Applications and Areas of Expertise
Xemet is continuously developing advanced methods, algorithms and software for more accurate and efficient computing and simulation of chemical and biological phenomena.
We have developed mathematical models and simulation software for example for…
- PBPK (Physiology Based Pharmacokinetics), more…
- Skin absorption/permeation, more…
- Controlled release, more…
- Blood-brain-barrier, more…
- Plasma protein binding, including drug-drug interaction, more…
- Neuronal receptor dynamics, more…
- Cell culture simulation, more...
Our customers include pharma, biomedicine, personal care, dermatology, cosmetics and chemical companies.
Physiology Based Pharmacokinetic (PBPK) simulation
Xemet provides Physiology Based Pharmacokinetic (PBPK) simulation services and PBPK-in-Silico™ software for prediction of absorption, distribution, metabolism and excretion (ADME) of drugs and other chemicals both in the human and animal body. Since general purpose PBPK software is often too cumbersome and cannot handle some of the customers’ proprietary systems, we tailor PBPK models and software to the customers’ exact needs, thus enhancing the accuracy for the relevant phenomena and tissues.
A typical system for human PBPK is presented in the Figure
PBPK simulation can be integrated with various administration routes like injection, oral administration, inhalation or skin contact, for one or repeated doses, or controlled release.
The results of the simulation include concentrations and total amounts in plasma, in the specified organs/tissues and in urine as a function of time. This information is necessary in drug development, but also in risk assessment of personal care products, cosmetics, household chemicals and industrial chemicals (exposure assessment required by REACH legislation in the EU). Development of functional foods and drinks will also benefit from such information.
See an example of our PBPK simulation of radiolabeled monoclonal antibodies (download article) (497.9 KB) .
PBPK models and simulation software can be adapted to different species. Thus it is useful for interspecies extrapolation.
Animal PBPK is an emerging tool for development of animal health products and for optimizing their formulations and dosing. As an example, Xemet has developed a local PBPK model and simulation software for a cow’s udder. The respective simulation software is available for licensing. The software can be used for studying milk and tissue concentrations of antibiotics after intramammary administration, and optimizing the dosing (amount and schedule).
Skin simulation is an invaluable tool for development of transdermal and dermal drugs, skin care products, and cosmetics and is increasingly used in risk assessment of industrial and household chemicals.
Xemet is the leading provider of skin simulation services and software for prediction of absorption and permeation of single chemicals and formulations into and through the skin both in vitro and in vivo.
Simulation can predict the absorption of the active compounds and solvent/vehicle into the skin and consequent diffusion through the skin and into the reception fluid (in vitro) or clearance into blood from the dermis (in vivo).
The results include time profiles of the following, both for the active compound and the solvent/vehicle
- concentration gradients in each layer of the skin
- average concentrations and total amounts remaining in the dose, in each layer of skin and in the reception fluid (in vitro) or in blood (in vivo)
- fluxes through the skin sample and into the systemic circulation
Many other results, such as the AUC (area under the concentration curve), can be calculated from the concentration curves and fluxes.
Simulation provides more information than in vitro or in vivo testing in a fraction of the time, for example a 48 hour test can be simulated in a few seconds. It also provides information which is difficult or impossible to measure with experimental methods.
The following software are available for licensing:
- Skin-in-Silico™ 4.0 a for simulation of absorption and permeation in vivo
- Skin-in-Silico™ 4.0 b for simulation of absorption and permeation in vitro (Franz cell experiments)
Xemet has considerable experience in modeling and simulation of controlled release of drugs or other chemicals from a polymer matrix. The controlled release administration includes oral capsules, implants, patches (on the skin) etc. The models cover transient diffusion in the polymer and mass transfer from polymer surface to surrounding tissue. Controlled release can be integrated with PBPK simulation for prediction of plasma and tissue concentrations of the released drug. In the case of patches, skin simulation can be used to predict flux from the patch through skin into the systemic circulation.
The blood-brain-barrier (bbb) can prevent promising CNS drug candidates entering the brain. As there are no reliable in vitro models for bbb, and in vivo measurements are difficult and cannot be done with humans, it is important to have an alternative method for predicting transport through bbb and the resulting brain concentration.
Xemet has a developmental software for simulation of passive diffusion and active transport (influx/efflux transporters) through bbb, which can be integrated with PBPK simulation. Metabolism in the liver and brain are included. This β-version of the B3-(PBPK)-in-Silico™ software can be further elaborated and modified to customers’ specific needs.
Example of the simulation results obtained with B3-(PBPK)-in-Silico™ simulation software. Plasma and brain concentration of L-dopa (used in the treatment of Parkinson’s disease) after oral administration.
It is seen that a high protein diet could reduce the brain concentration by 50%.
Plasma-protein binding, including drug-drug interaction
Xemet has developed a mathematical model for prediction of plasma protein binding for proteins with two binding sites and two drugs with competitive displacement. We also have experience in modeling the binding of sex hormones to SHBG.
These binding phenomena should be included in PBPK models, since the protein binding can be a dominating factor in pharmacokinetics.
The variation of the plasma protein concentration can be included in the models, if the concentration has circadian and other rhythms or other type of variation, like increase/decrease due to the presence of the drug in plasma.
Neuronal receptor dynamics
Xemet has experience in developing mathematical models for receptor dynamics.
Such models can predict for example the populations of the receptors in different stages or the probability that a receptor is in a certain stage as a function of substrate concentrations.
For example by using the simplified stochiometric model for acetylcholine receptor stages (as shown in the upper Figure) the population/probabilities of different stages of ACh receptors as a function of ACh concentration can be calculated (results shown in the Figure below).
The realistic models are much more complicated and require considerable modeling expertise.
Xemet can develop such models and simulation software for specific systems on request.
Stem cell culture simulation and SCC-in-Silico™ software for prediction and control of proliferation and differentiation of stem cell cultures.
Stem cells are being cultivated for several purposes, either for keeping them in an undifferentiated state or for production of differentiated cells, such liver and heart cells and neurons. Prediction and control of such cell cultures is becoming an important area of expertise.
We have developed a mathematical model and simulation software for proliferation and differentiation of stem cell cultures. It is a beta-version which shall be further developed and tailor made to each customer's specific needs.
We also provide on request data analytics, computing and simulation services and tailor made software for these and other chemical and biological applications
Our services and software reduce the need for animal testing in development of drugs, personal care products and cosmetics and in risk assessment of industrial chemicals.