Pharmacokinetic Analysis Method Research Articles

Bisoprolol: A comprehensive profile.

The present study describes a comprehensive profile of Bisoprolol including detailed nomenclature; formulae, elemental analysis, appearance, its uses, applications, and methods for the preparation are outlined. The profile contains physicochemical properties of Bisoprolol including pKa value, solubility, X-ray powder diffraction, and methods of analysis (including compendial, electrochemical, spectroscopic, chromatographic and capillary electrophoresis). The study also covers thermal analysis such as differential scanning calorimetry and thermogravimetry of Bisoprolol. Which gives a brief idea of melting point, glass transition as well as differentiation between anhydrous and hydrated forms. In addition to these functional groups and structural confirmation of bisoprolol also presented with the help of Fourier transform infrared spectrometry and nuclear magnetic resonance spectroscopy, respectively. The mass fragmentation pattern of bisoprolol fumarate was reported using the electrospray ionization technique. Some recently reported methods for pharmacokinetic analysis of bisoprolol using high-performance liquid chromatography as well as liquid chromatography-mass spectrometry were also included in the study.

Integrated UPLC-MS/MS and UHPLC-Q-orbitrap HRMS Analysis to Reveal Pharmacokinetics and Metabolism of Five Terpenoids from Alpiniae oxyphyllae Fructus in Rats.

Alpiniae oxyphyllae Fructus (AOF), a traditional Chinese medicine (TCM), is widely used in the treatment of urinary, gastrointestinal and neurologic diseases in China. Although terpenoids are the main active ingredients of AOF, there are few researches on their pharmacokinetics and metabolism. In this study, a sensitive, rapid, accurate and novel ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to evaluate the pharmacokinetic behavior of five terpenoids (oxyphyllenodiol B, (4S*,5E,10R*)-7-oxo-tri-nor-eudesm-5-en-4β-ol, 7-epi-teucrenone, (+)- (4R,5S,7R)-13-hydroxynootkatone, (E)-labda-12,14-dien-15(16)-olide-17-oic acid) in rats after oral administration of AOF extracts. 27 metabolic metabolites of the five terpenoids were identified by ultra high performance liquid chromatography -Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) based on precise mass and fragment ions. The established pharmacokinetic analysis method showed good linearity over a wide concentration range, and the lower quantitative limit (LLOQ) ranged from 0.97 to 4.25 ng/mL. Other validation parameters were within the acceptable range. In addition, 27 metabolites were identified in plasma, urine and feces samples, and the metabolic pathways of five terpenoids were mainly focused on glucoside conjugation, dehydration, desaturation and glycine conjugation. This is the first study on the pharmacokinetics and metabolism of five terpenoids in AOF, illuminating the disposal process of terpenoids in vivo. It was expected that the results of this study would provide some references for the apprehension of the action mechanism and the further pharmacological study of five terpenoids in AOF.

Analytical methodologies for measuring colistin levels in pharmacokinetic studies

Colistin is an old antibiotic reintroduced in response to an increased incidence of multi-resistant Gram-negative bacterial infections. It has a narrow therapeutic window, and dose optimization is required. Dose optimization requires accurate method of measurement. The goal of this manuscript is to review previously developed methods, their advantages and disadvantages, and problems to be addressed for colistin assay in pharmacokinetic studies. Articles published in English from December 2000 to 2019 were systematically searched using PubMed and Scopus. Reference lists of articles were reviewed to identify additional studies. A total of 220 articles were identified, 26 of which met the inclusion criteria in this review. Of those, six articles were found to contain relevant methods for pharmacokinetic analysis of colistin in subjects treated with colistimethate sodium. The report describes sample preparation techniques, analytical methods used for the determination, and quantification of colistimethate sodium and colistin, mobile phase use, and problems encountered. One of the greatest challenges in colistin bioanalysis is ensuring the stability of colistimethate sodium in vivo and in vitro prior analysis. This review also highlights the precautionary measures to minimize hydrolysis of colistimethate sodium during experiments.

In Vivo Pharmacokinetics Assessment of Indocyanine Green-Loaded Nanoparticles in Tumor Tissue with a Dynamic Diffuse Fluorescence Tomography System.

The purpose of this study was to show a systematic strategy for assessing the pharmacokinetics of indocyanine green (ICG)-loaded nanoparticles in the tumor tissue based on a dynamic diffuse fluorescence tomography (DFT) system. Twelve-seven-week-old male Balb/c nude mice bearing HepG2/ADR hepatocellular carcinoma were randomly divided into four groups (n= 3 per group). Four hundred microliters of three types of ICG-loaded nanoparticles (content of ICG: 50μg/ml) and free ICG (50μg/ml) was intravenously injected into the mice in each group, respectively. Afterwards, the real-time tomographic images on the spatial level were acquired at 2-11min, 30min, 1, 2, 3, 4, 6, 8, 10, 12, and 24h post-injection, and pharmacokinetic rates were derived for semi-quantitative assessment of the pharmacokinetics of nanoparticles at the tumor site using our proposed pharmacokinetic analysis method. The results obtained from our proposed dynamic DFT experiment demonstrated the distribution of different ICG formulations on the spatial level and enabled the semi-quantitative analysis of the pharmacokinetics of nanoparticles in the tumor tissue. The obtained pharmacokinetic rates effectively reflected the metabolic processes of nanoparticles in the tumor tissue, which proves to be beneficial for the development of tumor diagnosis and therapy.

Assessing indocyanine green pharmacokinetics in mouse liver with a dynamic diffuse fluorescence tomography system.

Fluorescence pharmacokinetic rates in tissues can provide additional specific and quantitative physiological and pathological information for evaluating organ function. This modality requires a highly sensitive diffuse fluorescence tomography (DFT) working in dynamic way to finally extract the pharmacokinetic rates from the measured pharmacokinetics-associated temporally varying boundary intensity, normally with the support of a priori anatomy. This paper is devoted to study pharmacokinetics of indocyanine green (ICG) in mouse liver based on synergistic dynamic-DFT and X-ray computer tomography (XCT): A highly sensitive dynamic DFT system of CT-scanning mode working with parallel 4 photomultiplier-tube photon-counting channels generates informative and instantaneous sampling datasets; An XCT system provides priori information of the target localization for improvement of the reconstruction quality; An analysis procedure extracts the pharmacokinetic rates from the reconstructed ICG concentration-time curves, using the Gauss-Newton scheme for fitting to a 2-compartment model. The uptake and excretion rates of ICG which were obtained in livers of 10 healthy mice in the in vivo experiments can be used to quantitatively evaluate liver function. The results can validate the effectiveness of both the imaging measurements system and pharmacokinetic analysis method.

Pharmacokinetics of the cannabinoid receptor ligand [18 F]MK-9470 in the rat brain - Evaluation of models using microPET.

The positron emission tomography ligand [18 F]MK-9470 is an inverse agonist that binds reversibly and with high affinity to the cannabinoid type 1 receptor. Due to its slow brain kinetics, care is required in the definition of its dissociation rates from the receptor. The goal of this study was to investigate pharmacokinetic analysis methods using an arterial input function. Five Sprague-Dawley rats received injections of 13 to 25 MBq of [18 F]MK-9470 and were scanned over a period of 90 min. Arterial blood samples were collected throughout the scan. Data were analyzed using four different compartmental models: a reversible one-tissue model, reversible two tissue models with and without parameter constraints and an irreversible two-tissue model. The outcome values were goodness of fit measures (Akaike information criterion; standard error), pharmacokinetic modeling parameters (volume of distribution; irreversible uptake constant) and intersubject variability. Goodness of fit measures indicated that the experimental data are more adequately described by a two-tissue model than a one-tissue model. Differences in mean Akaike information criterion values between all two-tissue models were < 5%. Mean standard errors of model parameters were lowest for the irreversible model (range: 1% to 6%). The irreversible model delivered plausible results for all animals that were less variable compared to results of the other two-tissue models. A reversible two-tissue model may not deliver stable results for all animals and regions within a 90-min microPET study protocol. Stable parameters for all animals and regions are obtained when an irreversible model is used. If the acquisition time of the experiment is limited, an irreversible model provides a consistent distribution of composite outcome parameters, suggesting its suitability for use in future studies.

In Vivo Quantification of ERβ Expression by Pharmacokinetic Modeling: Studies with 18F-FHNP PET.

The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERβ expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2-18F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (18F-FHNP) for assessment of ERβ levels with PET. In the current study, we investigated several pharmacokinetic analysis methods to quantify changes in ERβ availability with 18F-FHNP PET. Methods: Male nude rats were subcutaneously inoculated in the shoulder with ERα/ERβ-expressing SKOV3 human ovarian cancer cells. Two weeks after tumor inoculation, a dynamic 18F-FHNP PET scan with arterial blood sampling was acquired from rats treated with vehicle or various concentrations of estradiol (nonspecific ER agonist) or genistein (ERβ-selective agonist). Different pharmacokinetic models were applied to quantify ERβ availability in the tumor. Results: Irreversible-uptake compartmental models fitted the kinetics of 18F-FHNP uptake better than reversible models. The irreversible 3-tissue-compartment model, which included both the parent and the metabolite input function, gave results comparable to those of the irreversible 2-tissue-compartment model with only a parent input function, indicating that radioactive metabolites contributed little to the tumor uptake. Patlak graphical analysis gave metabolic rates (Ki, the irreversible uptake rate constant) comparable to compartment modeling. The Ki values correlated well with ERβ expression but not with ERα, confirming that Ki is a suitable parameter to quantify ERβ expression. SUVs at 60 min after tracer injection also correlated (r2 = 0.47; P = 0.04) with ERβ expression. A reduction in 18F-FHNP tumor uptake and Ki values was observed in the presence of estradiol or genistein. Conclusion:18F-FHNP PET enables assessment of ERβ availability in tumor-bearing rats. The most suitable parameter to quantify ERβ expression is the Ki However, a simplified static imaging protocol for determining the SUVs can be applied to assess ERβ levels.

Lack of Clinical Pharmacokinetic Studies to Optimize the Treatment of Neglected Tropical Diseases: A Systematic Review.

IntroductionNeglected tropical diseases (NTDs) affect more than one billion people, mainly living in developing countries. For most of these NTDs, treatment is suboptimal. To optimize treatment regimens, clinical pharmacokinetic studies are required where they have not been previously conducted to enable the use of pharmacometric modeling and simulation techniques in their application, which can provide substantial advantages.ObjectivesOur aim was to provide a systematic overview and summary of all clinical pharmacokinetic studies in NTDs and to assess the use of pharmacometrics in these studies, as well as to identify which of the NTDs or which treatments have not been sufficiently studied.MethodsPubMed was systematically searched for all clinical trials and case reports until the end of 2015 that described the pharmacokinetics of a drug in the context of treating any of the NTDs in patients or healthy volunteers.ResultsEighty-two pharmacokinetic studies were identified. Most studies included small patient numbers (only five studies included >50 subjects) and only nine (11 %) studies included pediatric patients. A large part of the studies was not very recent; 56 % of studies were published before 2000. Most studies applied non-compartmental analysis methods for pharmacokinetic analysis (62 %). Twelve studies used population-based compartmental analysis (15 %) and eight (10 %) additionally performed simulations or extrapolation. For ten out of the 17 NTDs, none or only very few pharmacokinetic studies could be identified.ConclusionsFor most NTDs, adequate pharmacokinetic studies are lacking and population-based modeling and simulation techniques have not generally been applied. Pharmacokinetic clinical trials that enable population pharmacokinetic modeling are needed to make better use of the available data. Simulation-based studies should be employed to enable the design of improved dosing regimens and more optimally use the limited resources to effectively provide therapy in this neglected area.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0467-3) contains supplementary material, which is available to authorized users.

The Principal of Dynamic Contrast Enhanced MRI, the Method of Pharmacokinetic Analysis, and Its Application in the Head and Neck Region

Many researchers have established the utility of the dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) in the differential diagnosis in the head and neck region, especially in the salivary gland tumors. The subjective assessment of the pattern of the time-intensity curve (TIC) or the simple quantification of the TIC, such as the time to peak enhancement (T peak) and the wash-out ratio (WR), is commonly used. Although the semiquantitative evaluations described above have been widely applied, they do not provide information on the underlying pharmacokinetic analysis in tissue. The quantification of DCE-MRI is preferable; therefore, many compartment model analyses have been proposed. The Toft and Kermode (TK) model is one of the most popular compartment models, which provide information about the influx forward volume transfer constant from plasma into the extravascular-extracellular space (EES) and the fractional volume of EES per unit volume of tissue is used in many clinical studies. This paper will introduce the method of pharmacokinetic analysis and also describe the clinical application of this technique in the head and neck region.

The pharmacokinetics of ceftriaxone based on population pharmacokinetics and the prediction of efficacy in Japanese adults

By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration. The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained. Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.

A method for pharmacokinetic modelling of dynamic contrast enhanced MRI studies of rapidly enhancing lesions acquired in a clinical setting

Abnormal microcirculation is a feature of many neoplastic and non-neoplastic diseases. Physiological variables that characterize tissue microcirculation (capillary permeability and the volume of the extravascular extracellular fluid) are altered in pathological states. Pharmacokinetic analysis of dynamic contrast enhanced MRI (DCE-MRI) has found a widespread use in the assessment of abnormal microcirculation due to the direct link between the contrast agent kinetics and underlying microcirculatory properties. A representation of temporal variation of contrast agent concentration in blood plasma (Cp(t)) is central to this analysis. In clinical applications of DCE-MRI, signal intensity curves derived from rapidly enhancing lesions often display a sigmoid shape during the initial phase of contrast uptake and rapid arrival at the equilibrium phase. In this work, the features of two principal methods for pharmacokinetic analysis of DCE-MRI which allow for theoretical representation of Cp(t) are examined and combined to improve analysis of this particular class of DCE-MRI curves. The proposed method allows the representation of the initial sigmoid part of the enhancement profiles whilst retaining a realistic representation of Cp(t) based on previously published measurements obtained in healthy volunteers. The results of the computer simulations indicate that in rapidly enhancing lesions, with the transfer constant Ktrans greater than 0.1 min−1, the DCE-MRI acquisition can be restricted to 5 min post-injection and a mono-exponential representation of Cp(t) decay is sufficient. Furthermore, non-ideal bolus delivery can be represented as a short constant rate infusion when the tissue under investigation exhibits a sigmoid pattern of contrast uptake.

Population one-compartment pharmacokinetic analysis with missing dosage data

Our objective was to develop a population 1-compartment pharmacokinetic (PK) method of analysis to deal with suspect or missing prior dosage history. Population PK data from a 1-compartment model with first-order elimination and absorption, described by PK parameters clearance, volume of distribution, and absorption rate constant, are simulated. A PK sample is drawn just before a test dose (Dt), followed by a (varying) number of additional samples over 1 interdose interval (tau). For 60% of the subjects, the true history of the scheduled dose (Ds) preceding Dt differs from that prescribed, whereas doses taken before Ds do not. Two settings are evaluated: considerable accumulation of drug in the body (typical drug half-life t1/2 approximately equal to tau) and very little such accumulation (t1/2 approximately equal to tau/5). Precision and bias of several PK analysis methods--Missing Dose Method (MDM), Missing Dose Mixture Method (MDMM) and Extrapolation-Subtraction Method (ESM), all of which essentially do not use prior dose history--are compared with those of the Prescribed Dose Method (PDM), which assumes nominal dosage, and an Ideal Method (IDM), which uses true (but unknown) pre-test dose history. At t1/2 approximately equal to tau, MDM and MDMM are the most precise methods. The accuracy of ESM and PDM is poor. At t1/2 approximately equal to tau/5, no significant differences, in terms of precision or bias, are observed between methods. Misspecification of the structural or statistical model seems not to influence these results. The results of analysis of a real (caffeine) data set are compatible with the findings from the simulations. When a test dose is given and a predose baseline observation is taken as part of an "intensive" PK study during outpatient therapy of a 1-compartment drug, an analysis that assumes that the nominal dose history is correct is not robust to past dosage history misspecification, whereas methods that do not do this are robust and reliable.

Liquid chromatographic–mass spectrometric quantitation of Δ 9-tetrahydrocannabinol and two metabolites in pharmacokinetic study plasma samples

A sensitive method for the determination of Δ 9-tetrahydrocannabinol and its metabolites, 11-nor-Δ 9-tetrahydrocannabinol-9-carboxylic acid and 11-hydroxy-Δ 9-tetrahydrocannabinol, in rat and guinea pig plasma was developed using high-performance liquid chromatographic separation with electrospray ionization mass spectrometry detection and a simple liquid–liquid extraction technique. The mean recoveries for Δ 9-tetrahydrocannabinol, 11-nor-Δ 9-tetrahydrocannabinol-9-carboxylic acid, and 11-hydroxy-Δ 9-tetrahydrocannabinol were 96, 92, and 85%, respectively. The lower limit of quantification (LLOQ) for all three compounds was 5 ng/ml and the limit of detection (LOD) was 2 ng/ml. This assay method utilizes the increased sensitivity and selectivity of mass spectrometric (MS) detection and a simple extraction step for the determination of Δ 9-tetrahydrocannabinol and its metabolites in plasma, and thus yields a more efficient pharmacokinetic analysis method than has previously been described.

Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients

1. 1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 ± 16.4 ng/ml were slightly lower than the other clozapine metabolite — desmethylclozapine (DCLOZ) plasma levels of 24.4 ± 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 ± 8.9 ng/ml vs 14.4 ± 8.8 ng/ml). 4. 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.

Do we need full compliance data for population pharmacokinetic analysis?

For population pharmacokinetic analysis of multiple oral doses one of the key issues is knowing as precisely as possible the dose inputs in order to fit a model to the input-output (dose-concentration) relationship. Recently developed electronic monitoring devices, placed on pill containers, permit precise records to be obtained over months, of the time/date opening of the container. Such records are reported to be the most reliable measurement of drug taking behavior for ambulatory patients. To investigate strategies for using and summarizing this new abundant information, a Markov chain process model was developed, that simulates compliance data from real data from electronically monitored patients, and data simulations and analyses were conducted. Results indicate that traditional population pharmacokinetic analysis methods that ignore actual dosing information tend to estimate biased clearance and volume and markedly overestimate random interindividual variability. The best dosing information summarization strategies consist of initially estimating population pharmacokinetic parameters, using no covariates and only a limited number of dose records, the latter chosen based on an a priori estimate of the half-life of the drug in the compartment of interest; then resummarizing the dose records using either population or individual posterior Bayes parameter estimates from the first population fit; and finally reestimating the population parameters using the newly summarized dose records. Such summarization strategies yield the same parameter estimates as using full dosing information records while reducing by at least 75% the CPU time needed for a population pharmacokinetic analysis.

Pharmacokinetics of Rocuronium in Children Aged 4???11 Years

Comment This investigation used two population-based pharmacokinetic analysis methods, mixed-effects modeling and naive pooled data analysis, to determine the pharmacokinetic variables for rocuronium. Rather than the two-stage approach, which uses frequent blood sampling, calculation of kinetic variables for each subject, and calculations of mean values, these methodologies analyze data from all subjects simultaneously to determine population kinetic values. Population methods have an advantage in that fewer samples (four samples per subject in this study) are required, which is advantageous for pediatric studies. The major finding was that rocuronium clearance was weight- (and presumably age-) dependent. Although absolute clearance increased with age, weight-normalized clearance was greater in children than adults and greatest in the smallest children. Thus, rocuronium elimination was fastest in the smallest children. Assuming rocuronium pharmacodynamics parallel the kinetics, recovery would also be fastest in the smallest children. Although not tested, these results suggest that higher doses of rocuronium may be used in smaller children, with the potential benefit of faster onset, without prolonging duration of effect compared with older children or adults. This hypothesis, however, remains to be tested.

徐放製剤のための薬物動態学的解析方法

徐放製剤のための薬物動態学的解析方法

Clinical pharmacokinetics of factor VIII in patients with classic haemophilia.

Studies of Factor VIII pharmacokinetics in haemophiliacs can be classified into 2 groups depending on whether single-dose or multiple-dose Factor VIII curves are used. This review analyses information published so far in both these areas, with particular emphasis on the choice of appropriate models for pharmacokinetic analysis. Single-dose studies of Factor VIII kinetics have previously used a wide variety of methods for pharmacokinetic analysis (empirical methods of Factor VIII level prediction, graphical techniques for semilog analysis, 1-compartment and 2-compartment models). However, Factor VIII poses unique problems to the pharmacokineticist because decay curves can be either monophasic (monoexponential) or biphasic (biexponential) for unknown reasons, and because Factor VIII concentrations are generally subject to significant assay error. Problems of compartmental analysis that occurred in previous studies are highlighted, and a model-independent non-compartmental approach for analysing Factor VIII curves is proposed. To date, fewer data have been published on multiple-dose kinetics of Factor VIII. From a clinical point of view, repeated-dose regimens are most commonly required in patients undergoing surgery and in patients with severe bleeding. A fairly well defined 'therapeutic window' of optimal Factor VIII plasma concentrations has been identified, particularly in surgical patients. This fact has spurred research aimed at applying to haemophilia patients the pharmacokinetic dosing methods commonly used for therapeutic monitoring of drugs (e.g. Bayesian method for dosage individualization). A few papers have already been published in this field, and this review summarises problems encountered by previous investigators, and evaluates comparatively the pharmacokinetic methods used.

Determinants of the diuretic response to furosemide in infants with congestive heart failure.

A wide interindividual variation in the degree of diuresis produced following treatment with furosemide has been observed in infants with congestive heart failure. A method of pharmacokinetic analysis that separates drug disposition from renal response to furosemide was used to compare the effect of this agent in infants with congestive heart failure with the effect seen in infants with fluid retention secondary to noncardiac factors. No differences in the drug elimination rate, urinary drug excretion, or renal diuretic response between the 2 groups were seen. Infants in both groups exhibited a wide range in all variables examined. The marked interindividual variation in response originates from decreased delivery of furosemide to its site of action in some patients and a decreased responsiveness to the drug in others.