Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing’s Disease Patients
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.
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.
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.
Compliance with Ethical Standards
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.
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 was obtained from all individual participants included in the individual studies.
- 6.Signifor label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Accessed 29 Dec 2016.
- 7.Golor G, Hu K, Ruffin M, Buchelt A, Bouillaud E, Wang Y, et al. A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers. Drug Des Devel Ther. 2016;6:71–9.Google Scholar
- 9.Petersenn S, Hu K, Maldonado M, Zhang Y, Lasher J, Bouillaud E, et al. Tolerability and dose proportional pharmacokinetics of pasireotide administered as a single dose or two divided doses in healthy male volunteers: a single-center, open-label, ascending-dose study. Clin Ther. 2012;34:677–88.CrossRefPubMedGoogle Scholar
- 10.Petersenn S, Unger N, Hu K, Weisshaar B, Zhang Y, Bouillaud E, et al. Pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue, is well tolerated when administered as a continuous 7-day subcutaneous infusion in healthy male volunteers. J Clin Pharmacol. 2012;52:1017–27.CrossRefPubMedGoogle Scholar
- 14.Burnham KP, Anderson DR. Model selection and multimodel inference: a practical information-theoretic approach. 2nd ed. New York: Springer; 2010.Google Scholar
- 19.Bonate P. Pharmacokinetic-pharmacodynamic modeling and simulation. New York: Springer; 2006.Google Scholar
- 20.FDA Office of Clinical Pharmacology. Good review practices: clinical pharmacology review of New Molecular Entity (NME) New Drug Applications (NDAs) and original Biologics License Applications (BLAs). https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffPoliciesandProcedures/ucm073007.pdf. Accessed 11 Jun 2017.