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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.


Related in: MedlinePlus

DCU nanosuspension SC dose plasma exposure simulation. Exposure versus cellular IC50 corrected for free fraction).
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Figure 6: DCU nanosuspension SC dose plasma exposure simulation. Exposure versus cellular IC50 corrected for free fraction).

Mentions: Modeling of the pharmacokinetic data was performed using the same in-house model (one compartment, first-order elimination) and revised to fit the in vivo data for SC dose. Based on the simulation, SC dosing of 30 mg/kg DCU nanosuspension once a day (s.i.d.) can provide continuous coverage of the plasma concentrations 0.2 μM (1 × cellular IC50 corrected for free fraction) and b.i.d. dose will cover 0.6 μM (3 × cellular IC50 corrected for free fraction) for target PK/PD (Figure 6). For the same coverage, the SC dose of the nanosuspension enabled a reduced total dose amount and frequency. This provides a welcomed advantage for a chronic dosing setting where a reduced burden to animals and manpower are desired. In addition, the significantly reduced plasma P/T ratio is less confounding for the interpretation of PK/PD relationships. When dosed s.i.d. via SC, a DCU plasma P/T ratio of 4 is expected (compare b.i.d oral P/T ratio of 25). When dosed b.i.d. via SC, a DCU plasma P/T ratio of less than 2 is expected (compare to t.i.d oral P/T ratio of >8). Our investigation with DCU provides an example of how nanosuspension can serve as a powerful formulation for the delivery of low solubility compounds in the preclinical setting. Based upon the positive results of our investigation, the continued use of nanosuspension to deliver low solubility compounds in preclinical PK/PD studies is expected.


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 SC dose plasma exposure simulation. Exposure versus cellular IC50 corrected for free fraction).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: DCU nanosuspension SC dose plasma exposure simulation. Exposure versus cellular IC50 corrected for free fraction).
Mentions: Modeling of the pharmacokinetic data was performed using the same in-house model (one compartment, first-order elimination) and revised to fit the in vivo data for SC dose. Based on the simulation, SC dosing of 30 mg/kg DCU nanosuspension once a day (s.i.d.) can provide continuous coverage of the plasma concentrations 0.2 μM (1 × cellular IC50 corrected for free fraction) and b.i.d. dose will cover 0.6 μM (3 × cellular IC50 corrected for free fraction) for target PK/PD (Figure 6). For the same coverage, the SC dose of the nanosuspension enabled a reduced total dose amount and frequency. This provides a welcomed advantage for a chronic dosing setting where a reduced burden to animals and manpower are desired. In addition, the significantly reduced plasma P/T ratio is less confounding for the interpretation of PK/PD relationships. When dosed s.i.d. via SC, a DCU plasma P/T ratio of 4 is expected (compare b.i.d oral P/T ratio of 25). When dosed b.i.d. via SC, a DCU plasma P/T ratio of less than 2 is expected (compare to t.i.d oral P/T ratio of >8). Our investigation with DCU provides an example of how nanosuspension can serve as a powerful formulation for the delivery of low solubility compounds in the preclinical setting. Based upon the positive results of our investigation, the continued use of nanosuspension to deliver low solubility compounds in preclinical PK/PD studies is expected.

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.


Related in: MedlinePlus