Biomedical subjects

Stefan Willmann

Publications and source records attributed to Stefan Willmann.

9 recordsLinked to original sources

PubMed2006

A mechanistic approach for the scaling of clearance in children.

BACKGROUND AND OBJECTIVE: Clearance is an important pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Accurate clearance scaling to children requires prior knowledge of adult clearance mechanisms and the age-dependence of physiological and enzymatic development. The objective of this research was to develop and evaluate ontogeny models that would provide an assessment of the age-dependence of clearance. METHODS: Using in vitro data and/or in vivo clearance values for children for eight compounds that are eliminated primarily by one process, models for the ontogeny of renal clearance, cytochrome P450 (CYP) 3A4, CYP2E1, CYP1A2, uridine diphosphate glucuronosyltransferase (UGT) 2B7, UGT1A6, sulfonation and biliary clearance were developed. Resulting ontogeny models were evaluated using six compounds that demonstrated elimination via multiple pathways. The proportion of total clearance attributed to each clearance pathway in adults was delineated. Each pathway was individually scaled to the desired age, inclusive of protein-binding prediction, and summed to generate a total plasma clearance for the child under investigation. The paediatric age range included in the study was premature neonates to sub-adults. RESULTS: There was excellent correlation between observed and predicted clearances for the model development (R2 = 0.979) and test sets (Q2 = 0.927). Clearance in premature neonates could also be well predicted (development R2 = 0.951; test Q2 = 0.899). CONCLUSION: Paediatric clinical trial development could greatly benefit from clearance scaling, particularly in guiding dosing regimens. Furthermore, since the proportion of clearance via different elimination pathways is age-dependent, information could be gained on the developmental extent of drug-drug interactions.

Aging↗

PubMed2006

Development and evaluation of a generic physiologically based pharmacokinetic model for children.

BACKGROUND: Clinical trials in children are being encouraged by regulatory authorities in light of the immense off-label and unlicensed use of drugs in the paediatric population. The use of in silico techniques for pharmacokinetic prediction will aid in the development of paediatric clinical trials by guiding dosing regimens, ensuring efficient blood sampling times, maximising therapeutic effect and potentially reducing the number of children required for the study. The goal of this study was to extend an existing physiologically based pharmacokinetic (PBPK) model for adults to reflect the age-related physiological changes in children from birth to 18 years of age and, in conjunction with a previously developed age-specific clearance model, to evaluate the accuracy of the paediatric PBPK model to predict paediatric plasma profiles. METHODS: The age-dependence of bodyweight, height, organ weights, blood flows, interstitial space and vascular space were taken from the literature. Physiological parameters that were used in the PBPK model were checked against literature values to ensure consistency. These included cardiac output, portal vein flow, extracellular water, total body water, lipid and protein. Five model compounds (paracetamol [acetaminophen], alfentanil, morphine, theophylline and levofloxacin) were then examined by gathering the plasma concentration-time profiles, volumes of distribution and elimination half-lives from different ages of children and adults. First, the adult data were used to ensure accurate prediction of pharmacokinetic profiles. The model was then scaled to the specific age of children in the study, including the scaling of clearance, and the generated plasma concentration profiles, volumes of distribution and elimination half-lives were compared with literature values. RESULTS: Physiological scaling produced highly age-dependent cardiac output, portal vein flow, extracellular water, total body water, lipid and protein values that well represented literature data. The pharmacokinetic profiles in children for the five compounds were well predicted and the trends associated with age were evident. Thus, young neonates had plasma concentrations greater than the adults and older children had concentrations less than the adults. Eighty-three percent, 97% and 87% of the predicted plasma concentrations, volumes of distribution and elimination half-lives, respectively, were within 50% of the study reported values. There was no age-dependent bias for term neonates to 18 years of age when examining volumes of distribution and elimination half-lives. CONCLUSION: This study suggests that the developed paediatric PBPK model can be used to scale pharmacokinetics from adults. The accurate prediction of pharmacokinetic parameters in children will aid in the development of dosing regimens and sampling times, thus increasing the efficiency of paediatric clinical trials.

Adolescent↗

PubMed2005

Measurement of the coagulation dynamics of bovine liver using the modified microscopic Beer-Lambert law.

BACKGROUND AND OBJECTIVES: During heating, the optical properties of biological tissues change with the coagulation state. In this study, we propose a technique, which uses these changes to monitor the coagulation process during laser-induced interstitial thermotherapy (LITT). STUDY DESIGN/MATERIALS AND METHODS: Untreated and coagulated (water bath, temperatures between 35 degrees C and 90 degrees C for 20 minutes.) samples of bovine liver tissue were examined using a Nd:YAG (lambda = 1064 nm) frequency-domain reflectance spectrometer. We determined the time integrated intensities (I(DC)) and the phase shifts (Phi) of the photon density waves after migration through the tissue. From these measured quantities, the time of flight (TOF) of the photons and the absorption coefficients of the samples were derived using the modified microscopic Beer-Lambert law. RESULTS: The absorption coefficients of the liver samples decreased significantly with the temperature in the range between 50 degrees C and 70 degrees C. At the same time, the TOF of the investigated photos was found increased indicating an increased scattering. The coagulation dynamics could be well described using the Arrhenius formalism with the activation energy of 106 kJ/mol and the frequency factor of 1.59 x 10(13)/second. CONCLUSIONS: Frequency-domain reflectance spectroscopy in combination with the modified microscopic Beer-Lambert (MBL) is suitable to measure heat induced changes in the absorption and scattering properties of bovine liver in vitro. The technique may be used to monitor the coagulation dynamics during local thermo-coagulation in vivo.

Algorithms↗

PubMed2005

From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools.

During the past decade, the pharmaceutical industry has invested considerably in technologies that have the potential to increase throughput in discovery projects. For large compound libraries, efficacy, availability and safety should be determined as early and as reliably as possible. The latest step in this effort is the implementation of in silico methods that combine and interpret (sometimes replace) experimental in vitro data. For ADME properties (absorption, distribution, metabolism and excretion) rational predictive models have been developed that rely on basic physicochemical input data and on mechanistic descriptions of the underlying biophysical and biochemical processes. Some of these models have become commercially available (e.g., GastroPlus: Simulations Plus; PK-Map, PK-Sim: Bayer Technology Services). The contribution of such models to an optimised research and development process will be discussed.

Animals↗

PubMed2004

A physiological model for the estimation of the fraction dose absorbed in humans.

A physiologically based model for gastrointestinal transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (F(abs)) of both neutral and ionizable compounds on the two main physicochemical input parameters (the intestinal permeability coefficient (P(int)) and the solubility in the intestinal fluids (S(int))) as well as physiological parameters such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between F(abs) and P(int). In case of solubility-limited absorption, the model enables calculation of the critical mass-solubility ratio, which defines the onset of nonlinearity in the response of fraction absorbed to dose. In addition, an analytical equation to calculate the intestinal permeability coefficient based on the compound's membrane affinity and molecular weight was used successfully in combination with the physiologically based pharmacokinetic (PB-PK) model to predict the human fraction dose absorbed of compounds with permeability-limited absorption. Cross-validation demonstrated a root-mean-square prediction error of 7% for passively absorbed compounds.

Algorithms↗

PubMed2004

Glucose quantification in dried-down nanoliter samples using mid-infrared attenuated total reflection spectroscopy.

The aim of this study was to determine the feasibility of minimally invasive glucose concentration measurement of a body fluid within the physiologically important range below 100 nL with a number of samples such as interstitial fluid, plasma, or whole blood using mid-infrared spectroscopy, but starting with preliminary measurements on samples of simple aqueous glucose solutions. The Fourier transform infrared spectrometer was equipped with a Golden Gate single reflection diamond attenuated total reflection (ATR) accessory and a room-temperature pyroelectric detector. As the necessary detection limits can be achieved only for dried samples within the spectrometric conditions realized by a commercial instrument, the work focused on the optimization of such ATR measurements. We achieved quantification of samples with volumes as low as 7 nL between 10 and 600 mg/dL. The standard error of prediction (SEP) for the concentration range 10-100 mg/dL is 3.2 mg/dL with full interval data between 1180 and 940 cm(-1). The performance of the prediction is given by a coefficient of variation of prediction (CV(pred) ) of 6.2%. When all samples within the whole concentration range are included, the SEP increases to 20.2 mg/dL, and hence the CV(pred) to 10.6% due to a nonlinear signal dependence on glucose concentration. A detection limit for glucose of 0.7 ng with a signal-to-noise ratio of 10 was obtained.

Glucose↗

PubMed2003

A physiologic model for simulating gastrointestinal flow and drug absorption in rats.

PURPOSE: The development of a physiologically based absorption model for orally administered drugs in rats is described. METHODS: Unlike other models that use a multicompartmental approach, the GI tract is modeled as a continuous tube with spatially varying properties. The mass transport through the intestinal lumen is described via an intestinal transit function. The only substance-specific input parameters of the model are the intestinal permeability coefficient and the solubility in the intestinal fluid. With this physiologic and physicochemical information, the complete temporal and spatial absorption profile can be calculated. RESULTS: A first performance test using portal concentration data published in the literature yielded an excellent agreement between measured and simulated temporal absorption profiles in the portal vein. Furthermore, the dose dependence of a compound with solubility-limited fraction dose absorbed in rats (chlorothiazide) could be adequately described by the model. CONCLUSIONS: The continuous absorption model is well suited to simulate drug flow and absorption in the GI tract of rats.

Animals↗

PubMed2003

Small-volume frequency-domain oximetry: phantom experiments and first in vivo results.

We describe a new method to determine the oxygen saturation and the total hemoglobin content of tissue in vivo absolutely at small source-detector separations (<10 mm). Phase and mean intensity of modulated laser light of various wavelengths was measured at several predetermined source-detector separations in the frequency domain. From these measured quantities, the absorption coefficient was derived using the modified time-integrated microscopic Beer-Lambert law (MBL). In addition, the interaction volume of the photons was determined using a multi-layer Monte-Carlo model of human skin. To evaluate the method, we employed homogenous solid phantoms (consisting of TiO2 particles embedded in resin) with mean scattering and absorbing properties comparable to those of human skin. Furthermore, in vivo measurements were performed in a healthy volunteer to demonstrate that the technique is applicable for the determination of the oxygen saturation and the total hemoglobin content in the skin in vivo. The proposed technique is especially suited for the on-line determination of the oxygen saturation and total hemoglobin content in applications where small applicators are required (e.g., fetal oxygen monitoring sub partu).

Algorithms↗

PubMedDate not supplied

Application of physiology-based pharmacokinetic and pharmacodynamic modeling to individualized target-controlled propofol infusions.

This study compared the ability of the physiology-based pharmacokinetic (PBPK) model with that of compartmental models used in propofol infusion devices to predict the pharmacokinetics and pharmacodynamics of propofol in various patient groups (children, pregnant women, young men, normal weight adults, and obese adults). With a PBPK model, loss of consciousness (LOC) and recovery of consciousness (ROC) corresponded to a narrow range of brain tissue concentrations (2.2-4.0 mg/L). With the compartmental models, predicted effect concentrations were also within a narrow range at LOC, but were outside the range at ROC. In individuals of normal weight, coefficients of variation (CV) of the predicted brain or effect concentrations at LOC were in a similar range-between 18% and 32%. In obese individuals, however, interindividual CV values for brain or effect concentrations were 41% (PBPK) and 93% (compartmental). This comparison suggests the increased flexibility of PBPK models over compartmental models, the latter of which rely heavily on the patient group from which the model was derived. The incorporation of PBPK models may provide target-controlled infusions with enhanced ability to predict response in a wide variety of patients.

Adult↗