Pharmacokinetics of Mycophenolic Acid and Determination of Area Under the Curve by Abbreviated Sampling Strategy in Chinese Liver Transplant Recipients

Authors: Chen, Hao¹; Peng, Chenghong¹; Yu, Zhicheng²; Shen, Baiyong¹; Deng, Xiaxing¹; Qiu, Weihua¹; Fei, Yue¹; Shen, Chuan¹; Zhou, Guangwen¹; Yang, Weiping¹; Li, Hongwei¹

Source: Clinical Pharmacokinetics, Volume 46, Number 2, 2007 , pp. 175-185(11)

Publisher: Adis International

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Abstract:

Objectives: This study aimed to: (i) define the clinical pharmacokinetics of mycophenolic acid (MPA) in Chinese liver transplant recipients; and (ii) develop a regression model best fitted for the prediction of MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC₁₂) by abbreviated sampling strategy.

Methods: Forty liver transplant patients received mycophenolate mofetil 1g as a single dose twice daily in combination with tacrolimus. MPA concentrations were determined by high-performance liquid chromatography before dose (C₀) and at 0.5 (C_0.5), 1 (C₁), 1.5 (C_1.5), 2 (C₂), 4 (C₄), 6 (C₆), 8 (C₈), 10 (C₁₀) and 12 (C₁₂) hours after administration on days 7 and 14. A total of 72 pharmacokinetic profiles were obtained. MPA AUC₁₂ was calculated with 3P97 software. The trough concentrations (C₀) of tacrolimus and hepatic function were also measured simultaneously. Multiple linear regression analysis was used to establish the models for estimated MPA AUC₁₂. The agreement between predicted MPA AUC₁₂ and observed MPA AUC₁₂ was investigated by Bland-Altman analysis.

Results: The pattern of MPA concentrations during the 12-hour interval on day 7 was very similar to that on day 14. In the total of 72 profiles, the mean maximum plasma concentration (C_max) and time to reach C_max (t_max) were 9.79 ± 5.26 mg/L and 1.43 ± 0.78 hours, respectively. The mean MPA AUC₁₂ was 46.50 ± 17.42 mg · h/L (range 17.99−98.73 mg · h/L). Correlation between MPA C₀ and MPA AUC₁₂ was poor (r² = 0.300, p = 0.0001). The best model for prediction of MPA AUC₁₂ was by using 1, 2, 6 and 8 hour timepoint MPA concentrations (r² = 0.921, p = 0.0001). The regression equation for estimated MPA AUC₁₂ was 5.503 + 0.919 · C₁ + 1.871 · C₂ + 3.176 · C₆ + 3.664 · C₈.

This model had minimal mean prediction error (1.24 ± 11.19%) and minimal mean absolute prediction error (8.24 ± 7.61%). Sixty-three of 72 (88%) estimated MPA AUC₁₂ were within 15% of MPA AUC₁₂. Bland-Altman analysis also revealed the best agreement of this model compared with the others and a mean error of ±9.89 mg · h/mL.

Conclusion: This study showed the wide variability in MPA AUC₁₂ in Chinese liver transplant recipients. Single timepoint MPA concentration during the 12-hour dosing interval cannot reflect MPA AUC₁₂. MPA AUC₁₂ could be predicted accurately using 1, 2, 6 and 8 hour timepoint MPA concentrations by abbreviated sampling strategy.

Keywords: Immunosuppressants; Inosine monophosphate dehydrogenase inhibitors; Liver transplant; Mycophenolate mofetil; Transplantation

Document Type: Research article

Affiliations: 1: 1 Center of Organ Transplantation, Ruijin Hospital, Medical School of Shanghai Jiaoton University, Shanghai, P.R. China 2: 2 Institute of Clinical Pharmacology, Ruijin Hospital, Medical School of Shanghai Jiaoton University, Shanghai, P.R. China

Publication date: 2007-01-01

Pharmacokinetics of Mycophenolic Acid and Determination of Area Under the Curve by Abbreviated Sampling Strategy in Chinese Liver Transplant Recipients

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