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Population pharmacokinetics of kahalalide F in advanced cancer patients

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Abstract

Purpose

In this study, we characterize the population pharmacokinetics of kahalalide F (KF), a novel marine anticancer drug, after intravenous (i.v.) administration in advanced cancer patients.

Methods

Data from 240 patients included in three Phase I and three Phase II trials receiving i.v. weekly and every 3 weeks infusions of KF, at doses ranging 266–6650 µg/m2, were analyzed using NONMEM™ VII. The effect of demographics and/or pathophysiologically relevant factors on KF pharmacokinetic parameters was evaluated. Model evaluation was conducted using nonparametric bootstrap and visual predictive check (in both internal and external datasets).

Results

An open two-compartment model with linear distribution and elimination from central compartment was suitable to describe the data. Volume of distribution at steady state and its between-subject variability (CV%) was estimated to be 6.56 L (28 %). Plasma clearance was estimated to be 6.25 L/h (43 %). Within the range of covariates evaluated, age, weight, body surface area, gender, ECOG performance status, presence of liver metastases, creatinine clearance, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein and serum albumin did not contribute to explain KF pharmacokinetic variability to a significant extent. The developed model was deemed appropriate to describe the time course of KF plasma concentrations and its variability in advanced cancer patients.

Conclusion

The integration of pharmacokinetic data from six clinical studies demonstrated KF linear elimination from plasma, dose-proportional exposure and time-independent pharmacokinetics. Based on analyzed data, no clinically relevant covariates were identified as predictors of KF pharmacokinetics.

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Acknowledgments

The authors would like to thank the hundreds of patients, investigators and their medical, nursing and laboratory staff that participated in the clinical studies included in the present pooled study. We also thank Hilde Rosing and Josh H. Beijnen (Slootervart Hospital, Amsterdam, the Netherlands) for their bioanalysis work provided during this development of KF.

Conflict of interest

Bernardo Miguel-Lillo and Arturo Soto-Matos are employees of Pharma Mar SA, which supported this study. No other conflict of interest was declared.

Author information

Authors and Affiliations

  1. Clinical Pharmacology, Pharma Mar, Madrid, Spain

    Bernardo Miguel-Lillo & Arturo Soto-Matos

  2. Platform of Oncology, Hospital Quirón Torrevieja, Torrevieja, Spain

    Belén Valenzuela

  3. Cathedra of Multidisciplinary Oncology, UCAM Catholic University of San Antonio, Murcia, Spain

    Belén Valenzuela

  4. Pharmacy and Pharmaceutical Technology Department, Valencia University, Valencia, Spain

    José Esteban Peris-Ribera

  5. Clinical Development, Pharma Mar, Madrid, Spain

    Arturo Soto-Matos

  6. Model Based Drug Development, Janssen Research & Developments, Beerse, Belgium

    Juan José Pérez-Ruixo

  7. Department of Clinical Pharmacology, Clinical Research and Development of Pharma Mar, Avenida de los Reyes, 1, Po. Ind. La Mina, 28770, Colmenar Viejo, Madrid, Spain

    Bernardo Miguel-Lillo

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  1. Bernardo Miguel-Lillo
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  2. Belén Valenzuela
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  3. José Esteban Peris-Ribera
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  4. Arturo Soto-Matos
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  5. Juan José Pérez-Ruixo
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Correspondence to Bernardo Miguel-Lillo.

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Miguel-Lillo, B., Valenzuela, B., Peris-Ribera, J.E. et al. Population pharmacokinetics of kahalalide F in advanced cancer patients. Cancer Chemother Pharmacol 76, 365–374 (2015). https://doi.org/10.1007/s00280-015-2800-1

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