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 Latner; Meg 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

doi:10.1002/psp4.12218

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

Neurology

Research output: Contribution to journal › Article › peer-review

9 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 language	English (US)
Pages (from-to)	525-534
Number of pages	10
Journal	CPT: Pharmacometrics and Systems Pharmacology
Volume	6
Issue number	9
DOIs	https://doi.org/10.1002/psp4.12218
State	Published - Sep 2017

ASJC Scopus subject areas

Modeling and Simulation
Pharmacology (medical)

Access to Document

10.1002/psp4.12218

Cite this

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

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

@article{69462a2cde7e4a829aa28c6ee25d95a7,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2017.",

year = "2017",

month = sep,

doi = "10.1002/psp4.12218",

language = "English (US)",

volume = "6",

pages = "525--534",

journal = "CPT: Pharmacometrics and Systems Pharmacology",

issn = "2163-8306",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Population pharmacokinetics/pharmacodynamics of 3,4-diaminopyridine free base in patients with Lambert-Eaton myasthenia

AU - Thakkar, Nilay

AU - Aleš, Kathy

AU - Jacobus, David

AU - Jacobus, Laura

AU - Peloquin, Charles

AU - Cohen-Wolkowiez, Michael

AU - Gonzalez, Daniel

AU - Juel, Vern C.

AU - Guptill, Jeffrey T.

AU - Massey, Janice M.

AU - Hobson-Webb, Lisa D.

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

AU - Satayaprasert, Mananya

AU - Dimitrova, Diana

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

PY - 2017/9

Y1 - 2017/9

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85029911627&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029911627&partnerID=8YFLogxK

U2 - 10.1002/psp4.12218

DO - 10.1002/psp4.12218

M3 - Article

C2 - 28623849

AN - SCOPUS:85029911627

SN - 2163-8306

VL - 6

SP - 525

EP - 534

JO - CPT: Pharmacometrics and Systems Pharmacology

JF - CPT: Pharmacometrics and Systems Pharmacology

IS - 9

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this