Time Course Of Pharmacokinetics Research Articles

Use of Outpatient-Derived COVID-19 Convalescent Plasma in COVID-19 Patients Before Seroconversion.

BackgroundTransfusion of COVID-19 convalescent plasma (CCP) containing high titers of anti-SARS-CoV-2 antibodies serves as therapy for COVID-19 patients. Transfusions early during disease course was found to be beneficial. Lessons from the SARS-CoV-2 pandemic could inform early responses to future pandemics and may continue to be relevant in lower resource settings. We sought to identify factors correlating to high antibody titers in convalescent plasma donors and understand the magnitude and pharmacokinetic time course of both transfused antibody titers and the endogenous antibody titers in transfused recipients.MethodsPlasma samples were collected up to 174 days after convalescence from 93 CCP donors with mild disease, and from 16 COVID-19 patients before and after transfusion. Using ELISA, anti-SARS-CoV-2 Spike RBD, S1, and N-protein antibodies, as well as capacity of antibodies to block ACE2 from binding to RBD was measured in an in vitro assay. As an estimate for viral load, viral RNA and N-protein plasma levels were assessed in COVID-19 patients.ResultsAnti-SARS-CoV-2 antibody levels and RBD-ACE2 blocking capacity were highest within the first 60 days after symptom resolution and markedly decreased after 120 days. Highest antibody titers were found in CCP donors that experienced fever. Effect of transfused CCP was detectable in COVID-19 patients who received high-titer CCP and had not seroconverted at the time of transfusion. Decrease in viral RNA was seen in two of these patients.ConclusionOur results suggest that high titer CCP should be collected within 60 days after recovery from donors with past fever. The much lower titers conferred by transfused antibodies compared to endogenous production in the patient underscore the importance of providing CCP prior to endogenous seroconversion.

Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis.

BackgroundEthnic variability in the pharmacokinetics of organic anion transporting polypeptide (OATP) 1B1 substrates has been observed, but its basis is unclear. A previous study hypothesizes that, without applying an intrinsic ethnic variability in transporter activity, allele frequencies of transporters cannot explain observed ethnic variability in pharmacokinetics. However, this hypothesis contradicts the data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates.ObjectiveThe objective of this study is to evaluate a hypothesis that is physiologically reasonable and more consistent with clinical observations.MethodsWe evaluated if allele frequencies of two transporters (OATP1B1 and BCRP) are key contributors to ethnic variability. In this hypothesis, the same genotype leads to the same activity independent of ethnicity, in contrast to the previous hypothesis of intrinsic ethnic variability in OATP1B1 activity. As a validation, we perform mechanistic pharmacokinetic modeling for SLCO1B1 (encoding OATP1B1) and ABCG2 (encoding BCRP) genotyped pharmacokinetic data from 18 clinical studies with healthy Caucasian and/or Asian subjects.ResultsSimulations based on the current hypothesis reasonably describe SLCO1B1 and ABCG2 genotyped pharmacokinetic time course data for five transporter substrates (atorvastatin, pitavastatin, pravastatin, repaglinide, and rosuvastatin) in Caucasian and Asian populations.ConclusionThis hypothesis covers the observations that can (e.g., ethnic differences in rosuvastatin pharmacokinetics) or cannot (e.g., lack of differences for pitavastatin pharmacokinetics) be explained by the previous hypothesis. It helps to characterize sources of ethnic variability and provides a foundation for predicting ethnic variability in transporter substrate pharmacokinetics.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0568-7) contains supplementary material, which is available to authorized users.

Pharmacokinetic Time Course Scaling of a Subcutaneously Administered Pegylated Peptide Conjugate for a First-in-Human Investigation

Predicting absorption of macromolecules in humans following subcutaneous administration is complicated by interspecies differences in skin anatomy. The objective of this research was to test the hypothesis that an empiric relationship exists between non-human primates (NHPs) and humans in the absorption of a subcutaneously administered macromolecule which was then used to predict the time course of a pegylated peptide conjugate for planning of a first-in-human investigation. Concentration data obtained from NHPs receiving intravenous and subcutaneous doses of a novel pegylated peptide conjugate were fit to a pharmacokinetic model. The model was then scaled to a virtual population of humans through incorporation of allometric scaling factors on clearance, volume and first-order rate absorption processes. Several scenarios of simulated data were compared with observed data obtained from a first-in-human investigation. NHP data were best described by a 2-compartment model with dual-parallel, first-order absorption processes, one of which exhibited a lag time. Empirically selected scaling factors, assuming an inverse relationship of body weight and absorption provided reasonable prediction of the peptide's time course in plasma. Employing fitted exponents based on observed human data improved the fit somewhat, however, did not correct entirely for over prediction observed with the empiric exponents. For macromolecules where the absorption can be described by first-order rate processes, an assumption of an inverse relationship in species size may predict the time course after subcutaneous administration and may support optimal study design for a first-in-human investigation.

Diffusion properties of conventional and calcium‐sensitive MRI contrast agents in the rat cerebral cortex

Calcium-sensitive MRI contrast agents can only yield quantitative results if the agent concentration in the tissue is known. The agent concentration could be determined by diffusion modeling, if relevant parameters were available. We have established an MRI-based method capable of determining diffusion properties of conventional and calcium-sensitive agents. Simulations and experiments demonstrate that the method is applicable both for conventional contrast agents with a fixed relaxivity value and for calcium-sensitive contrast agents. The full pharmacokinetic time-course of gadolinium concentration estimates was observed by MRI before, during and after intracerebral administration of the agent, and the effective diffusion coefficient D* was determined by voxel-wise fitting of the solution to the diffusion equation. The method yielded whole brain coverage with a high spatial and temporal sampling. The use of two types of MRI sequences for sampling of the diffusion time courses was investigated: Look-Locker-based quantitative T(1) mapping, and T(1) -weighted MRI. The observation times of the proposed MRI method is long (up to 20 h) and consequently the diffusion distances covered are also long (2-4 mm). Despite this difference, the D* values in vivo were in agreement with previous findings using optical measurement techniques, based on observation times of a few minutes. The effective diffusion coefficient determined for the calcium-sensitive contrast agents may be used to determine local tissue concentrations and to design infusion protocols that maintain the agent concentration at a steady state, thereby enabling quantitative sensing of the local calcium concentration.

Pharmacokinetic timecourse from rodent GLP studies without disturbance to measured parameters or use of additional animals

Pharmacokinetic timecourse from rodent GLP studies without disturbance to measured parameters or use of additional animals

Pharmacokinetics screening for multi-components absorbed in the rat plasma after oral administration traditional Chinese medicine formula Yin-Chen-Hao-Tang by ultra performance liquid chromatography-electrospray ionization/quadrupole-time-of-flight mass spectrometry combined with pattern recognition methods

Traditional Chinese medicine (TCM) has been widely used in many oriental countries for thousands of years and played an indispensable role in the prevention and treatment of diseases, especially the complicated and chronic ones. It is a very complex mixture containing hundreds or thousands of different components. Pharmacokinetic study on active constituents in TCM preparations is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of TCM. A selective and sensitive method of ultra performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) was first developed to screen the potentially bioactive components in vivo, using the semi-quantitative determination of multicomponents in the rat plasma after a single oral administration of Yin-Chen-Hao-Tang (YCHT), a famous TCM formula for liver disorders. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were built to evaluate the differences of pharmacokinetic behaviors (time-course) of the absorbed components of YCHT. Here, we report that the developed method was successfully applied to monitoring the pharmacokinetic time-course of 21 compounds in rat plasma, and were grouped in 3 separate clusters using pattern recognition approaches (both HCA and PCA). Comparing the body dynamics of each composition, the initial choice of the following 9 compounds as the candidate components was: 7-methoxycoumarin-6-hydroxyl sulfate, genipingentiobioside, geniposide, 6,7-dimethylesculetin, peak 16, chimaphylin, 6-dementhoxycapillarisin, capillarisin, rhein. Pharmacokinetics based-UPLC-ESI-Q-TOF-MS/MS combined with HCA and PCA approaches can provide a reliable and suitable means of identifying and screening potentially bioactive components contributing to pharmacological effects of TCM, further prospecting natural products in the search for new leads in drug discovery.

A Pharmacokinetic Formalism Explicitly Integrating the Patient Drug Compliance

The adherence phenomenon is now well recognized to seriously compromise drug efficacy. In this paper, we analyze the role of compliance through drug intake history as an integral part of the pharmacokinetic process. Being concerned with what is accessible in medical practice, we develop a stochastic approach to model the drug intake behavior that we combine with a conventional pharmacokinetic model in order to investigate the effect of drug intake history on the pharmacokinetic time-course. For this purpose, we explicitly formalize the plasma concentration variations for the most common administration routes. This analytical approach allows to characterize drug concentration variations directly inherited from patient compliance.

Agreement of pesticide biomarkers between morning void and 24-h urine samples from farmers and their children

In pesticide biomonitoring studies, researchers typically collect either single voids or daily (24-h) urine samples. Collection of 24-h urine samples is considered the "gold-standard", but this method places a high burden on study volunteers, requires greater resources, and may result in misclassification of exposure or underestimation of dose due to noncompliance with urine collection protocols. To evaluate the potential measurement error introduced by single void samples, we present an analysis of exposure and dose for two commonly used pesticides based on single morning void (MV) and 24-h urine collections in farmers and farm children. The agreement between the MV concentration and its corresponding 24-h concentration was analyzed using simple graphical and statistical techniques and risk assessment methodology. A consistent bias towards overprediction of pesticide concentration was found among the MVs, likely in large part due to the pharmacokinetic time course of the analytes in urine. These results suggest that the use of single voids can either over- or under-estimate daily exposure if recent pesticide applications have occurred. This held true for both farmers as well as farm children, who were not directly exposed to the applications. As a result, single void samples influenced the number of children exposed to chlorpyrifos whose daily dose estimates were above levels of toxicologic significance. In populations where fluctuations in pesticide exposure are expected (e.g., farm families), the pharmacokinetics of the pesticide and the timing of exposure events and urine collection must be understood when relying on single voids as a surrogate for longer time-frames of exposure.

Determination of a thermally labile metabolite of a novel growth hormone secretagogue in human and dog plasma by liquid chromatography with ion spray tandem mass spectrometric detection

A sensitive and selective assay for the determination of N-{1( R)-[(1,2-dihydro-1-methylsulfonylspiro[3H-indole-3,4′-piperidin]-1′-yl)carbonyl]-2-(phenylmethoxy)-ethyl}-2-hydroxyamino-2-methylpropanamide ( I), a hydroxyl amine metabolite of a novel growth hormone secretagouge ( II) has been developed utilizing high-performance liquid chromatography with ion spray tandem mass spectrometric detection (HPLC–MS–MS). The analyte and an internal standard ( III) were isolated from the basified biological matrix using a liquid–liquid extraction with methyl tert.-butyl ether (MTBE). The organic extract was evaporated to dryness at room temperature. The residue was reconstituted in the mobile phase and injected into the HPLC–MS–MS system. Multiple reaction monitoring using the precursor→product ion combinations of m/ z 545→267 and 543 →267 was used to quantify I and III, respectively, after chromatographic separation under isocratic conditions. The assay was validated in the concentration range of 0.5 to 500 ng/0.1 ml in both human and dog plasma. The precision of the assay, expressed as relative standard deviation, was less than 10% over the entire concentration range with the exception of the low concentration of 0.5 ng/0.1 ml which was 14.0% for human plasma. The HPLC–MS–MS method provided sufficient sensitivity to completely map the pharmacokinetic time course of I following a single 5 mg dose of II to human subjects and a 0.5 mg/kg dose to beagle dogs.