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Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin

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Abstract

Purpose

The purpose of the study was to construct a population pharmacokinetic model for pegylated liposomal doxorubicin and use the final model to investigate the discrimination performance of pharmacokinetic metrics (e.g., Cmax, AUC and partial AUC) of various analytes (e.g., liposome encapsulated doxorubicin, free doxorubicin and total doxorubicin) for the identification of formulation differences by means of Monte Carlo simulations.

Methods

A model was simultaneously built to characterize the concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin using NONMEM. The different scenarios associated with changes in release rate (Rel) were simulated based on the final parameters. 500 simulated virtual bioequivalence (BE) studies were performed for each scenario, and power curves for the probability of declaring BE were also computed.

Results

The concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin were well described by a one- and two-compartment model, respectively. pAUC0-24 h and pAUC0-48 h of free doxorubicin was most responsive to changes in the Rel when the Rel (test)/Rel (reference) ratios decreased. In contrast, when the Rel (test) increased, AUC0-t of liposome-encapsulated doxorubicin was the most responsive metric.

Conclusions

In addition to the traditional metrics, partial AUC should be included for the BE assessment of pegylated liposomal doxorubicin.

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Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the curve

AUC0-t :

Area under the curve up to last measurable time point

BE:

Bioequivalence

CLfree :

Clearance of the free doxorubicin

CLres :

Uptake clearance of liposome-encapsulated doxorubicin by the reticuloendothelial system

Cmax :

Maximum concentration

CWRES:

Conditional weighted residuals

E%:

Encapsulation percentage

EMA:

European medicines agency

FOCE:

First-order conditional estimation

ICTRP:

International clinical trials registry platform

IIV:

Inter-individual variability

IV:

Intravenous

IWRES:

Individual weighted residuals

k0 :

Infusion rate

l/h:

Liter per hour

m2 :

Square meter

mg/m2 :

Milligram per square meter

ng/ml:

Nanogram per milliliter

NONMEM:

Nonlinear mixed effects modeling

pAUC:

Partial area under the curve

Q:

Inter-compartmental clearance of the free doxorubicin

Rel:

Release rate of the free doxorubicin from the liposome carrier

RES:

Reticuloendothelial system

RMSE:

Root mean square error

TFDA:

Taiwan food and drug administration

Tmax :

Time to maximum concentration

USFDA:

United states food and drug administration

V1:

Volume of distribution of the liposome-encapsulated doxorubicin

V2:

Central volume of distribution of the free doxorubicin

V3:

Peripheral volume of distribution of the free doxorubicin

WfN:

Wings for nonlinear mixed effects modeling

References

  1. Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet. 2003;42(5):419–36. https://doi.org/10.2165/00003088-200342050-00002.

    Article  CAS  PubMed  Google Scholar 

  2. Barenholz Y. Doxil®--the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34. https://doi.org/10.1016/j.jconrel.2012.03.020.

    Article  CAS  PubMed  Google Scholar 

  3. Drugs@FDA Website Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm Accessed 2 September 2017.

  4. Taiwan Food and Drug Administration Website Available at: http://www.fda.gov.tw/MLMS/H0001.aspx Accessed 2 September 2017.

  5. Kapoor M, Lee SL, Tyner KM. Liposomal drug product development and quality: current US experience and perspective. AAPS J. 2017;19(3):632–41. https://doi.org/10.1208/s12248-017-0049-9.

    Article  CAS  PubMed  Google Scholar 

  6. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Draft Guidance for Industry: Doxorubicin HCl. Revised April 2017. Available from: https://www.fda.gov/downloads/Drugs/.../Guidances/UCM199635.pdf Accessed 2 September 2017.

  7. European Medicines Agency. Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product. Final February 2013. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500140351.pdf. Accessed 2 September 2017.

  8. Hsu LF, Huang JD. A statistical analysis to assess the most critical bioequivalence parameters for generic liposomal products. Int J Clin Pharmacol Ther. 2014;52(12):1071–82. https://doi.org/10.5414/cp202129.

    Article  CAS  PubMed  Google Scholar 

  9. Dosne AG, Bergstrand M, Karlsson MO. A strategy for residual error modeling incorporating scedasticity of variance and distribution shape. J Pharmacokinet Pharmacodyn. 2016;43(2):137–51. https://doi.org/10.1007/s10928-015-9460-y.

    Article  PubMed  Google Scholar 

  10. Drummond DC, Noble CO, Hayes ME, Park JW, Kirpotin DB. Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development. J Pharm Sci. 2008;97(11):4696–740. https://doi.org/10.1002/jps.21358.

    Article  CAS  PubMed  Google Scholar 

  11. Macheras P, Iliadis A. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics: homogeneous and heterogeneous approaches. In: Karalis V, editor. Modeling and simulation in bioequivalence. 2rd ed. Switzerland: Springer; 2016. p. 227–54.

    Google Scholar 

  12. Sm A, S S. Bioequivalence Study of Pegylated Doxorubicin Hydrochloride Liposome (PEGADRIA) and DOXIL® in Ovarian Cancer Patients: Physicochemical Characterization and Pre-clinical Studies. J Nanosci Nanotechnol 2016;07(02). https://doi.org/10.4172/2157-7439.1000361.

  13. Zhang X, Lionberger RA. Modeling and simulation of biopharmaceutical performance. Clin Pharmacol Ther. 2014;95(5):480–2. https://doi.org/10.1038/clpt.2014.40.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang X, Duan J, Kesisoglou F, Novakovic J, Amidon GL, Jamei M, et al. Mechanistic oral absorption modeling and simulation for formulation development and bioequivalence evaluation: report of an FDA public workshop. CPT Pharmacometrics Syst Pharmacol. 2017;6(8):492–5. https://doi.org/10.1002/psp4.12204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hussaarts L, Muhlebach S, Shah VP, McNeil S, Borchard G, Fluhmann B, et al. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks. Ann N Y Acad Sci. 2017;1407:39–49. https://doi.org/10.1111/nyas.13347.

    Article  PubMed  Google Scholar 

  16. Fourie Zirkelbach J, Jackson AJ, Wang Y, Schuirmann DJ. Use of partial AUC (PAUC) to evaluate bioequivalence--a case study with complex absorption: methylphenidate. Pharm Res. 2013;30(1):191–202. https://doi.org/10.1007/s11095-012-0862-x.

    Article  CAS  PubMed  Google Scholar 

  17. Jackson A. Impact of release mechanism on the pharmacokinetic performance of PAUC metrics for three methylphenidate products with complex absorption. Pharm Res. 2014;31(1):173–81. https://doi.org/10.1007/s11095-013-1150-0.

    Article  CAS  PubMed  Google Scholar 

  18. Amantea MA, Forrest A, Northfelt DW, Mamelok R. Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma. Clin Pharmacol Ther. 1997;61(3):301–11. https://doi.org/10.1016/s0009-9236(97)90162-4.

    Article  CAS  PubMed  Google Scholar 

  19. Wu H, Ramanathan RK, Zamboni BA, Strychor S, Ramalingam S, Edwards RP, et al. Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies. J Clin Pharmacol. 2012;52(2):180–94. https://doi.org/10.1177/0091270010394851.

    Article  CAS  PubMed  Google Scholar 

  20. Wu H, Infante JR, Keedy VL, Jones SF, Chan E, Bendell JC, et al. Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors. Eur J Clin Pharmacol. 2013;69(12):2073–81. https://doi.org/10.1007/s00228-013-1580-y.

    Article  CAS  PubMed  Google Scholar 

  21. Allen TM, Hansen C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta. 1991;1068(2):133–41.

    Article  CAS  PubMed  Google Scholar 

  22. Zamboni WC. Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin Cancer Res. 2005;11(23):8230–4. https://doi.org/10.1158/1078-0432.ccr-05-1895.

    Article  CAS  PubMed  Google Scholar 

  23. Kontny NE, Wurthwein G, Joachim B, Boddy AV, Krischke M, Fuhr U, et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol. 2013;71(3):749–63. https://doi.org/10.1007/s00280-013-2069-1.

    Article  CAS  PubMed  Google Scholar 

  24. Yu Y, Desjardins C, Saxton P, Lai G, Schuck E, Wong YN. Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice. Int J Pharm. 2013;443(1–2):9–16. https://doi.org/10.1016/j.ijpharm.2013.01.010.

    Article  CAS  PubMed  Google Scholar 

  25. Nageeb El-Helaly S, Abd Elbary A, Kassem MA, El-Nabarawi MA. Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies. Drug Deliv. 2017;24(1):692–700. https://doi.org/10.1080/10717544.2017.1309476.

    Article  CAS  PubMed  Google Scholar 

  26. Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine injection following a single administration at the surgical site. Clin Drug Investig. 2013;33(2):109–15. https://doi.org/10.1007/s40261-012-0043-z.

    Article  CAS  PubMed  Google Scholar 

  27. Lee LH, Choi C, Gershkovich P, Barr AM, Honer WG, Procyshyn RM. Proposing the use of partial AUC as an adjunctive measure in establishing bioequivalence between deltoid and gluteal Administration of Long-Acting Injectable Antipsychotics. Eur J Drug Metab Pharmacokinet. 2016;41(6):659–64. https://doi.org/10.1007/s13318-016-0348-z.

    Article  CAS  PubMed  Google Scholar 

  28. Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000;89(5):1037–47. https://doi.org/10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z.

    Article  CAS  PubMed  Google Scholar 

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The views expressed in this article are the author’s personal opinions and do not necessarily reflect the recommendations of the Taiwan CDE.

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  1. Division of Pharmaceutical Science, Center for Drug Evaluation (CDE), 3F, No.465, Sec.6, Zhongxiao E. Rd, Taipei, 11557, Taiwan

    Li-feng Hsu

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Hsu, Lf. Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin. Pharm Res 35, 106 (2018). https://doi.org/10.1007/s11095-018-2387-4

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