantly lower than that in the TMEA group with clearly prolonged Tmax and increased CL/F. These findings indicate that the changes in the pharmacokinetic parameters of TMEA may be caused by pathological and combination conditions.

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