Cancer Chemotherapy and Pharmacology

, Volume 36, Issue 3, pp 233–238 | Cite as

A limited sampling strategy for the study of pirarubicin pharmacokinetics in humans

  • Dominique Marchiset-Leca
  • François-René Leca
  • Anne Galeani
  • Alex Noble
  • Athanassios Iliadis
Original Article Pirarubicin, Limited Sampling Strategy, Pharmacokinetics, Maximum-Likelihood Estimation, Bayesian Estimation

Abstract

Pirarubicin (4′-O-tetrahydropyranyldoxorubicin, THP-Adriamycin) is a new anthracycline antibiotic that has recently been developed because its reduced cardiac toxicity is associated with an antitumour efficacy similar to that of doxorubicin. Pirarubicin is characterised by strong haematological toxicity, which has been shown to be correlated with pharmacokinetic parameters, especially the area under the time-concentration curve. To obtain routine pharmacokinetic evaluations of pirarubicin for dose monitoring we developed a limited sampling strategy relying on three blood samples taken at the end of the infusion and at 12 and 24 h post-infusion. The characteristics of interindividual variability were assessed on the first courses of treatment performed in 18 patients; the model was then validated on 10 independent first courses of treatment performed in 10 other patients. The main pharmacokinetic parameters (half-lives, total volume of distribution, total plasma clearance) were estimated in the test group by maximum-likelihood estimation using all samples and by Bayesian estimation using three samples. The concordance between the two estimates was correct (the bias and precision for clearance were 2.3% and 12.1%, respectively), which shows that this limited sampling strategy can be used in routine drug monitoring.

Key words

Pirarubicin Limited sampling strategy Pharmacokinetics Maximum-likelihood estimation Bayesian estimation 

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References

  1. 1.
    Aarons L (1991) Population pharmacokinetics: theory and practice. Br J Clin Pharmacol 32:669Google Scholar
  2. 2.
    Bressolle F, Ray P, Jacquet JM, Galtier M, Donadio D, Jourdan J, Rossi JF (1991) Bayesian estimation of doxorubicin pharmacokinetic parameters. Cancer Chemother Pharmacol 29:53Google Scholar
  3. 3.
    Dixon WJ, Brown MB, Engelman L, Frane JW, Hill M, Jennrich RI, Toposek JD (1985) BMDP statistical software. University of California Press, BerkeleyGoogle Scholar
  4. 4.
    Dobbs NA, Twelves CJ, Ramirez AJ, Towlson KE, Gregory WM, Richards MA (1993) Patient acceptability and practical implications of pharmacokinetic studies in patients with advanced cancer. Eur J Cancer 29A:1707Google Scholar
  5. 5.
    Hérait P, Poutignat N, Marty A, Bugat R (1992) Early assessment of a new anticancer drug analogue. Are historical comparisons obsolete? The French experience with pirarubicin. Eur J Cancer 28A:1670Google Scholar
  6. 6.
    Iliadis A (1992) Population pharmacokinetics: methodological concerns in applications. In: Crommelin DJA, Midha KK (eds) Topics in pharmaceutical sciences 1991 Medpharm, Stuttgart, pp 441–460Google Scholar
  7. 7.
    Iliadis A, Brown AC, Huggins ML (1992) APIS: a software for model identification, simulation and dosage regimen calculations in clinical and experimental pharmacokinetics. Comput Methods Programs Biomed 38:227Google Scholar
  8. 8.
    Launay MC, Milano G, Iliadis A, Frenay M, Namer N (1989) A limited sampling procedure for estimating adriamycin pharmacokinetics in cancer patients. Br J Cancer 60:89Google Scholar
  9. 9.
    Leca F, Marchiset-Leca D, Noble A, Antonetti M (1991) New data on the pharmacokinetics of adriamycin and its major metabolite adriamycinol. Eur J Drug Metab Pharmacokinet 16:107Google Scholar
  10. 10.
    Majima H, Igushi H, Tone H (1983) Pharmacokinetic studies of 4′-O-tetrahydropyranyl-adriamycin. Jpn J Cancer Chemother 13:542Google Scholar
  11. 11.
    Marchiset-Leca D, Leca F (1993) A highly sensitive method for the determination of a new anthracycline, pirarubicin. Chromatographia 35:435Google Scholar
  12. 12.
    Miller AA, Schmidt CG (1987) Clinical pharmacology and toxicity of 4′-O-tetrahydropyranyl-adriamycin. Cancer Res 47:1461Google Scholar
  13. 13.
    Munck JN, Fourcase A, Bennoun M, Tapiero H (1985) Relationship between the intracellular level and growth inhibition of a new anthracycline, 4′-O-tetrahydropyranyl-adriamycin, in Friend leukemia cell variants. Leuk Res 9:289Google Scholar
  14. 14.
    Nagasawa K, Yokoyama T, Ohnishi N, Iwakawa S, Okumura K, Kosaka Y, Sano K, Murakami R, Nakamura H (1991) Pharmacokinetics of pirarubicin in pedriatic patients. J Pharmacobiodyn 14:222Google Scholar
  15. 15.
    Raber MN, Newman RA, Lu K, Legha S, Gorski C, Benjamin RS, Krakoff IH (1989) Phase I clinical trial and pharmacokinetic evaluation of 4′-O-tetrahydropyranyl-Adriamycin. Cancer Chemother Pharmacol 23:311Google Scholar
  16. 16.
    Ratain MJ, Robert J, VanDerVijgh WJM (1991) Limited sampling models for doxorubicin pharmacokinetics. J Clin Oncol 9:871Google Scholar
  17. 17.
    Robert J, Gianni L (1993) Pharmacokinetics and metabolism of anthracyclines. Cancer Surv 17:219Google Scholar
  18. 18.
    Robert J, David M, Huet S, Chauvergne J (1988) Pharmacokinetics and metabolism of pirarubicin in advanced cancer patients. Eur J Cancer Clin Oncol 24:1289Google Scholar
  19. 19.
    Robert J, Monnier A, Poutignat N, Hérait P (1991) A pharmacokinetic and pharmacodynamic study of the new anthracycline pirarubicin in breast cancer patients. Cancer Chemother Pharmacol 29:75Google Scholar
  20. 20.
    Schott B, Robert J (1989) Comparative activity of anthracycline 13-dihydrometabolites against rat glioblastoma cells in culture. Biochem Pharmacol 38:4069Google Scholar
  21. 21.
    Sridhar KS, Samy TSA, Agarwal RP, Duncan R, Benedetto P, Krishan AG, Vogel CL, Feun LG, Savaraj NM, Richman SP, Zubrod CG (1990) A phase I study of 4′-O-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics. Cancer 66:2082Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Dominique Marchiset-Leca
    • 1
    • 2
  • François-René Leca
    • 1
  • Anne Galeani
    • 3
  • Alex Noble
    • 3
  • Athanassios Iliadis
    • 2
  1. 1.Laboratoire de PharmacocinétiqueCentre Hospitalier Départemental de CastelluccioAjaccio CedexFrance
  2. 2.Laboratoire de PharmacocinétiqueFaculté de PharmacieMarseille Cedex 5France
  3. 3.Service d'OncologieCentre Hospitalier Départemental de CastelluccioAjaccio CedexFrance

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