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Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects

Evidence for Injection Interval of Up to 2 Months

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Abstract

Background and objective

Lanreotide is a somatostatin analogue used for the treatment of acromegaly and neuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustainedrelease formulation lanreotide Autogel® after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose.

Subjects and methods

This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4–7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18–45 years were included. Subjects received a rapid intravenous bolus of 7 μg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel® at a dose of 60, 90 or 120 mg.

Pharmacokinetic and statistical analysis

Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4- to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel®. Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM® version VI software. The model was validated externally using data from patients with acromegaly.

Results

In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel® 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel® pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel® was 63%. The rate of absorption and bioavailability of lanreotide Autogel® were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05).

Conclusions

Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 μg/kg) and the pharmacokinetics of lanreotide Autogel® after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel® to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel® was independent of the dose and was not affected by sex.

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Acknowledgements

The clinical study in healthy subjects was designed by Ipsen Pharma S.p.A. and the Institute for Pharmacokinetics and Analytical Studies (IPAS), conducted at the IPAS clinic (Ligornetto, Switzerland) and coordinated by Ipsen. All pharmacokinetics-related activities, including assays of lanreotide plasma concentrations and pharmacokinetic analyses, were performed by Ipsen in collaboration with University of Navarra. Maria Garrido and Iñaki Trocóniz have received research funding from Ipsen. Josep-María Cendrós, Concepción Peraire, Joaquim Ramis and Paolo Boscani are employed by Ipsen. The manuscript was prepared by Rosendo Obach, an employee of Ipsen.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain

    Iñaki F. Trocóniz & Maria J. Garrido

  2. Pharmacokinetics and Metabolism Service, Ipsen Pharma S.A., Sant Feliu de Llobregat, Barcelona, Spain

    Josep-María Cendrós, Concepción Peraire, Joaquim Ramis &  Rosendo Obach

  3. Ipsen S.p.A., Milan, Italy

    Paolo F. Boscani

Authors
  1. Iñaki F. Trocóniz
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  2. Josep-María Cendrós
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  3. Concepción Peraire
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  4. Joaquim Ramis
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  5. Maria J. Garrido
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  6. Paolo F. Boscani
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  7. Rosendo Obach
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Corresponding author

Correspondence to Rosendo Obach.

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Trocóniz, I.F., Cendrós, JM., Peraire, C. et al. Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects. Clin Pharmacokinet 48, 51–62 (2009). https://doi.org/10.2165/0003088-200948010-00004

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