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A Minimal PBPK Model for Plasma and Cerebrospinal Fluid Pharmacokinetics of Trastuzumab after Intracerebroventricular Administration in Patients with HER2-Positive Brain Metastatic Localizations

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Abstract

Background

Dosing regimens of trastuzumab administered by intracerebroventricular (icv) route to patients with HER2-positive brain localizations remain empirical. The objectives of this study were to describe pharmacokinetics (PK) of trastuzumab in human plasma and cerebrospinal fluid (CSF) after simultaneous icv and intravenous (iv) administration using a minimal physiologically-based pharmacokinetic model (mPBPK) and to perform simulations of alternative dosing regimens to achieve therapeutic concentrations in CSF.

Methods

Plasma and CSF PK data were collected in two patients with HER2-positive brain localizations. A mPBPK model for mAbs consisting of four compartments (tight and leaky tissues, plasma and lymph) was enriched by an additional compartment for ventricular CSF. The comparison between observed and model-predicted concentrations was evaluated using prediction error (PE).

Results

The developed mPBPK model described plasma and CSF trastuzumab concentrations reasonably well with mean PE for plasma and CSF data of 41.8% [interquartile range, IQR = -9.48; 40.6] and 18.3% [-36.7; 60.6], respectively, for patient 1 and 11.4% [-10.8; 28.7] and 22.5% [-27.7; 77.9], respectively, for patient 2. Trastuzumab showed fast clearance from CSF to plasma with Cmin,ss of 0.56 and 0.85 mg/L for 100 and 150 mg q1wk, respectively. Repeated dosing of 100 and 150 mg q3day resulted in Cmin,ss of 10.3 and 15.4 mg/L, respectively. Trastuzumab CSF target concentrations are achieved rapidly and maintained above 60 mg/L from 7 days after a continuous perfusion at 1.0 mg/h.

Conclusion

Continuous icv infusion of trastuzumab at 1.0 mg/h could be an alternative dosing regimen to rapidly achieve intraventricular CSF therapeutic concentrations.

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Data Availability

The datasets analysed during the current study are available from the corresponding author on reasonable request.

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The authors did not receive support from any organization for the submitted work.

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Authors and Affiliations

  1. Université Paris Cité, Inserm UMRS1144, Paris, France

    Alicja Puszkiel, Lucie Chevillard, Stéphane Goutagny & Xavier Declèves

  2. Laboratory of Pharmacology and Toxicology, Cochin University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    Alicja Puszkiel & Xavier Declèves

  3. Oncology Department, Avicenne Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    Guilhem Bousquet

  4. Université Paris Cité, Inserm UMR_S942 MASCOT, Paris, France

    Guilhem Bousquet

  5. Université Sorbonne Paris Nord, Villetaneuse, France

    Guilhem Bousquet

  6. Laboratory of Pharmacology, Toxicology and Pharmacogenetics, Grenoble-Alpes University Hospital, 38043, Grenoble, France

    Françoise Stanke-Labesque

  7. Université Grenoble Alpes, HP2 INSERM U1300, Grenoble, France

    Françoise Stanke-Labesque

  8. Department of Pharmacy, Beaujon Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    Jeanick Stocco

  9. Department of Neurosurgery, Beaujon University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    Philippe Decq & Stéphane Goutagny

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Puszkiel, A., Bousquet, G., Stanke-Labesque, F. et al. A Minimal PBPK Model for Plasma and Cerebrospinal Fluid Pharmacokinetics of Trastuzumab after Intracerebroventricular Administration in Patients with HER2-Positive Brain Metastatic Localizations. Pharm Res 40, 2687–2697 (2023). https://doi.org/10.1007/s11095-023-03614-w

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