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

Our plain-English summary of Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose, by M. Van Nuland, H. Rosing, B. Thijssen, et al (Clinical Pharmacology in Drug Development, 2020).

The study

• Authors: M. Van Nuland, H. Rosing, B. Thijssen, J.A. Burgers, A.D.R. Huitema, S. Marchetti, J.H.M. Schellens, J.H. Beijnen
• Journal: Clinical Pharmacology in Drug Development
• Published: 2020;9(8):929-937
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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/m2 ) 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 (AUC0-8 ) of gemcitabine after microdosing was 0.00074 h·mg/L and after therapeutic dosing was 16 h·mg/L. The mean AUC0-8 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/m2 . However, the shape of the concentration-time 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 AUC0-8 of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg/m2 . 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.

© 2020, The American College of Clinical Pharmacology.

In plain English

This pilot study concerned the cancer drug gemcitabine, not asbestos. The authors tested whether a tiny 'microdose' (100 µg) of gemcitabine could predict how the body handles a full treatment dose (1250 mg/m2). Both doses were given as 30-minute intravenous infusions in a crossover design. Ten patients were enrolled; one was excluded after receiving 1 mg because of a production error. The nine patients analyzed were being treated for non–small cell lung cancer (4), mesothelioma (3) or thymoma (2). The article does not report any asbestos exposure. Mean gemcitabine exposure (AUC over 8 hours) was 0.00074 h·mg/L after the microdose and 16 h·mg/L after the treatment dose. Exposure and clearance were predictable within the authors' 2-fold criterion. Volume of distribution (939 L versus 222 L) and elimination rate were not. Dose-adjusted microdose levels of phosphorylated drug inside blood cells were 32 times the treatment-dose levels for gemcitabine and 13 times for its metabolite dFdU. No adverse events were reported after the microdose. The authors concluded that the microdose could not predict all measures, which shows limits of the approach in this case.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: prospective, open-label, single-arm microdose study with a crossover design (pharmacokinetic pilot study)
• Who was studied: Adult patients with solid tumors scheduled for gemcitabine treatment. The nine analyzed patients had non–small cell lung cancer (n = 4), mesothelioma (n = 3) or thymoma (n = 2). The study was registered in the Netherlands Trial Register.
• Exposure: The drug gemcitabine, given as a 100 µg microdose and then a 1250 mg/m2 therapeutic dose, both by 30-minute intravenous infusion. No asbestos or fiber exposure was studied.
• Main results:
  • Ten patients were enrolled. One was excluded from analysis for receiving 1 mg instead of 100 µg, leaving nine patients analyzed.
  • Mean gemcitabine AUC over 8 hours was 0.00074 h·mg/L after the microdose and 16 h·mg/L after the therapeutic dose.
  • Gemcitabine AUC and clearance at the therapeutic dose could be predicted from the microdose within the 2-fold criterion.
  • Volume of distribution was 939 L after the microdose and 222 L after the therapeutic dose.
  • Volume of distribution and elimination rate constant at the therapeutic dose were not predictable from the microdose within a 2-fold ratio.
  • Mean AUC over 8 hours of the metabolite dFdU was 0.022 h·mg/L after the microdose and 169 h·mg/L after the therapeutic dose.
  • The dFdU AUC predicted from the microdose by linear extrapolation was 330 h·mg/L.
  • The ratio between the predicted and observed dFdU AUCs was exactly 2.
  • Inside blood cells (PBMCs), the ratio of dose-adjusted microdose concentrations to therapeutic-dose concentrations was 13 for phosphorylated dFdU and 32 for phosphorylated gemcitabine. The authors judged these not predictable.
  • No adverse events were reported after the microdose.
• The authors' conclusion: The authors concluded that volume of distribution, elimination rate constant and intracellular pharmacokinetics at the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case.
• Limitations the authors state:
  • The noncompartmental analysis means the calculated half-lives underestimate the terminal elimination phase.
  • Intracellular metabolites could not be quantified individually.
  • Although within 2-fold, the microdose underpredicted exposure by 1.5-fold.
  • The elimination rate was estimated from the last 3 measurements, and the exact elimination profile is unknown.

Topics

Medical terms in this study, explained in our Lexicon: Gemcitabine.

Related studies

• A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies — J.P. Delord, E. Raymond, et al. (2000)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)
• Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial — C.J. de Gooijer, V. van der Noort, et al. (2021)
• Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts — S.E. Pratt, S. Durland-Busbice, et al. (2013)
• The role of gemcitabine in the treatment of malignant mesothelioma — H.L. Kindler, J.P. van Meerbeeck (2002)
• Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor — S.G. Gray, A.M. Baird, et al. (2012)

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