Millidose

[Jenine Killebrew]

Docetaxelis a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity.

Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Docetaxel, a second-generation taxane, is one of the most widely used chemotherapeutic agents [1, 2] and is effective as monotherapy in a variety of tumor types, including breast, lung, and prostate cancer [2]. Currently, drug dosing is individualized based on body surface area (BSA) alone. However, body surface area is a poor predictor for systemic exposure [3], which shows a wide interpatient variability [4]. Since toxicity and efficacy of docetaxel are directly related to systemic exposure [5,6,7], this variability leads to unwanted outcomes like febrile neutropenia, which affects 15% of prostate cancer patients [8], or reduced efficacy due to subtherapeutic plasma levels. It is pivotal to develop a better dosing strategy for docetaxel from the first dose and onwards to reach an adequate systemic exposure ensuring maximal efficacy, while limiting toxicity.

Microdose phenotyping has been previously proposed as an attractive method to individualize dosing of anticancer drugs [9,10,11]. This strategy is appealing since it would also allow for correction of subtherapeutic dosing, in contrast to current clinical care in which dosing is only reduced in case of toxicity. In addition, it has the advantage of dose individualization from the first dose onwards, as opposed to pos-hoc adjustment with therapeutic drug monitoring. Docetaxel is dosed based on body surface area with therapeutic doses ranging from 75 to 100 mg/m2 on day one of a 21-day cycle. A microdose is defined as a dose of drug that is 1% of the pharmacologically active dose with a maximum of 100 g [12]. Microdosing has an excellent track record of representing the pharmacokinetics of a drug at a therapeutic dose [13]. However, clinical implication of microdosing studies is often hindered by the lack of limited sampling strategies and absence of highly sensitive assays in the clinical setting. Therefore, we chose to use a subpharmacological (

All patients who received docetaxel as part of routine care (for breast, prostate or non-small cell lung cancer) were eligible for participation in the Microdoce study. Thirty patients with prostate cancer treated with docetaxel 75 mg/m2 as part of routine clinical care in a general hospital between 2017 and 2020 were included. Written informed consent was retrieved from all patients. This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Medical research Ethical Committees United (MEC-U) in the Netherlands and was registered at clinicaltrials.eu (2016-003785-77).

Study subjects received an intravenous millidose of 1000 g docetaxel (bolus), one to seven days prior to therapeutic docetaxel administration (60 min infusion). We verified the docetaxel concentration in the syringe before millidose administration. Blood samples were taken 0.25, 1, 2, 4, 6 and 8 h after the end of both the milli- and therapeutic dose. Samples were immediately centrifuged and stored at -80 C until analysis. Plasma docetaxel concentrations were measured by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS; TSQ Altis, Triple Quadrupole Mass Spectrometer, Thermo Scientific). The lower limit of quantification was 0.01 g/L. Bioanalytical inaccuracy and imprecision were less than 15% across the measured concentrations. Serum α-1-acidic glycoprotein (AAG) concentrations were measured on both days.

Dose and clearance are the only determinants for the area under the plasma concentration versus time curve (AUC) of a drug. In order to evaluate whether the therapeutic docetaxel dose AUC could be predicted using a millidose, we investigated the correlation between millidose and therapeutic dose docetaxel clearance. The majority of docetaxel (95%) is bound to plasma proteins. Since only the unbound docetaxel fraction is metabolized, the extent of plasma protein binding can have a substantial effect on docetaxel clearance. Interpatient variability in α-1-acidic glycoprotein (AAG) concentrations is considered a covariate for docetaxel protein binding [14]. Therefore, we measured AAG levels at the time of each docetaxel administration.

In this study we show that there is no significant correlation between docetaxel millidose and therapeutic dose clearance. This finding is in line with a smaller study by Fujita et al., in which pharmacokinetics of a 100 g docetaxel microdose were compared to those after full dose administration in nine patients [17]. Unfortunately, increasing the test dose to 1000 g docetaxel and testing a larger cohort did not improve the observed correlation. A PET-imaging study using a [11C]docetaxel did show that therapeutic dose docetaxel volume of distribution and tumor uptake could be predicted using microdose data [18]. However, sampling in this study was limited to the first 80 min after infusion due to the short half-life of [11C] and therefore does not allow for comparison of terminal half-life and clearance.

To investigate why we did not observe strong correlation between millidose and full dose docetaxel clearance, we verified the docetaxel concentration in the syringe prior to millidose administration. We hereby excluded solubility issues that could occur due to different concentrations of excipients.

Although the plasma AAG concentration is known to account for the largest variation in unbound fraction between patients [14], intrapatient AAG concentration was constant and correction for the unbound docetaxel fraction did not improve the observed correlation. An inverse correlation between docetaxel clearance and AAG concentration was reported at therapeutic dose levels [21], however a clear correlation at the millidose level was lacking in another study [17]. Potentially the contribution of AAG-binding to the total plasma protein binding of docetaxel is larger at therapeutic dose levels, due to saturation of binding to other proteins with higher binding constants and lower plasma concentrations (e.g. lipoproteins) [17].

Docetaxel clearance is largely hepatic and in addition to differences in the unbound fraction, interpatient variability in docetaxel exposure is largely attributable to CYP3A4 activity [14]. However, since CYP3A4 activity, is expected to be stable in individual patients, we do not expect CYP3A4 levels to explain why we did not observe a strong correlation between millidose and full dose clearance. Of note, several other studies found discrepancies between therapeutic and microdose PK-parameters, as has been discussed elsewhere [22].

Docetaxel dose optimization in individual patients remains an unresolved challenge. Although alternative methods like therapeutic drug monitoring and erythromycin breath tests have been proposed [23], these approaches have thus far failed to significantly reduce the interpatient variability in docetaxel exposure. Notably, chemotherapy-induced neutropenia has been linked to increased overall survival in non-small cell lung cancer patients [24]. Dose optimization algorithms based upon neutrophil counts after the first cycle of docetaxel have been suggested and deserve further clinical exploration [24]. Although docetaxel millidosing could not be used for dose optimization at the individual patient level, docetaxel clearance at milli- and therapeutic dose levels were within a two-fold range (geometric mean ratio 1.43) on a population level. This level of concordance is considered sufficient to facilitate pharmacokinetic studies that cannot be performed at therapeutic dose levels, like pharmacokinetic drug-drug interaction studies or pediatric studies [12].

MHVV and RtH wrote the main manuscript text and performed data analysis. RtH prepared the figures. HB and JD included patients and retrieved data, JN, RtH and HB designed the study. All authors reviewed the manuscript.

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