Limits...
Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery.

Chiang PC, Ran Y, Chou KJ, Cui Y, Wong H - Nanoscale Res Lett (2011)

Bottom Line: Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal.In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling.It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.

ABSTRACT
1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

No MeSH data available.


DCU nanosuspension oral dose simulation for PK/PD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3211509&req=5

Figure 4: DCU nanosuspension oral dose simulation for PK/PD.

Mentions: A prediction of the oral dose amount and frequency to cover different plasma concentrations were based on maintaining free fraction plasma concentrations of DCU (3% unbound) above a multiple of the cellular IC50 (6 nM) at the trough levels. Modeling of the pharmacokinetic data was performed using in-house model (1 compartment, first-order elimination), the pharmacokinetic parameters Vf (5.8 L), K01 (absorption rate constant, 26.3 h-1) and K10 (elimination rate constant, 0.277 h-1) were estimated [15]. Several concentrations were used as "target coverage" since PK/PD investigations often require a broad range of target coverage (i.e., from 0.25 × IC50 to 10 × IC50). Based on the simulation (figure 4), oral dosing of 30 mg/kg of DCU nanosuspension twice a day (b.i.d.) is needed to provide continuous coverage of the plasma concentrations of 0.2 μM (1 × cellular IC50 corrected for free fraction) and t.i.d. dosing will be needed to cover 0.6 μM (3 × cellular IC50 corrected for free fraction). The increase in dosing frequency in order to cover three time the cellular IC50 is one shortcoming for the oral dosing of DCU especially for chronic studies. An additional drawback of this design is the high plasma P/T ratio. Higher than needed exposure resulting from the high P/T ratio can result in unwanted side effects and confound the efficacy read out [29]. Thus, oral dosing DCU to obtain the PK/PD relationship remains less than ideal.


Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery.

Chiang PC, Ran Y, Chou KJ, Cui Y, Wong H - Nanoscale Res Lett (2011)

DCU nanosuspension oral dose simulation for PK/PD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3211509&req=5

Figure 4: DCU nanosuspension oral dose simulation for PK/PD.
Mentions: A prediction of the oral dose amount and frequency to cover different plasma concentrations were based on maintaining free fraction plasma concentrations of DCU (3% unbound) above a multiple of the cellular IC50 (6 nM) at the trough levels. Modeling of the pharmacokinetic data was performed using in-house model (1 compartment, first-order elimination), the pharmacokinetic parameters Vf (5.8 L), K01 (absorption rate constant, 26.3 h-1) and K10 (elimination rate constant, 0.277 h-1) were estimated [15]. Several concentrations were used as "target coverage" since PK/PD investigations often require a broad range of target coverage (i.e., from 0.25 × IC50 to 10 × IC50). Based on the simulation (figure 4), oral dosing of 30 mg/kg of DCU nanosuspension twice a day (b.i.d.) is needed to provide continuous coverage of the plasma concentrations of 0.2 μM (1 × cellular IC50 corrected for free fraction) and t.i.d. dosing will be needed to cover 0.6 μM (3 × cellular IC50 corrected for free fraction). The increase in dosing frequency in order to cover three time the cellular IC50 is one shortcoming for the oral dosing of DCU especially for chronic studies. An additional drawback of this design is the high plasma P/T ratio. Higher than needed exposure resulting from the high P/T ratio can result in unwanted side effects and confound the efficacy read out [29]. Thus, oral dosing DCU to obtain the PK/PD relationship remains less than ideal.

Bottom Line: Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal.In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling.It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.

ABSTRACT
1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

No MeSH data available.