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Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor Fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics

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Abstract

Purpose

This study evaluated the preclinical pharmacokinetics (PK) and disposition of Fruquintinib (HMPL-013), a small molecule vascular endothelial growth factor receptors inhibitor.

Methods

In vitro and in vivo PK/ADME assays were conducted. Allometry and PK modeling/simulation were conducted to predict human PK parameters and the time course profiles.

Results

HMPL-013 has high permeability without efflux. It shows moderate oral bioavailability of 42–53 % and T max < 4 h in mouse, rat, dog and monkey, with exposure-dose linearity proved in rats and dogs. No significant food effect is on dog PK. HMPL-013 has moderately high tissue distribution. It majorly distributes in gastrointestinal tract, liver, kidney, adrenal and adipose. The plasma protein binding fraction is 88–95 % in mouse, rat, dog and human, invariable up to 10 µM. The in vivo clearance of HMPL-013 is low, consistent with the in vitro scaling. Three major oxidative metabolites were identified in liver microsomes of mouse, rat, dog, monkey and human. Dog is mostly similar to human regarding in vitro metabolism. Demethylation, hydroxylation and sequential glucuronidation are the major in vivo metabolic reactions. Direct urinary and biliary excretion of HMPL-013 is negligible. Metabolizing to M1 (demethylation), sequentially glucuronidating, followed by biliary excretion, and to a less extent, by urinary excretion, are important elimination pathways for HMPL-013 in rats. HMPL-013 has low risk of drug–drug interaction. It is predicted to have favorable human PK properties and low efficacious dose.

Conclusion

HMPL-013 demonstrates good preclinical PK and enables successful human PK and dose projection. It is valuable for further clinical development.

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Abbreviations

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptors

TKI:

Tyrosine kinase inhibitors

PK:

Pharmacokinetics

ADME:

Absorption, distribution, metabolism and excretion

RED:

Rapid equilibrium dialysis

CYP:

Cytochrome P450

API:

Active pharmaceutical ingredient

AUCinf :

Area under the concentration–time curve from time zero to infinity

C max :

Maximal concentration

T max :

Time to reach the maximal concentration

MID:

Metabolite identification

IS:

Internal standard

t 1/2 :

Half-lives

CLR :

Renal clearance

CLB :

Biliary clearance

CL:

Plasma total clearance

V z :

Volume of distribution at the terminal phase

BW:

Body weight

RoE:

Rule of exponents

FIH:

First-in-human

PD:

Pharmacodynamic

CLhep,pred :

Predicted hepatic clearance

CLint :

In vitro intrinsic clearance

BDC:

Bile duct cannulated

MLP:

Maximal life span potential

Tlag:

Lag time

Ka:

Absorption rate constant

DDI:

Drug–drug interaction

f e :

Fraction excreted

f m :

Fraction metabolized

GFR:

Glomerular filtration rate

PBPK:

Physiological-based PK

References

  1. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors. Clin Cancer Res 9:327–337

    CAS  PubMed  Google Scholar 

  2. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803

    Article  CAS  PubMed  Google Scholar 

  3. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  CAS  PubMed  Google Scholar 

  4. Morabito A, De Maio E, Di Maio M, Normanno N, Perrone F (2006) Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 11:753–764

    Article  CAS  PubMed  Google Scholar 

  5. Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60:222–243

    Article  PubMed Central  PubMed  Google Scholar 

  6. Chow LQM, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25:884–896

    Article  CAS  PubMed  Google Scholar 

  7. Iyer R, Fetterly G, Lugade A, Thanavala Y (2010) Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother 11:1943–1955

    Article  CAS  PubMed  Google Scholar 

  8. Bhargava P, Robinson MO (2011) Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep 13:103–111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Azmi AS, Wang Z, Philip PA, Mohammad RM, Sarkar FH (2010) Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations. Mol Cancer Ther 9:3137–3144

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543–553

    Article  PubMed Central  PubMed  Google Scholar 

  11. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283

    Article  CAS  PubMed  Google Scholar 

  12. Patson B, Cohen BR, Olszanski AJ (2012) Pharmacokinetic evaluation of axitinib. Expert Opin Drug Metab Toxicol 8:259–270

    Article  CAS  PubMed  Google Scholar 

  13. Gu Y, Wang GJ, Wu XL, Zheng YT, Zhang JW, Ai H, Sun JG, Jia YW (2010) Intestinal absorption mechanisms of ginsenoside Rh2: stereoselectivity and involvement of ABC transporters. Xenobiotica 40:602–612

    Article  CAS  PubMed  Google Scholar 

  14. Kuhnz W, Gieschen H (1998) Predicting the oral bioavailability of 19-nortestosterone progestins in vivo from their metabolic stability in human liver microsomal preparations in vitro. Drug Metab Dispos 26:1120–1127

    CAS  PubMed  Google Scholar 

  15. Obach RS (1999) Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350–1359

    CAS  PubMed  Google Scholar 

  16. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, Macintyre F, Rance DJ, Wastall P (1997) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 283:46–58

    CAS  PubMed  Google Scholar 

  17. Center for Drug Evaluation and Research FaDA (2001) Guidance for industry: bioanalytical method validation

  18. Fura A, Vyas V, Humphreys W, Chimalokonda A, Rodrigues D (2008) Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compounds. Biopharm Drug Dispos 29:455–468

    Article  CAS  PubMed  Google Scholar 

  19. Mahmood I, Balian JD (1996) Interspecies scaling: predicting clearance of drugs in humans. Three different approaches. Xenobiotica 26:887–895

    Article  CAS  PubMed  Google Scholar 

  20. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095

    Article  CAS  PubMed  Google Scholar 

  21. Wilkinson GR, Shand DG (1975) Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther 18:377–390

    CAS  PubMed  Google Scholar 

  22. Toutain PL, Bousquet-Melou A (2004) Plasma clearance. J Vet Pharmacol Ther 27:415–425

    Article  CAS  PubMed  Google Scholar 

  23. Rowland M, Tozer T (2011) Clinical pharmacokinetics and pharmacodynamics: concepts and application, 4th edn. Lippincott Williams & Wilkins, a Wolters Kluwer business, New York

    Google Scholar 

  24. Toutain PL, Bousquet-Melou A (2004) Volumes of distribution. J Vet Pharmacol Ther 27:441–453

    Article  CAS  PubMed  Google Scholar 

  25. Berezhkovskiy LM (2008) Prediction of the possibility of the second peak of drug plasma concentration time curve after iv bolus administration from the standpoint of the traditional multi-compartmental linear pharmacokinetics. J Pharm Sci 97:2385–2393

    Article  CAS  PubMed  Google Scholar 

  26. Rolan PE (1994) Plasma-protein binding displacement interactions—why are they still regarded as clinically important. Br J Clin Pharmacol 37:125–128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Benet LZ, Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71:115–121

    Article  CAS  PubMed  Google Scholar 

  28. Tillement JP, Urien S, Chaumet-Riffaud P, Riant P, Bree F, Morin D, Albengres E, Barre J (1988) Blood binding and tissue uptake of drugs. recent advances and perspectives. Fundam Clin Pharmacol 2:223–238

    Article  CAS  PubMed  Google Scholar 

  29. Toutain PL, Bousquet-Melou A (2004) Plasma terminal half-life. J Vet Pharmacol Ther 27:427–439

    Article  CAS  PubMed  Google Scholar 

  30. Poulin P, Jones RDO, Jones HM, Gibson CR, Rowland M, Chien JY, Ring BJ, Adkison KK, Ku MS, He H, Vuppugalla R, Marathe P, Fischer V, Dutta S, Sinha VK, Bjornsson T, Lave T, Yates JWT (2011) PHRMA CPCDC initiative on predictive models of human pharmacokinetics, Part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach. J Pharm Sci 100:4127–4157

    Article  CAS  Google Scholar 

  31. Rowland M, Peck C, Tucker G (2011) Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol 51:45–73

    Article  CAS  PubMed  Google Scholar 

  32. Huang W, Lee SL, Yu LX (2009) Mechanistic approaches to predicting oral drug absorption. AAPS J 11:217–224

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lee KJ, Mower R, Hollenbeck T, Castelo J, Johnson N, Gordon P, Sinko PJ, Holme K, Lee YH (2003) Modulation of nonspecific binding in ultrafiltration protein binding studies. Pharm Res 20:1015–1021

    Article  CAS  PubMed  Google Scholar 

  34. Niggebrugge AE, MacLauchlin C, Dai D, Ford LA, Menendez AT, Chilton AS (2002) A high throughput protein binding assay by cohesive turbulent flow liquid chromatography mass spectrometry to support drug discovery. In: The 50th ASMS conference on mass spectrometry and allied topics, Orlando, Florida

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Acknowledgments

The authors are sincerely thankful for the great contributions of Prof. Dafang Zhong and Prof. Xiaoyan Chen from Shanghai Institute of Materia Medica to the rat and dog’s studies, Prof. Zhuohan Hu from Research Institute for Liver Diseases (Shanghai) Co. Ltd. to the human hepatocyte study and Dr. Renke Dai from Zhongshan PharmaSS Corporation to the hPXR study. Appreciations are also given to all the colleagues in Hutchison MediPharma who contributed to the HMPL-013 project.

Conflict of interest

The authors were all employees of Hutchison MediPharma Limited when the study was conducted and are alone responsible for the content and writing of this paper.

Author information

Author notes

  1. Ke Li

    Present address: Preclinical Development and Safety Asia Pacific, Janssen Research and Development, Shanghai, China

Authors and Affiliations

  1. Department of Clinical Pharmacology and DMPK, Hutchison MediPharma Limited, Building 4, 720 Cailun Road, Zhang-Jiang Hi-Tech Park, Shanghai, 201203, China

    Yi Gu, Jian Wang, Ke Li, Li Zhang, Hongcan Ren, Lixia Guo, Yang Sai, Weihan Zhang & Weiguo Su

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  1. Yi Gu
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Correspondence to Yang Sai.

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Gu, Y., Wang, J., Li, K. et al. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor Fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. Cancer Chemother Pharmacol 74, 95–115 (2014). https://doi.org/10.1007/s00280-014-2471-3

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  • DOI: https://doi.org/10.1007/s00280-014-2471-3

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