Rubin et al., 2006

% Prince et al., 2009

\$ Steele et al., 2011

& first time in Man

Table 3. Comparison of oral clinical pharmacokinetics of Pracinostat with hydroxamic acid HDAC inhibitors

## **6. Conclusions**

The clinical use of the less potent short chain fatty acid HDACi (PB, SP and sodium valproate) in cancer patients was limited by the requirement of high doses and short halflife. The cyclic peptide drug Depsipeptide had to be administered intravenously because of poor solubility and oral bioavailability. The most clinically advanced hydroxamic acid HDACi such as Zolinza, Belinostat and Panabinostat were initially administered IV in patients owing to their poor solubility and oral bioavailability in preclinical species. Formulations were subsequently developed for oral administration. We succeeded in designing the hydroxamic acid pan HDACi Pracinostat (SB939) which had high solubility and permeability, with superior preclinical ADME and PK/PD properties when compared to the other hydroxamic acid HDACi, which subsequently helped to achieve pharmacologically active exposures upon oral dosing in cancer patients.

## **7. References**

[1] van de Waterbeemd H and Gifford E. 2003. ADMET IN SILICO MODELLING: TOWARDS PREDICTION PARADISE? *Nat Rev Drug Disc* 2:192-204

In summary, the superior preclinical ADME of Pracinostat over Zolinza, Panabinostat and

Vorinostat (SAHA)#

Dosage regimen thrice weekly once daily thrice weekly once daily

inf(ng.h/mL) 1226(3.4µM) 1716 (6.5 µM) 183(0.54 µM) 2767 (8.7 µM)

FTIM dose was given IV due to poor F in preclinical species.

Table 3. Comparison of oral clinical pharmacokinetics of Pracinostat with hydroxamic acid

The clinical use of the less potent short chain fatty acid HDACi (PB, SP and sodium valproate) in cancer patients was limited by the requirement of high doses and short halflife. The cyclic peptide drug Depsipeptide had to be administered intravenously because of poor solubility and oral bioavailability. The most clinically advanced hydroxamic acid HDACi such as Zolinza, Belinostat and Panabinostat were initially administered IV in patients owing to their poor solubility and oral bioavailability in preclinical species. Formulations were subsequently developed for oral administration. We succeeded in designing the hydroxamic acid pan HDACi Pracinostat (SB939) which had high solubility and permeability, with superior preclinical ADME and PK/PD properties when compared to the other hydroxamic acid HDACi, which subsequently helped to achieve

[1] van de Waterbeemd H and Gifford E. 2003. ADMET IN SILICO MODELLING: TOWARDS PREDICTION PARADISE? *Nat Rev Drug Disc* 2:192-204

pharmacologically active exposures upon oral dosing in cancer patients.

Dose (mg) 60 400 20 250 t1/2(h) 7-9 0.8-3.9 16 1.5

Panabinostat (LBH589)%

FTIM dose was given IV due to poor F in preclinical species. Limited exposure.

Belinostat (PXD101)\$

FTIM dose was given IV due to poor F in preclinical species. Poor PK/PD

Belinostat was translated into the clinic.

Parameter Pracinostat

Recommended

AUC0-

Remarks

\* Yong et al., 2011 # Rubin et al., 2006 % Prince et al., 2009 \$ Steele et al., 2011 & first time in Man

HDAC inhibitors

**6. Conclusions** 

**7. References** 

(SB939)\*

Orally active exposures achieved at FTIM&. Best-inclass profile.


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**Part 2** 

**Anti-Infectives** 

