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
N1 - Funding Information:
Conflict of Interest. This study was funded by Jacobus Pharmaceutical Company. D.G. receives support for research from the National Institute for Child Health and Human Development (K23HD083465), the nonprofit organization Thrasher Research Fund (www.thrasherresearch. org), and from industry (Cempra, Inc. and Jacobus Pharmaceutical Company, Inc.) for drug development in adults and children. M.C.W. receives support for research from the National Institutes of Health (NIH; 1R01-HD076676–01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the NIAID (HHSN272201500006I and HHSN272201300017I), the NICHD (HHSN275201000003I), the US Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), the nonprofit Thrasher Research Fund (www.thrasherresearch.org), and from industry for drug development in adults and children (www.dcri.duke. edu/research/coi.jsp). J.T.G. receives support for research from the NIH (K23NS085049), the Myasthenia Gravis Foundation of America and from industry for drug development in adults (www.dcri.duke.edu/research/coi. jsp). The remaining authors have no conflicts of interest to disclose.
Publisher Copyright:
© 2017.
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.
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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 -