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Pharmacokinetic Modeling to Assess Factors Affecting the Oral Bioavailability of the Lactone and Carboxylate Forms of the Lipophilic Camptothecin Analogue AR-67 in Rats

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ABSTRACT

Purpose

Camptothecin analogues are anticancer drugs effective when dosed in protracted schedules. Such treatment is best suited for oral formulations. AR-67 is a novel lipophilic analogue with potent efficacy in preclinical models. Here we assessed factors that may influence its oral bioavailability in rats.

Methods

Plasma pharmacokinetic (PK) studies were conducted following administration of AR-67 lactone or carboxylate doses alone or after pre-dosing with inhibitors of the efflux transporters P-gp and Bcrp. A population PK model that simultaneously fitted to oral and intravenous data was used to estimate the bioavailability (F) and clearance of AR-67.

Results

An inverse Gaussian function was used as the oral input into the model and provided the best fits. Covariate analysis showed that the bioavailability of the lactone, but not its clearance, was dose dependent. Consistent with this observation, the bioavailability of AR-67 increased when animals were pretreated orally with GF120918 or Zosuquidar.

Conclusion

Absorption of AR-67 is likely affected by solubility of its lactone form and interaction with efflux pumps in the gut. AR-67 appears to be absorbed as the lactone form, most likely due to gastric pH favoring its formation and predominance. F increased at higher doses suggesting saturation of efflux mechanisms.

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Abbreviations

AUC:

area under the plasma concentration versus time curve

BCRP/bcrp:

breast cancer resistance protein

OATP/Oatp:

organic anion transporting polypeptide

P-gp:

p-glycoprotein

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Acknowledgments & Disclosures

This work was supported in part by the National Institutes of Health (CA123867) and research grants from Arno Therapeutics.

Markos Leggas and Bradley D. Anderson have received research funding from Arno Therapeutics. The authors disclose no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, 40536, USA

    Eyob D. Adane, Zhiwei Liu, Tian-Xiang Xiang, Bradley D. Anderson & Markos Leggas

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  1. Eyob D. Adane
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  2. Zhiwei Liu
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  5. Markos Leggas
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Correspondence to Markos Leggas.

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Adane, E.D., Liu, Z., Xiang, TX. et al. Pharmacokinetic Modeling to Assess Factors Affecting the Oral Bioavailability of the Lactone and Carboxylate Forms of the Lipophilic Camptothecin Analogue AR-67 in Rats. Pharm Res 29, 1722–1736 (2012). https://doi.org/10.1007/s11095-011-0617-0

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