Skip to main content

Advertisement

SpringerLink
Log in

Model-Based Evaluation of the Impact of Formulation and Food Intake on the Complex Oral Absorption of Mavoglurant in Healthy Subjects

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To compare the pharmacokinetics of intravenous (IV), oral immediate-release (IR) and oral modified-release (MR) formulations of mavoglurant in healthy subjects, and to assess the food effect on the MR formulation’s input characteristics.

Methods

Plasma concentration-time data from two clinical studies in healthy volunteers were pooled and analysed using NONMEM®. Drug entry into the systemic circulation was modelled using a sum of inverse Gaussian (IG) functions as an input rate function, which was estimated specifically for each formulation and food state.

Results

Mavoglurant pharmacokinetics was best described by a two-compartment model with a sum of either two or three IG functions as input function. The mean absolute bioavailability from the MR formulation (0.387) was less than from the IR formulation (0.436). The MR formulation pharmacokinetics were significantly impacted by food: bioavailability was higher (0.508) and the input process was shorter (complete in approximately 36 versus 12 h for the fasted and fed states, respectively).

Conclusions

Modelling and simulation of mavoglurant pharmacokinetics indicate that the MR formulation might provide a slightly lower steady-state concentration range with lower peaks (possibly better drug tolerance) than the IR formulation, and that the MR formulation’s input properties strongly depend on the food conditions at drug administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

BQL:

Below the quantification limit

BW:

Actual bodyweight

CL:

Plasma clearance

IG:

Inverse Gaussian

IMPMAP:

Monte Carlo importance sampling method assisted by mode a posteriori with interaction

IR:

Immediate-release

ISV:

Intersubject variability

IV:

Intravenous

mGluR5:

Metabotropic glutamate receptor 5

MR:

Modified-release

OFV:

Objective function minimum value

Q:

Inter-compartmental clearance

Vc:

Volume of distribution of the central compartment

Vp:

Volume of distribution of the peripheral compartment

REFERENCES

  1. Glass IA. X linked mental retardation. J Med Genet. 1991;28:361–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Brown WT, Jenkins EC, Cohen IL, Fisch GS, Wolf-Schein EG, Gross A, et al. Fragile X and autism: a multicenter survey. Am J Med Genet. 1986;23:341–52.

    Article  CAS  PubMed  Google Scholar 

  3. Li SY, Chen YC, Lai TJ, Hsu CY, Wang YC. Molecular and cytogenetic analyses of autism in Taiwan. Hum Genet. 1993;92:441–5.

    Article  CAS  PubMed  Google Scholar 

  4. Estecio M, Fett-Conte AC, Varella-Garcia M, Fridman C, Silva AE. Molecular and cytogenetic analyses on Brazilian youths with pervasive developmental disorders. J Autism Dev Disord. 2002;32:35–41.

    Article  PubMed  Google Scholar 

  5. Reddy KS. Cytogenetic abnormalities and fragile-X syndrome in autism spectrum disorder. BMC Med Genet. 2005;6:3.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122:4314–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Dolen G, Carpenter RL, Ocain TD, Bear MF. Mechanism-based approaches to treating fragile X. Pharmacol Ther. 2010;127:78–93.

    Article  PubMed  Google Scholar 

  8. Levenga J, Hayashi S, de Vrij FM, Koekkoek SK, van der Linde HC, Nieuwenhuizen I, et al. AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol Dis. 2011;42:311–7.

    Article  CAS  PubMed  Google Scholar 

  9. Gantois I, Pop AS, de Esch CE, Buijsen RA, Pooters T, Gomez-Mancilla B, et al. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav Brain Res. 2013;239:72–9.

    Article  CAS  PubMed  Google Scholar 

  10. Pop AS, Levenga J, de Esch CE, Buijsen RA, Nieuwenhuizen IM, Li T, et al. Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant. Psychopharmacology. 2014;231:1227–35.

    Article  CAS  PubMed  Google Scholar 

  11. Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3:64ra61.

    Article  Google Scholar 

  12. Walles M, Wolf T, Jin Y, Ritzau M, Leuthold LA, Krauser J, et al. Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects. Drug Metab Dispos. 2013;41:1626–41.

    Article  CAS  PubMed  Google Scholar 

  13. Berg D, Godau J, Trenkwalder C, Eggert K, Csoti I, Storch A, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011;26:1243–50.

    Article  PubMed  Google Scholar 

  14. Stocchi F, Rascol O, Destee A, Hattori N, Hauser RA, Lang AE, et al. AFQ056 in Parkinson patients with levodopa-induced dyskinesia: 13-week, randomized, dose-finding study. Mov Disord. 2013;28:1838–46.

    Article  CAS  PubMed  Google Scholar 

  15. Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60:717–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Zhou H. Pharmacokinetic strategies in deciphering atypical drug absorption profiles. J Clin Pharmacol. 2003;43:211–27.

    Article  CAS  PubMed  Google Scholar 

  17. Jakab A, Winter S, Raccuglia M, Picard F, Dumitras S, Woessner R, et al. Validation of an LC-MS/MS method for the quantitative determination of mavoglurant (AFQ056) in human plasma. Anal Bioanal Chem. 2013;405:215–23.

    Article  CAS  PubMed  Google Scholar 

  18. Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM 7.2.0 users' guides. Ellicott City: ICON Development Solutions; 2011.

    Google Scholar 

  19. Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed. 2005;79:241–57.

    Article  Google Scholar 

  20. R.D.C. Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2009.

    Google Scholar 

  21. Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34:711–26.

    Article  CAS  PubMed  Google Scholar 

  22. Holford NH, Ambros RJ, Stoeckel K. Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil. J Pharmacokinet Biopharm. 1992;20:421–42.

    Article  CAS  PubMed  Google Scholar 

  23. Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm. 1993;21:735–50.

    Article  CAS  PubMed  Google Scholar 

  24. Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28:481–504.

    Article  CAS  PubMed  Google Scholar 

  25. Csajka C, Drover D, Verotta D. The use of a sum of inverse Gaussian functions to describe the absorption profile of drugs exhibiting complex absorption. Pharm Res. 2005;22:1227–35.

    Article  CAS  PubMed  Google Scholar 

  26. Weiss M. A novel extravascular input function for the assessment of drug absorption in bioavailability studies. Pharm Res. 1996;13:1547–53.

    Article  CAS  PubMed  Google Scholar 

  27. Gueorguieva I, Ogungbenro K, Graham G, Glatt S, Aarons L. A program for individual and population optimal design for univariate and multivariate response pharmacokinetic-pharmacodynamic models. Comput Methods Prog Biomed. 2007;86:51–61.

    Article  Google Scholar 

  28. Duffull SB, Dooley MJ, Green B, Poole SG, Kirkpatrick CM. A standard weight descriptor for dose adjustment in the obese patient. Clin Pharmacokinet. 2004;43:1167–78.

    Article  PubMed  Google Scholar 

  29. Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009;11:558–69.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Bergstrand M, Karlsson MO. Handling data below the limit of quantification in mixed effect models. AAPS J. 2009;11:371–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Shen J, Boeckmann A, Vick A. Implementation of dose superimposition to introduce multiple doses for a mathematical absorption model (transit compartment model). J Pharmacokinet Pharmacodyn. 2012;39:251–62.

    Article  CAS  PubMed  Google Scholar 

  32. Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol. 2002;42:620–43.

    Article  CAS  PubMed  Google Scholar 

  33. Karmakar MK, Ho AM, Law BK, Wong AS, Shafer SL, Gin T. Arterial and venous pharmacokinetics of ropivacaine with and without epinephrine after thoracic paravertebral block. Anesthesiology. 2005;103:704–11.

    Article  CAS  PubMed  Google Scholar 

  34. Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, et al. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther. 2002;71:286–96.

    Article  CAS  PubMed  Google Scholar 

  35. Lotsch J, Weiss M, Ahne G, Kobal G, Geisslinger G. Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers. Anesthesiology. 1999;90:1026–38.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang X, Nieforth K, Lang JM, Rouzier-Panis R, Reynes J, Dorr A, et al. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition. Clin Pharmacol Ther. 2002;72:10–9.

    Article  CAS  PubMed  Google Scholar 

  37. Chhikara R, Folks JL. The inverse Gaussian distribution as a lifetime model. Technometrics. 1977;19:461–8.

    Article  Google Scholar 

  38. Tannergren C, Bergendal A, Lennernas H, Abrahamsson B. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment. Mol Pharm. 2009;6:60–73.

    Article  CAS  PubMed  Google Scholar 

  39. Olivares-Morales A, Kamiyama Y, Darwich A, Aarons L, Rostami-Hodjegan A. Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model. Eur J Pharm Sci. 2014. doi:10.1016/j.ejps.2014.10.018.

    PubMed Central  Google Scholar 

  40. Weitschies W, Wedemeyer RS, Kosch O, Fach K, Nagel S, Soderlind E, et al. Impact of the intragastric location of extended release tablets on food interactions. J Control Release Off J Control Release Soc. 2005;108:375–85.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Nikolaos Tsamandouras (Manchester Pharmacy School, The University of Manchester, Manchester, United-Kingdom), for providing technical support including the methodology on the use of the logistic-normal distribution; Andres Olivares-Morales (Manchester Pharmacy School, The University of Manchester, Manchester, United-Kingdom) for the invaluable discussions on absorption mechanisms; Subramanian Ganesan (Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Hyderabad, India) for the useful discussions on mavoglurant pharmacokinetics.

Author information

Authors and Affiliations

  1. Manchester Pharmacy School, The University of Manchester, Manchester, UK

    Thierry Wendling, Kayode Ogungbenro & Leon Aarons

  2. Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland

    Thierry Wendling, Swati Dumitras & Ralph Woessner

  3. Pharmacometrics, Novartis Pharma AG, Basel, Switzerland

    Etienne Pigeolet

Authors
  1. Thierry Wendling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kayode Ogungbenro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Etienne Pigeolet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Swati Dumitras
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ralph Woessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leon Aarons
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leon Aarons.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 1.01 MB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wendling, T., Ogungbenro, K., Pigeolet, E. et al. Model-Based Evaluation of the Impact of Formulation and Food Intake on the Complex Oral Absorption of Mavoglurant in Healthy Subjects. Pharm Res 32, 1764–1778 (2015). https://doi.org/10.1007/s11095-014-1574-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1574-1

KEY WORDS

Search

Navigation