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Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing’s Disease Patients

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Abstract

Background and Objective

Pasireotide (SOM230, Signifor®) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing’s disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing’s disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics.

Methods

The analysis dataset included five phase I studies and one each from phase II and phase III. A three-compartment, linear structural pharmacokinetic model was used. Models were specified a priori that varied in the relationship between HVs and CDPs, and the model with the lowest value of the Bayes Information Criterion (BIC) was selected. It was then used to illustrate various features of pasireotide pharmacokinetics.

Results and Conclusions

In the final model, the estimated values of apparent clearance (CL/F), central volume of distribution, and deep peripheral volume of distribution of pasireotide in CDP were 59, 43, and 225% those of HVs at the same age and body size. Clearance increased with body size and decreased with age similarly for CDPs and HVs. The estimated CL/F for a typical CDP (40 years old, lean body weight [LBW] 49 kg) was 3.72 L/h, and for a typical HV (29 years old, LBW 61 kg) was 7.96 L/h. The model was judged adequate by visual predictive checks and diagnostic plots separately for HVs and CDPs and can be used for simulations for deriving exposure–response metrics for pharmacokinetic/pharmacodynamic analyses.

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Acknowledgements

The authors are grateful to the following colleagues who over the years have contributed to the PopPK modelling effort for pasireotide: programming—Vincent Buchheit, Clarisse Chavanne, and Gregory Pinault; and data analysis—Ulrika Waehlby Hamrén and Justin Wilkins.

Author information

Author notes

  1. Jerry Nedelman

    Present address: TB Alliance, 40 Wall St # 24, New York, NY, 10005, USA

  2. Roland Fisch

    Present address: Im Rotländ 21, CH-4112, Flüh, Switzerland

  3. Ke Hu

    Present address: Rafael Pharmaceuticals, 520 Broad St, Newark, NJ, 07102, USA

  4. Jocelyn Zhou

    Present address: Novartis Sandoz Division, 100 College Road West, Princeton, NJ, USA

Authors and Affiliations

  1. Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936, USA

    Jerry Nedelman, Ke Hu & Jocelyn Zhou

  2. Modeling and Simulation, Novartis Pharma AG, Postfach, CH-4002, Basel, Switzerland

    Roland Fisch & Ines Paule

Authors
  1. Jerry Nedelman
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Corresponding author

Correspondence to Jocelyn Zhou.

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Funding

The studies and analysis reported here were sponsored and performed by Novartis. Jerry Nedelman, Roland Fisch, and Ke Hu were employees of Novartis at the time of this work. The authors agreed to submit the manuscript for publication.

Conflicts of interest

Jerry Nedelman, Roland Fisch, Ke Hu, Ines Paule, and Jocelyn Zhou were or are current employees of Novartis. There is no other conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the individual studies.

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Nedelman, J., Fisch, R., Hu, K. et al. Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing’s Disease Patients. Clin Pharmacokinet 57, 855–866 (2018). https://doi.org/10.1007/s40262-017-0600-y

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  • DOI: https://doi.org/10.1007/s40262-017-0600-y

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