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Intravesical Drug Delivery

Pharmacokinetic and Clinical Considerations

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  • Drug Delivery Systems
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Abstract

Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are mitomycin (mitomycin C), thiotepa, etoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guérin (BCG) and, more recently, taxol and the new mitomycin derivative KW-2149.

Recurrence rates in patients with superficial bladder cancer have been substantially reduced by combined transurethral resection and intravesical pharmacotherapy. The high concentration of cytotoxics in urine and tumour tissue explain the high efficacy rates. Furthermore, the low systemic availability of most intravesical agents is consistent with the low frequency of acute and delayed systemic adverse effects. Systemic toxicity is almost negligible, except in the case of thiotepa, and local toxicity is transient and tolerable.

Pharmacokinetic models of drug absorption from the bladder have been developed, both in animals and humans. These have led to the identification of optimal intravescial treatment regimens.

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References

  1. Semple JE. Papillomata of bladder treated with podophyllin: preliminary report. BMJ 1948; 1: 1235–7.

    Article  PubMed  CAS  Google Scholar 

  2. Lum BL. Intravesical chemotherapy of superficial bladder cancer. In: Torti FM, editor. Urologic cancer: chemotherapeutic principles and management. Berlin: Springer-Verlag 1983: 3–36.

    Chapter  Google Scholar 

  3. Mishina T, Watanabe H, Kobayashi T, et al. Absorption of anticancer drugs through bladder epithelium. Urology 1986; 27: 148–57.

    Article  PubMed  CAS  Google Scholar 

  4. Dalton JT, Wientjes MG, Au JL-S. Effects of bladder resorption on pharmacokinetic data analysis. J Pharmacokinet Biopharm 1994; 22: 183–205.

    PubMed  CAS  Google Scholar 

  5. Jacobi GH, Kurth KH. Studies on the intravesical action of topically administered G3H-doxorubicin hydrochloride in men: plasma uptake and tumor penetration. J Urol 1980; 124: 34–7.

    PubMed  CAS  Google Scholar 

  6. Fluchter SH, Hlobil H, Harzmann R, et al. Serum und gewebe mitomycin C Spiegel nach intravesikaler instillation. Urol Int 1983; 38: 321–8.

    Article  PubMed  CAS  Google Scholar 

  7. Larson A, Eksborg S, Fritjofsson A. Intravesical instillation of adriamycin early after transurethral resection: measurements of plasma levels. Eur Urol 1984; 10: 398–400.

    PubMed  CAS  Google Scholar 

  8. Kurth KH, de Wall G, van Oosterom AT, et al. Plasma levels during intravesical instillation of mitomycin-C. In: Schroeder FH, Richards B, editors. EORTC Genitourinary Group Monograph 2. New York: Alan Liss, 1984: 81–91.

    Google Scholar 

  9. Hopkins SC, Buice RG, Matheny R, et al. The stability and antitumor activity of recycled (intravesical) mitomycin C. Cancer 1984; 53: 2063–8.

    Article  PubMed  CAS  Google Scholar 

  10. Wajsman ZEV, Dhafir RA, Pfeffer M, et al. Studies of mitomycin C absorption after intravesical treatment of superficial bladder tumors. J Urol 1984; 132: 30–3.

    PubMed  CAS  Google Scholar 

  11. Mross K, Maessen P, van der Vijgh WJF, et al. Absorption of Epi-doxorubicin after intravesical administration in patients with in situ transitional cell carcinoma of the bladder. Eur J Cancer Clin Oncol 1987; 23: 505–8.

    Article  PubMed  CAS  Google Scholar 

  12. Wientjes MG, Badalament RA, Au JL-S. Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer. Cancer Chemother Pharmacol 1993; 32: 255–62.

    Article  PubMed  CAS  Google Scholar 

  13. Au JL-S, Dalton JT, Wientjes MG. Evidence of significant absorption of sodium salicylate from urinary bladder of rats. J Pharmacol Exp Ther 1991; 258: 357–64.

    PubMed  CAS  Google Scholar 

  14. Dalton JT, Harrington MD, Au JL-S. Evidence of significant absorption of antipyrine from urinary bladder of rats. J Pharmacol Exp Ther 1992; 260: 608–13.

    PubMed  CAS  Google Scholar 

  15. Gao X, Buffington CAT, Au JL-S. Effect of interstitial cystitis on drug absorption from urinary bladder. J Pharmacol Exper Ther 1994; 271: 818–23.

    CAS  Google Scholar 

  16. De Bruijn EA. Chromatographic analysis of anticancer drugs. In: De Bruijn EA, editor. Monitoring anticancer agents. The Hague: Pasmans, 1992: 23–119.

    Google Scholar 

  17. De Bruijn EA, Sleeboom HP, Van Helsdingen PJRO, et al. Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int J Cancer 1992; 51: 359–64.

    Article  PubMed  Google Scholar 

  18. Dalton JT, Wientjes MG, Badalament RA, et al. Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res 1991; 51: 5144–52.

    PubMed  CAS  Google Scholar 

  19. Horii A, Kyo M, Yasumoto R, et al. Clinical effect on tumor regression and tissue concentration of peplomycin in patients treated with peplomycin emulsion in hydroxypropylcellulo-sum [in Japanese]. Hinyokika Kiyo 1991; 37: 21–4.

    PubMed  CAS  Google Scholar 

  20. Wientjes MG, Dalton JT, Badalament RA, et al. Bladder wall penetration of intravesical mitomycin C in dogs. Cancer Res 1991; 51: 4347–54.

    PubMed  CAS  Google Scholar 

  21. Wientjes MG, Dalton JT, Badalament RA, et al. A method to study drug concentration-depth profiles in tissues: mitomycin C in dog bladder wall. Pharm Res 1991; 8: 168–73.

    Article  PubMed  CAS  Google Scholar 

  22. Mross K, Hamm K, Schultze-Seemann W, et al. Tissue disposition and plasma concentrations of idarubicin after intravesical therapy in patients with bladder tumors. Cancer Chemother Pharmacol 1992; 29: 490–4.

    Article  PubMed  CAS  Google Scholar 

  23. Cho Y-H, Chi S-C, Hernanadez AD, et al. Adriamycin absorption after Nd:YAG laser coagulation compared to electrosurgical resection of the bladder wall. J Urol 1992; 147: 1139–41.

    PubMed  CAS  Google Scholar 

  24. Massad CA, Kogan BA, Trigo-Rocha FE. The pharmacokinetics of intravesical and oral oxybutynin chloride. J Urol 1992; 148: 595–7.

    PubMed  CAS  Google Scholar 

  25. De Bruijn EA, Van Helsdingen PJRO, Sleeboom HP, et al. Systemic mitomycin C upon repeated intravesical instillation. Reg Cancer Treat 1992; 4: 195–9.

    Google Scholar 

  26. Hashimoto H, Tokunaka S, Sasaki M, et al. Dimethylsulfoxide enhances the absorption of chemotherapeutic drug instilled into the bladder. Urol Res 1992; 20: 233–6.

    Article  PubMed  CAS  Google Scholar 

  27. Wientjes MG, Badalament RA, Wang RC, et al. Penetration of mitomycin C in human bladder. Cancer Res 1993; 53: 3314–20.

    PubMed  CAS  Google Scholar 

  28. Van Helsdingen PJRO, De Bruijn EA, Sleeboom HP, et al. Behavior and resorption of mitomycin C following multiple intravesical administrations. J Pharm Sci 1988; 77: 843–6.

    Article  PubMed  Google Scholar 

  29. Crooke ST, Henderson M, Samson M, et al. Phase I study of oral mitomycin C. Cancer Treat Rep 1976; 60: 1633–6.

    PubMed  CAS  Google Scholar 

  30. Sonneveld P, Kurth KH, Hagemeyer A, et al. Secondary hematologic neoplasm after intravesical chemotherapy for superficial bladder carcinoma. Cancer 1990; 65: 23–5.

    Article  PubMed  CAS  Google Scholar 

  31. Schmittgen TD, Wientjes MG, Badalament RA, et al. Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res 1991; 51: 3849–56.

    PubMed  CAS  Google Scholar 

  32. De Bruijn EA, Kuppen PJK, Leeflang P, et al. Constructing an in vitro area under the curve for testing antitumor agents with the mean residence time as starting point [abstract]. Br J Pharmacol 1986; 89: 510P.

    Google Scholar 

  33. Dedrick RL, Flessner MF, Collins JM, et al. Is the peritoneum a membrane? Am Soc Artif Intern Organs J 1982; 5: 1–5.

    Google Scholar 

  34. Flessner MF, Dedrick RL, Schultz JS. A distributed model of peritoneal-plasma transport: analysis of experimental data in the rat. Am J Physiol 1985; 248: F413–24.

    PubMed  CAS  Google Scholar 

  35. Flessner MF, Fenstermacher JD, Dedrick RL, et al. Adistributed model of peritoneal-plasma transport: tissue concentration gradients. Am J Physiol 1985; 248: F425–35.

    PubMed  CAS  Google Scholar 

  36. Chai M, Wientjes MG, Badalament RA, et al. Pharmacokinetics of intravesical doxorubicin in superficial bladder cancer patients. J Urol 1994; 152: 374–8.

    PubMed  CAS  Google Scholar 

  37. Pavone-Macaluso M, Gebbia N, Biondo F, et al. Permeability of the bladder mucosa to thiotepa, adriamycin, and daunomycin in men and rabbits. Urol Res 1976; 4: 9–13.

    PubMed  CAS  Google Scholar 

  38. Lunglmayr G, Czech K. Absorption studies on intraluminal thio-tepa for topical cytostatic treatment of low-stage bladder tumors. J Urol 1971; 106: 72–4.

    PubMed  CAS  Google Scholar 

  39. Gu FL, Shi T, Feng T, et al. Factors influencing the absorption of antineoplastic agents in intravesical instillation treatment of bladder tumors: an experimental and clinical study. Chin Med J 1987; 100: 127–31.

    PubMed  CAS  Google Scholar 

  40. Song D, Wientjes MG, Au JL-S. Bladdertissue pharmacokinetics of intravesical taxol. Cancer Chemother Pharmacol 1997; 40: 285–92.

    Article  PubMed  CAS  Google Scholar 

  41. Song D, Wientjes MG, Gan Y, et al. Bladder tissue pharmacokinetics and antitumor effect of intravesical 5-fluorouridine. Clin Cancer Res 1997; 3: 901–9.

    PubMed  CAS  Google Scholar 

  42. Herr HW. Intravesical therapy: a critical review. Urol Clin North Am 1987; 14: 399–404.

    PubMed  CAS  Google Scholar 

  43. Witjes JA, Van der Meijden AP, Debruyne FM. Use of intravesical bacillus Calmette-Guerin in the treatment of superficial transitional cell carcinoma of the bladder: an overview. Urol Int 1990; 45: 129–36.

    Article  PubMed  CAS  Google Scholar 

  44. Herr HW, Laudone VP, Whitmore Jr WF. An overview of intravesical therapy for superficial bladder tumors. J Urol 1987; 138: 1363–8.

    PubMed  CAS  Google Scholar 

  45. Huland H, Otto U, Droese M, et al. Long term mitomycin C instillation after transurethral resection of superficial bladder carcinoma: influence on recurrence, progression and survival. J Urol 1984; 132:27–9.

    PubMed  CAS  Google Scholar 

  46. Witjes JA, Van der Meijden APM, Witjes WPJ, et al. A randomised prospective study comparing intravesical instillations of mitomycin-C, BCG-Tice, and BCG-RIVM in pTa-pTl tumours and primary carcinoma in situ of the urinary bladder. Eur J Cancer 1993; 29A: 1672–6.

    Article  PubMed  CAS  Google Scholar 

  47. Kurth KH, Schroder FH, Tunn U, et al. Adjuvant chemotherapy of superficial transitional cell bladder carcinoma: preliminary results of a European Organisation for Research and Treatment of Cancer randomised trial comparing doxorubicin hydrochloride, ethoglucid and transurethral resection alone. J Urol 1984; 132: 258–62.

    PubMed  CAS  Google Scholar 

  48. Bouffioux Ch, Denis L, Oosterlinck W, et al. Adjuvant chemotherapy of recurrent superficial transitional cell carcinoma: results of a European Organisation for Research and Treatment of Cancer randomised trial comparing intravesical instillation of thiotepa, doxorubicin and cisplatin. J Urol 1992; 148: 297–301.

    PubMed  CAS  Google Scholar 

  49. Kawamura J, Tochigi H, Obata K, et al. A randomized study of pirarubicin (THP) versus adriamycin (ADM) for intravesical instillation therapy against superficial bladder cancer. Hinyokika Kiyo 1992; 38: 379–85.

    PubMed  CAS  Google Scholar 

  50. Crawford ED, McKenzie D, Mansson W, et al. Adverse reactions to the intravesical administration of doxorubicin hydrochloride: report of 6 cases. J Urol 1986; 136: 668–9.

    PubMed  CAS  Google Scholar 

  51. Prout Jr GR, Koontz Jr WW, Coombs LJ, et al. Long term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 1983; 130: 677–80.

    PubMed  Google Scholar 

  52. Lum BL, Torti FM. Adjuvant intravesicular pharmacotherapy for superficial bladder cancer. J Natl Cancer Inst 1991; 83: 682–94.

    Article  PubMed  CAS  Google Scholar 

  53. Soloway MS, Ford KS. Thiotepa-induced myelosuppression: review of 670 bladder instillations. J Urol 1983; 130: 889–91.

    PubMed  CAS  Google Scholar 

  54. Green DF, Robinson MRG, Glashan R, et al. Does intravesical chemotherapy prevent invasive bladder cancer. J Urol 1984; 131:33–5.

    PubMed  CAS  Google Scholar 

  55. Oosterlinck W, Kurth KH, Schroder F, et al. A prospective European Organisation for Research and Treatment of Cancer genitourinary group randomised trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 1993; 149: 749–52.

    PubMed  CAS  Google Scholar 

  56. Giannakopoulos S, Gekas A, Alivizatos G, et al. Efficacy of escalating doses of intravesical interferon α-2b in reducing recurrance rates and progression in superficial transitional cell carcinoma. Br J Urol 1998; 82: 829–34.

    Article  PubMed  CAS  Google Scholar 

  57. Glashan RW. A randomised controlled study of intravesical α-2b-interferon in carcinoma in situ of the bladder. J Urol 1990; 144: 658–61.

    PubMed  CAS  Google Scholar 

  58. Ohi Y, Ohmori H, Shirahama T, et al. Intravesical instillation of adriamycin in the presence or absence of verapamil for the treatment of superficial bladder cancer: preliminary report of a collaborative study. Cancer Chemother Pharmacol 1992; 30 Suppl.: S50–4.

    Article  PubMed  Google Scholar 

  59. Lukkarinen O, Paul C, Hellstrom P, et al. Intravesical epirubicin with and without verapamil for the prophylaxis of superficial bladder tumours. Scand J Urol Nephrol 1991; 25: 25–8.

    Article  PubMed  CAS  Google Scholar 

  60. Naito S, Kotoh S, Omoto T, et al. Prophylactic intravesical instillation chemotherapy against recurrance after a transurethral resection of superficial bladder cancer: a randomised controlled trial of doxorubicin plus verapamil versus doxorubicin alone. Cancer Chemother Pharmacol 1998; 42: 367–72.

    Article  PubMed  CAS  Google Scholar 

  61. Van Der Heyden SAM, Highley MS, De Bruijn EA, et al. Pharmacokinetics and bioavailability of oral 5′-deoxy-5-fluorouridine in cancer patients. Br J Clin Pharmacol 1999; 47: 351–6.

    Article  Google Scholar 

  62. Bamias A, Keane P, Krausz T, et al. Intravesical administration of radiolabeled antitumor monoclonal antibody in bladder carcinoma. Cancer Res 1991; 51: 724–8.

    PubMed  CAS  Google Scholar 

  63. Lee K, O’Donnell RW, Cockett AT. Influence of intravesical administration of tumor necrosis factor alpha and systemic gamma-interferon on murine bladder cancer: lack of dose response. Urol Res 1990; 18: 287–9.

    Article  PubMed  CAS  Google Scholar 

  64. Hobarth K, Maier U, Marberger M. Topical chemoprophylaxis of superficial bladder cancer with mitomycin C and adjuvant hyaluronidase. Eur Urol 1992; 21: 206–10.

    PubMed  CAS  Google Scholar 

  65. Gao X, Au JL-S, Badalament RA, et al. Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine. Clin Cancer Res 1998; 4: 139–43.

    PubMed  CAS  Google Scholar 

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Highley, M.S., van Oosterom, A.T., Maes, R.A. et al. Intravesical Drug Delivery. Clin Pharmacokinet 37, 59–73 (1999). https://doi.org/10.2165/00003088-199937010-00004

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