Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose

Abstract

Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the pharmacokinetics of gemcitabine at a therapeutic dose could be predicted from the pharmacokinetics of a microdose. In this prospective, open-label microdosing study, a gemcitabine microdose (100 µg) was given intravenously to participants on day 1, followed by a therapeutic dose (1250 mg/m 2) on day 2. Gemcitabine and its metabolite 2',2'-difluorodeoxyuracil (dFdU) were quantified in plasma and intracellularly by using liquid chromatography-mass spectrometry). Noncompartmental pharmacokinetic analysis was performed. Ten patients participated in this study. The mean area under the plasma concentration-time curve (AUC 0-8) of gemcitabine after microdosing was 0.00074 h•mg/L and after therapeutic dosing was 16 h•mg/L. The mean AUC 0-8 of dFdU following the microdose and therapeutic dose were 0.022 h•mg/L and 169 h•mg/L, respectively. Exposure to gemcitabine after the therapeutic dose was within 2-fold of the exposure following a microdose, when linearly extrapolated to 1250 mg/m 2. However, the shape of the concentrationtime curve was different, as reflected by poor scalability in volume of distribution (939 L versus 222 L). Furthermore, intracellularly phosphorylated gemcitabine and phosphorylated dFdU levels could not be predicted from the microdose. The AUC 0-8 of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg/m 2. Volume of distribution, elimination rate constant, and intracellular pharmacokinetics of the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case.

A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens

“…Figure 4 depicts differences in the shape of the pharmacokinetic curve for gemcitabine and dFdU The results from the NPD modeling approach were not fully in accordance with the previously published evaluation of gemcitabine, dFdU, and anastrozole microdose predictability based on NCA (see Table 3). 11,16 The gemcitabine Phase 0 microdose reported predictability for the gemcitabine pharmacokinetic metrics AUC 0-8 , AUC inf , maximum concentration (C max ), and clearance, whereas elimination rate constant, terminal half-life (t 1/2 ), and volume of distribution fell outside the two-fold. In addition, the NPD modeling approach demonstrated a difference in shape of the pharmacokinetics profile between the microdose and therapeutic dose despite having similar AUC values.…”

“…c Area under the concentration time curve (AUC) from zero to 8 h, AUC extrapolated to infinity, maximum concentration, and clearance met the two-fold criterion whereas elimination rate constant, half-life, and volume of distribution did not. 16 the anticipated range of exposure. Therefore, microdose Phase 0 trials have the potential reduce the number of dose levels in Phase I clinical trials.…”

“…The trial received institutional ethical approval, was conducted in accordance with the principles of the Declaration of Helsinki, and was registered in the Netherlands Trial Register (NTR6183). The study design and results of the NCA have been described in detail previously 16 …”

“…Patient characteristics are described in Table S1. Patients received 100 μg gemcitabine and 1250 mg/m 2 gemcitabine within a 24‐h interval 16 . Both the microdose and therapeutic dose were administered as a 30‐min i.v.…”

“…The study design and results of the NCA have been described in detail previously. 16 Ten patients (>18 years old) with solid tumors and an indication for treatment with gemcitabine according to standard of care were included in the study. Patient characteristics are described in Table S1.…”