Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice - PubMed (original) (raw)

Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice

Hironobu Minami et al. Cancer Sci. 2009 Jan.

Abstract

To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, alpha1-acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We developed a population pharmacokinetic model for docetaxel, which can be used in the setting of an oncology practice. Based on the model, dose reduction by approximately 20 and 40% should be considered for patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase, respectively.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Observed plasma concentration of docetaxel. Concentrations were normalized by the actual dose of docetaxel in each patient.

Figure 2

Figure 2

(a) Observed docetaxel concentration versus predicted docetaxel concentration from a Bayesian post hoc analysis of the model. The solid line represents the unit line. (b) Weighted residuals versus predicted concentration. The horizontal line represents the zero level.

Figure 3

Figure 3

Box plot of estimated systemic clearance of docetaxel according to hepatic function calculated by Bayesian estimation. The top, middle, and bottom lines of each box correspond to the 75% (top quartile), 50% (median), and 25% (bottom quartile) values. The whiskers show the range values that fall between 10 and 90%. 1, 2, and 3 HEP denote normal (n = 183), mildly (increased alkaline phosphatase [ALP] in combination with grade 2 elevation of aspartate aminotransferase [AST] or alanine aminotransferase [ALT], n = 10), and moderately elevated liver function tests (increased ALP in combination with grade 3 or greater elevation of AST or ALT, n = 7), respectively.

References

    1. Ratain MJ, Schilsky RL, Conley BA, Egorin MJ. Pharmacodynamics in cancer therapy. J Clin Oncol 1990; 8: 1739–53. - PubMed
    1. Minto C, Schnider T. Expanding clinical applications of population pharmacodynamic modelling. Br J Clin Pharmacol 1998; 46: 321–33. - PMC - PubMed
    1. Sun H, Fadiran E, Jones C et al . Population pharmacokinetics. A regulatory perspective. Clin Pharmacokinet 1999; 37: 41–58. - PubMed
    1. Samara E, Granneman R. Role of population pharmacokinetics in drug development: a pharmaceutical industry perspective. Clin Pharmacokinet 1997; 32: 294–312. - PubMed
    1. Ludden T. Population pharmacokinetics. J Clin Pharmacol 1988; 28: 1059–63. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources