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In silico evaluation of gadofosveset pharmacokinetics in different population groups using the Simcyp ® simulator platform

View Article: PubMed Central - PubMed

ABSTRACT

Purpose: Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic distribution models are implemented in T1-weighted dynamic contrast-enhanced perfusion MRI for characterization of lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of drugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico modelling of pharmacokinetic properties of gadofosveset in different population groups through the application of physiologically-based pharmacokinetic models (PBPK) embedded in Simcyp® population pharmacokinetics platform.

Methods: Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp® simulator platform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of the recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese, renal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic pharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and estimation of ratio of geometric mean between healthy volunteers and the other population groups.

Results: Simcyp® predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic CL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and CL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in Cmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences regarding AUC when compared with healthy volunteers.

Conclusions: This work employed Simcyp® population pharmacokinetics platform in order to compute gadofosveset’s pharmacokinetic profiles through PBPK models and in silico clinical trials and evaluate possible differences between population groups. The approach showed promising results that could provide new insights regarding administration of contrast agents in special population cohorts. In silico pharmacokinetics could further be used for evaluating of possible toxicity, interpretation of MRI PK image maps and development of novel contrast agents.

No MeSH data available.


Contrast agent and PBPK model used in this study. (A) Chemical structure of gadofosveset. (B) Graphical representation of the min-PBPK model applied for gadofosveset from the Simcyp® simulator platform with hepatic clearance set to zero (x) and elimination occurring only from the systemic compartment through kidneys.
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Fig1: Contrast agent and PBPK model used in this study. (A) Chemical structure of gadofosveset. (B) Graphical representation of the min-PBPK model applied for gadofosveset from the Simcyp® simulator platform with hepatic clearance set to zero (x) and elimination occurring only from the systemic compartment through kidneys.

Mentions: Gadofosveset trisodium (Vasovist®, Ablavar®, Figure 1A) is a Gd-based contrast agent (GBCA) used in dynamic-contrast enhancement magnetic resonance image (DCE-MRI). The mechanism of action of GBCAs in DCE-MRI relies in the alteration of relaxation times of atoms within body tissues due to the paramagnetic behavior of Gd and the interaction with nearby hydrogen nuclei which shortens the longitudinal relaxation (T1) times of water in the local tissue and increases signal intensity on T1-weighted images (Gossuin et al. 2010). In DCE-MRI, depending on the distribution rate of the contrast agent in a specific organ lesion, several essential information are gathered such as transfer constant rates (ktrans, kep), extravascular extracellular space volume per unit volume of tissue (ve), blood plasma volume per unit volume of tissue (vp) and the concentration-time profile in a near-by artery (arterial input function, AIF) (Koh et al. 2011; Tofts et al. 1999). A main characteristic of gadofosveset is the reversible binding to endogenous serum albumin with a moderate affinity (Kd = 85 μΜ) which leads in a prolonged vascular residence time compared to non-protein binding contrast agents and also facilitates high resolution in arterial and venus images (Caravan et al. 2002). Gadofosveset, as DCE-MRI contrast agent, has been applied for diagnosis and characterization of brain and rectal tumors associating DCE-MRI calculated parameters with microvascularity and in particular, with angiogenesis related leakage for tumorous areas (Lambregts et al. 2013; Puig et al. 2013). The contrast agent also belongs to the category of blood-pool contrast agents for magnetic resonance angiography (MRA) in cases of peripheral vascular disease (PVD) or aortoiliac occlusive disease (AIOD) (Goyen 2008). As a DCE-MRI contrast agent, gadofosveset is available in US with approval from FDA (FDA 2011), whereas in EU, the European Commission issued a decision (EMA/854517/2011) to withdraw the marketing authorization for gadofosveset based on commercial reasons from marketing authorization holder (MAH) (EMA 2011).Figure 1


In silico evaluation of gadofosveset pharmacokinetics in different population groups using the Simcyp ® simulator platform
Contrast agent and PBPK model used in this study. (A) Chemical structure of gadofosveset. (B) Graphical representation of the min-PBPK model applied for gadofosveset from the Simcyp® simulator platform with hepatic clearance set to zero (x) and elimination occurring only from the systemic compartment through kidneys.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644137&req=5

Fig1: Contrast agent and PBPK model used in this study. (A) Chemical structure of gadofosveset. (B) Graphical representation of the min-PBPK model applied for gadofosveset from the Simcyp® simulator platform with hepatic clearance set to zero (x) and elimination occurring only from the systemic compartment through kidneys.
Mentions: Gadofosveset trisodium (Vasovist®, Ablavar®, Figure 1A) is a Gd-based contrast agent (GBCA) used in dynamic-contrast enhancement magnetic resonance image (DCE-MRI). The mechanism of action of GBCAs in DCE-MRI relies in the alteration of relaxation times of atoms within body tissues due to the paramagnetic behavior of Gd and the interaction with nearby hydrogen nuclei which shortens the longitudinal relaxation (T1) times of water in the local tissue and increases signal intensity on T1-weighted images (Gossuin et al. 2010). In DCE-MRI, depending on the distribution rate of the contrast agent in a specific organ lesion, several essential information are gathered such as transfer constant rates (ktrans, kep), extravascular extracellular space volume per unit volume of tissue (ve), blood plasma volume per unit volume of tissue (vp) and the concentration-time profile in a near-by artery (arterial input function, AIF) (Koh et al. 2011; Tofts et al. 1999). A main characteristic of gadofosveset is the reversible binding to endogenous serum albumin with a moderate affinity (Kd = 85 μΜ) which leads in a prolonged vascular residence time compared to non-protein binding contrast agents and also facilitates high resolution in arterial and venus images (Caravan et al. 2002). Gadofosveset, as DCE-MRI contrast agent, has been applied for diagnosis and characterization of brain and rectal tumors associating DCE-MRI calculated parameters with microvascularity and in particular, with angiogenesis related leakage for tumorous areas (Lambregts et al. 2013; Puig et al. 2013). The contrast agent also belongs to the category of blood-pool contrast agents for magnetic resonance angiography (MRA) in cases of peripheral vascular disease (PVD) or aortoiliac occlusive disease (AIOD) (Goyen 2008). As a DCE-MRI contrast agent, gadofosveset is available in US with approval from FDA (FDA 2011), whereas in EU, the European Commission issued a decision (EMA/854517/2011) to withdraw the marketing authorization for gadofosveset based on commercial reasons from marketing authorization holder (MAH) (EMA 2011).Figure 1

View Article: PubMed Central - PubMed

ABSTRACT

Purpose: Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic distribution models are implemented in T1-weighted dynamic contrast-enhanced perfusion MRI for characterization of lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of drugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico modelling of pharmacokinetic properties of gadofosveset in different population groups through the application of physiologically-based pharmacokinetic models (PBPK) embedded in Simcyp® population pharmacokinetics platform.

Methods: Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp® simulator platform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of the recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese, renal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic pharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and estimation of ratio of geometric mean between healthy volunteers and the other population groups.

Results: Simcyp® predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic CL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and CL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in Cmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences regarding AUC when compared with healthy volunteers.

Conclusions: This work employed Simcyp® population pharmacokinetics platform in order to compute gadofosveset’s pharmacokinetic profiles through PBPK models and in silico clinical trials and evaluate possible differences between population groups. The approach showed promising results that could provide new insights regarding administration of contrast agents in special population cohorts. In silico pharmacokinetics could further be used for evaluating of possible toxicity, interpretation of MRI PK image maps and development of novel contrast agents.

No MeSH data available.