Clinical Pharmacokinetics of Paclitaxel Monotherapy: An Updated Literature Review

Abstract

Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract the maximum concentration (C _max), clearance (CL), and time of paclitaxel plasma concentration above 0.05 µmol/L (T > 0.05 µmol/L) following monotherapy of both the widely used cremophor-diluted paclitaxel and nanoparticle albumin-bound (nab-)paclitaxel. We identified a total of 53 studies yielding 121 aggregated pharmacokinetic profiles for paclitaxel monotherapy and extracted reported mean and median estimates of pharmacokinetic parameters. Paclitaxel has been studied formally at doses of 15-825 mg/m² and infused over 0.5-96 h; included studies examined both weekly and every 3-weeks dosing cycles. The most widely used dose of cremophor-diluted paclitaxel, 175 mg/m² given as a 3-h infusion, leads to an interstudy median C _max of 5.1 µmol/L [interquartile range (IQR) 4.5-5.7], CL of 12.0 L/h/m² (IQR 10.9-12.9), and T > 0.05 µmol/L of 23.8 h (IQR 21.5-26.8). Importantly, the significant interindividual variation widely reported in the literature is not reflected in these interstudy estimates of pharmacokinetic parameters. Cremophor-diluted paclitaxel pharmacokinetics are non-linear following short (<6 h) but not long (>24 h) infusions. A similar pattern of non-linearity was observed for nab-paclitaxel, although the number of studies was limited. The pharmacokinetics of paclitaxel monotherapy have been widely studied at numerous dose levels of the Cremophor EL^® formulation, but are less well-characterized for the newer nab-paclitaxel formulation. In conclusion, paclitaxel pharmacokinetics are non-linear for short infusion times but not for longer infusions. Whether a similar conclusion can be drawn for nab-paclitaxel formulations requires further study.

Figure 1.. Flowchart showing overview of literature search.

The criteria for inclusion of papers for the final analysis are outlined as an iterative process. PK: pharmacokinetics, IV: intravenous.

Figure 2.. Distribution of dosage regimens included in this analysis.

The solid line represents the median dose, the box represents the interquartile range (IQR (25^th – 75^th percentiles)) and the whiskers represent 5^th – 95^th percentiles. A single outlier with a dose of 825 mg/m² infused over 24 hours is excluded due to extension of the dose-axis and compression of the majority of the data.

Figure 3.. Paclitaxel clearance is dose-dependent.

Paclitaxel clearance (CL, L/h/m²) plotted as a function of dose for short (≤6 hours, 3A) and long (> 6 hours, 3B) infusion times.

Figure 4.. Peak paclitaxel concentrations are not dose proportional with short infusion times.

Maximum concentration of paclitaxel (C_max, μM) during short (4A) and long (4B) infusion is expressed as a function of dose and infusion time. Solid lines represent a quadratic fit for short infusion times and a linear fit for long infusion times.

Figure 5.. The time of paclitaxel concentration above 0.05 μM is largely independent of infusion time.

The time of paclitaxel concentration above 0.05 μM is plotted as a function of dose and infusion time.

Figure 6.. Nonlinear clearance of paclitaxel administered in its nanoparticle albumin-bound formulation.

Paclitaxel clearance (CL, L/h/m²) is plotted as a function of dose and infusion time.

Figure 7.. Relationship of paclitaxel C_max values to dose following nanoparticle albumin-bound paclitaxel administration.

Maximum concentration (C_max, μM) of nanoparticle albumin-bound paclitaxel as a function of dose and infusion time.