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Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

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Abstract

Purpose

Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance.

Methods

To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters.

Results

Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data.

Conclusions

Simulations predicted lower steady-state peak/trough olaparib exposure through 24–36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

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References

  1. Tutt A, Ashworth A (2002) The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 8:571–576

    Article  CAS  PubMed  Google Scholar 

  2. Bao Z, Cao C, Geng X, Tian B, Wu Y, Zhang C, Chen Z, Li W, Shen H, Ying S (2015) Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: a systematic review and meta-analysis. Oncotarget 7:7629–7639

    PubMed Central  Google Scholar 

  3. Scott CL, Swisher EM, Kaufmann SH (2015) Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol 33:1397–1406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. US Food and Drug Administration (2014) LYNPARZA prescribing information

  5. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852–861

    Article  CAS  PubMed  Google Scholar 

  6. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U (2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382–1392

    Article  CAS  PubMed  Google Scholar 

  7. Yamamoto N, Nokihara H, Yamada Y, Goto Y, Tanioka M, Shibata T, Yamada K, Asahina H, Kawata T, Shi X, Tamura T (2012) A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci 103:504–509

    Article  CAS  PubMed  Google Scholar 

  8. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134

    Article  CAS  PubMed  Google Scholar 

  9. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, Lubinski J, Shanley S, Messiou C, A’Hern R, Tutt A, Ashworth A, Stone J, Carmichael J, Schellens JH, de Bono JS, Kaye SB (2010) Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28:2512–2519

    Article  CAS  PubMed  Google Scholar 

  10. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861

    Article  CAS  PubMed  Google Scholar 

  11. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376:245–251

    Article  CAS  PubMed  Google Scholar 

  12. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244

    Article  CAS  PubMed  Google Scholar 

  13. Choy E, Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, D’Adamo D, Cote GM, Flamand Y, Benes CH, Haber DA, Baselga JM, Demetri GD (2014) Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 14:813

    Article  PubMed  PubMed Central  Google Scholar 

  14. Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, Lee H, Whalen C, Tyburski K, Winer E, Ivy P, Matulonis UA (2013) A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 49:2972–2978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel B, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA (2014) Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15:1207–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee JM, Trepel JB, Choyke P, Cao L, Sissung T, Houston N, Yu M, Figg WD, Turkbey IB, Steinberg SM, Lee MJ, Ivy SP, Liu JF, Matulonis UA, Kohn EC (2015) CECs and IL-8 Have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the randomized phase-2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive ovarian cancer. Front Oncol 5:123

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dean E, Middleton MR, Pwint T, Swaisland H, Carmichael J, Goodege-Kunwar P, Ranson M (2012) Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer 106:468–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372–379

    Article  CAS  PubMed  Google Scholar 

  19. Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, Cassidy J (2012) Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Investig New Drugs 30:1493–1500

    Article  CAS  Google Scholar 

  20. Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, Singer CF, Lowe ES, Watkins CL, Carmichael J (2013) Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 15:R88

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rajan A, Carter CA, Kelly RJ, Gutierrez M, Kummar S, Szabo E, Yancey MA, Ji J, Mannargudi B, Woo S, Spencer S, Figg WD, Giaccone G (2012) A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res 18:2344–2351

    Article  CAS  PubMed  Google Scholar 

  22. Minami D, Takigawa N, Takeda H, Takata M, Ochi N, Ichihara E, Hisamoto A, Hotta K, Tanimoto M, Kiura K (2013) Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells. Mol Cancer Res 11:140–148

    Article  CAS  PubMed  Google Scholar 

  23. Balmana J, Tung NM, Isakoff SJ, Grana B, Ryan PD, Saura C, Lowe ES, Frewer P, Winer E, Baselga J, Garber JE (2014) Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 25:1656–1663

    Article  CAS  PubMed  Google Scholar 

  24. Lee JM, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, Yu M, Gordon N, Ji J, Sissung TM, Figg WD, Azad N, Wood BJ, Doroshow J, Kohn EC (2014) Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 106:089

    Google Scholar 

  25. van der Noll R, Marchetti S, Steeghs N, Beijnen JH, Mergui-Roelvink MW, Harms E, Rehorst H, Sonke GS, Schellens JH (2015) Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 113:396–402

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lee JM, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, Houston N, Goey AK, Sissung TM, Parker B, Minasian L, Chiou V, Murphy RF, Widemann BC, Figg WD, Kohn EC (2016) Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women’s cancer. Clin Cancer Res 23:1397–1406

    Article  PubMed  Google Scholar 

  27. Del Conte G, Sessa C, von Moos R, Vigano L, Digena T, Locatelli A, Gallerani E, Fasolo A, Tessari A, Cathomas R, Gianni L (2014) Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br J Cancer 111:651–659

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rolfo C, Swaisland H, Leunen K, Rutten A, Soetekouw P, Slater S, Verheul HM, Fielding A, So K, Bannister W, Dean E (2015) Effect of food on the pharmacokinetics of olaparib after oral dosing of the capsule formulation in patients with advanced solid tumors. Adv Ther 32:510–522

    Article  CAS  PubMed  Google Scholar 

  29. Plummer R, Swaisland H, Leunen K, van Herpen CM, Jerusalem G, De Greve J, Lolkema MP, Soetekouw P, Mau-Sorensen M, Nielsen D, Spicer J, Fielding A, So K, Bannister W, Molife LR (2015) Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother Pharmacol 76:723–729

    Article  CAS  PubMed  Google Scholar 

  30. Roth JEP, Peer CJ, Mannargudi B, Swaisland H, Lee JM, Khon EC, Figg WD (2014) A sensitive and robust ultra HPLC assay with tandem mass spectrometric detection for the quantitation of the PARP inhibitor olaparib (AZD2281) in human plasma for pharmacokinetic application. Chromatography 1:82–95

    Article  Google Scholar 

  31. Hah SS, Stivers KM, de Vere White RW, Henderson PT (2006) Kinetics of carboplatin-DNA binding in genomic DNA and bladder cancer cells as determined by accelerator mass spectrometry. Chem Res Toxicol 19:622–626

    Article  CAS  PubMed  Google Scholar 

  32. Gaver RC, Colombo N, Green MD, George AM, Deeb G, Morris AD, Canetta RM, Speyer JL, Farmen RH, Muggia FM (1988) The disposition of carboplatin in ovarian cancer patients. Cancer Chemother Pharmacol 22:263–270

    Article  CAS  PubMed  Google Scholar 

  33. Oguri S, Sakakibara T, Mase H, Shimizu T, Ishikawa K, Kimura K, Smyth RD (1988) Clinical pharmacokinetics of carboplatin. J Clin Pharmacol 28:208–215

    Article  CAS  PubMed  Google Scholar 

  34. Molife LR, Forster MD, Krebs M, Pwint T, Middleton MR, Kaye SB, McCormack P, Swaisland H, Carmichael J, Ranson M (2010) A phase I study to determine the comparative bioavailability of two different oral formulations of the PARP inhibitor, olaparib (AZD2281), in patients with advanced solid tumors. J Clin Oncol 28:2599–2600

    Article  Google Scholar 

  35. Bundred N, Gardovskis J, Jaskiewicz J, Eglitis J, Paramonov V, McCormack P, Swaisland H, Cavallin M, Parry T, Carmichael J, Dixon JM (2013) Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery. Investig New Drugs 31:949–958

    Article  CAS  Google Scholar 

  36. US Food and Drug Administration PARAPLATIN prescribing information

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Acknowledgements

The authors would like to thank the patients who participated in this trial, all clinical support staff and AstraZeneca for providing the study drug in this trial.

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Authors and Affiliations

  1. Clinical Pharmacology Program, CCR, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD, 20892, USA

    Cody J. Peer, Jeffrey Roth, Louis Rodgers, Jeffers Nguyen & William D. Figg

  2. Women’s Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Jung-Min Lee, Christina M. Annunziata & Elise C. Kohn

  3. Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Lori Minasian

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  1. Cody J. Peer
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Contributions

Designed study: ECK, JML, CMA. Performed research: ECK, JML, NH, CJP, JR, SS, AG. Analyzed Data: ECK, JML, NH, CJP, WDF, AG, TMS. Wrote Manuscript: CJP, LR, JL. Critical manuscript revision: ECK, JML, CMA, WDF, TMS, CJP, AG.

Corresponding author

Correspondence to William D. Figg.

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All authors declared no conflicts of interest.

Financial support

This project has been funded in whole or in part with federal funds from the National Cancer Institute (National Institutes of Health). This work was supported by the Intramural Research Program of the NIH, National Cancer Institute.

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The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Peer, C.J., Lee, JM., Roth, J. et al. Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers. Cancer Chemother Pharmacol 80, 165–175 (2017). https://doi.org/10.1007/s00280-017-3346-1

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  • DOI: https://doi.org/10.1007/s00280-017-3346-1

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