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Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up

  • Original Articles
  • Protein Binding ACNU, Plasma Concentration, Nimustine Hydrochloride, Animal Scale-up
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Summary

Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Loglog plots of body weight (W; kg) vs total plasma clearance (CLtot, p; ml/min) and steady-state distribution volume (Vd, ss; 1) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was >97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CLtot,p=50.6 W0.957; Bd, ss=1.29 W1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CLu tot,p and Vd,u ss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CLu tot,p=71.7 W0.891; Bd,u ss=1.82 W0.966) were also high (r≥0.991). The extrapolated values vs those observed in a 70-kg human were the following: CLu tot,p, 3,160 vs 2,290 ml/min; Vd,u ss, 110 vs 1061. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.

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Author notes

  1. Shogo Ozawa

    Present address: Department of Pharmacology School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, 160, Tokyo, Japan

Authors and Affiliations

  1. Bioscience Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, 140, Tokyo, Japan

    Yoshihiro Mitsuhashi, Takuzo Nishimura & Tomowo Kobayashi

  2. Product Development Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, 140, Tokyo, Japan

    Takashi Nitanai & Kunihiro Sasahara

  3. Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, 140, Tokyo, Japan

    Kan-Ichi Nakamura & Miroru Tanaka

  4. Faculty of Pharmaceutical Sciences, University of Tokyo, 3-1, Bunkyo-ku 7-chome, 113, Tokyo, Japan

    Yuichi Sugiyama

  5. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 37-1, Kami-Ikebukuro 1-chome, Toshima-ku, 170, Tokyo, Japan

    Shogo Ozawa & Makoto Inaba

Authors
  1. Yoshihiro Mitsuhashi
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  2. Yuichi Sugiyama
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  3. Shogo Ozawa
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  4. Takashi Nitanai
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  5. Kunihiro Sasahara
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  6. Kan-Ichi Nakamura
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  7. Miroru Tanaka
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  8. Takuzo Nishimura
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  9. Makoto Inaba
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  10. Tomowo Kobayashi
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Mitsuhashi, Y., Sugiyama, Y., Ozawa, S. et al. Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up. Cancer Chemother. Pharmacol. 27, 20–26 (1990). https://doi.org/10.1007/BF00689271

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  • DOI: https://doi.org/10.1007/BF00689271

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