Population pharmacokinetics/pharmacodynamics of 3,4-diaminopyridine free base in patients with Lambert-Eaton myasthenia

Nilay Thakkar, Kathy Aleš, David Jacobus, Laura Jacobus, Charles Peloquin, Michael Cohen-Wolkowiez, Daniel Gonzalez, Vern C. Juel, Jeffrey T. Guptill, Janice M. Massey, Lisa D. Hobson-Webb, Katherine Beck, Yadollah Harati, Ali Arvantaj, Cecile Phan, Shima Mousavi, Claire Mac-Adam, A. Gordon Smith, J. Rob Singleton, Charles LatnerMeg Lessard, Amanda Peltier, Peter Donofrio, Christopher Lee, Kay Artibee, Jau Shin Lou, Tessa Marburger, Alexandra Dimitrova, Brent Burroughs, Ghazaleh Jafari, Julie Khoury, Mananya Satayaprasert, Diana Dimitrova, Robert M. Pascuzzi, Cynthia Bodkin, John Kincaid, Riley Snook, Angela Micheels, Sandra Guingrich, David P. Richman, Mark A Agius, Janelle Butters, Molly Lindsay, Vardenick Khalatyan

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two-compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (Emax) model characterized the exposureresponse relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4-DAP free base.

Original languageEnglish (US)
Pages (from-to)525-534
Number of pages10
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume6
Issue number9
DOIs
StatePublished - Sep 1 2017

ASJC Scopus subject areas

  • Modeling and Simulation
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

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    Thakkar, N., Aleš, K., Jacobus, D., Jacobus, L., Peloquin, C., Cohen-Wolkowiez, M., Gonzalez, D., Juel, V. C., Guptill, J. T., Massey, J. M., Hobson-Webb, L. D., Beck, K., Harati, Y., Arvantaj, A., Phan, C., Mousavi, S., Mac-Adam, C., Smith, A. G., Rob Singleton, J., ... Khalatyan, V. (2017). Population pharmacokinetics/pharmacodynamics of 3,4-diaminopyridine free base in patients with Lambert-Eaton myasthenia. CPT: Pharmacometrics and Systems Pharmacology, 6(9), 525-534. https://doi.org/10.1002/psp4.12218