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

4 Citations (Scopus)

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

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Pharmacodynamics
Pharmacokinetics
Metabolites
Orphan Drug Production
Investigational Drugs
Population
Compartment Model
Muscle Weakness
Clearance
Muscle
Disorder
Lower Extremity
Creatinine
Drugs
Fractional
Body Weight
Outcome Assessment (Health Care)
Model
Serum
3,4-diaminopyridine

ASJC Scopus subject areas

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

Cite this

Population pharmacokinetics/pharmacodynamics of 3,4-diaminopyridine free base in patients with Lambert-Eaton myasthenia. / Thakkar, Nilay; Aleš, Kathy; Jacobus, David; Jacobus, Laura; Peloquin, Charles; Cohen-Wolkowiez, Michael; Gonzalez, Daniel; Juel, Vern C.; Guptill, Jeffrey T.; Massey, Janice M.; Hobson-Webb, Lisa D.; Beck, Katherine; Harati, Yadollah; Arvantaj, Ali; Phan, Cecile; Mousavi, Shima; Mac-Adam, Claire; Smith, A. Gordon; Rob Singleton, J.; Latner, Charles; Lessard, Meg; Peltier, Amanda; Donofrio, Peter; Lee, Christopher; Artibee, Kay; Lou, Jau Shin; Marburger, Tessa; Dimitrova, Alexandra; Burroughs, Brent; Jafari, Ghazaleh; Khoury, Julie; Satayaprasert, Mananya; Dimitrova, Diana; Pascuzzi, Robert M.; Bodkin, Cynthia; Kincaid, John; Snook, Riley; Micheels, Angela; Guingrich, Sandra; Richman, David P.; Agius, Mark A.; Butters, Janelle; Lindsay, Molly; Khalatyan, Vardenick.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 6, No. 9, 01.09.2017, p. 525-534.

Research output: Contribution to journalArticle

Thakkar, N, Aleš, K, Jacobus, D, Jacobus, L, Peloquin, C, Cohen-Wolkowiez, M, Gonzalez, D, Juel, VC, Guptill, JT, Massey, JM, Hobson-Webb, LD, Beck, K, Harati, Y, Arvantaj, A, Phan, C, Mousavi, S, Mac-Adam, C, Smith, AG, Rob Singleton, J, Latner, C, Lessard, M, Peltier, A, Donofrio, P, Lee, C, Artibee, K, Lou, JS, Marburger, T, Dimitrova, A, Burroughs, B, Jafari, G, Khoury, J, Satayaprasert, M, Dimitrova, D, Pascuzzi, RM, Bodkin, C, Kincaid, J, Snook, R, Micheels, A, Guingrich, S, Richman, DP, Agius, MA, Butters, J, Lindsay, M & Khalatyan, V 2017, 'Population pharmacokinetics/pharmacodynamics of 3,4-diaminopyridine free base in patients with Lambert-Eaton myasthenia', CPT: Pharmacometrics and Systems Pharmacology, vol. 6, no. 9, pp. 525-534. https://doi.org/10.1002/psp4.12218
Thakkar, Nilay ; Aleš, Kathy ; Jacobus, David ; Jacobus, Laura ; Peloquin, Charles ; Cohen-Wolkowiez, Michael ; Gonzalez, Daniel ; Juel, Vern C. ; Guptill, Jeffrey T. ; Massey, Janice M. ; Hobson-Webb, Lisa D. ; Beck, Katherine ; Harati, Yadollah ; Arvantaj, Ali ; Phan, Cecile ; Mousavi, Shima ; Mac-Adam, Claire ; Smith, A. Gordon ; Rob Singleton, J. ; Latner, Charles ; Lessard, Meg ; Peltier, Amanda ; Donofrio, Peter ; Lee, Christopher ; Artibee, Kay ; Lou, Jau Shin ; Marburger, Tessa ; Dimitrova, Alexandra ; Burroughs, Brent ; Jafari, Ghazaleh ; Khoury, Julie ; Satayaprasert, Mananya ; Dimitrova, Diana ; Pascuzzi, Robert M. ; Bodkin, Cynthia ; Kincaid, John ; Snook, Riley ; Micheels, Angela ; Guingrich, Sandra ; Richman, David P. ; Agius, Mark A. ; Butters, Janelle ; Lindsay, Molly ; Khalatyan, Vardenick. / Population pharmacokinetics/pharmacodynamics of 3,4-diaminopyridine free base in patients with Lambert-Eaton myasthenia. In: CPT: Pharmacometrics and Systems Pharmacology. 2017 ; Vol. 6, No. 9. pp. 525-534.
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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.",
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AU - Jacobus, Laura

AU - Peloquin, Charles

AU - Cohen-Wolkowiez, Michael

AU - Gonzalez, Daniel

AU - Juel, Vern C.

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AU - Beck, Katherine

AU - Harati, Yadollah

AU - Arvantaj, Ali

AU - Phan, Cecile

AU - Mousavi, Shima

AU - Mac-Adam, Claire

AU - Smith, A. Gordon

AU - Rob Singleton, J.

AU - Latner, Charles

AU - Lessard, Meg

AU - Peltier, Amanda

AU - Donofrio, Peter

AU - Lee, Christopher

AU - Artibee, Kay

AU - Lou, Jau Shin

AU - Marburger, Tessa

AU - Dimitrova, Alexandra

AU - Burroughs, Brent

AU - Jafari, Ghazaleh

AU - Khoury, Julie

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AU - Pascuzzi, Robert M.

AU - Bodkin, Cynthia

AU - Kincaid, John

AU - Snook, Riley

AU - Micheels, Angela

AU - Guingrich, Sandra

AU - Richman, David P.

AU - Agius, Mark A.

AU - Butters, Janelle

AU - Lindsay, Molly

AU - Khalatyan, Vardenick

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N2 - 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.

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