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Population PKPD of voclosporin in renal allograft patients
Author(s) -
Mayo P.R.,
Ling S.Y.,
Huizinga R.B.,
Freitag D.G.,
Aspeslet L.J.,
Foster R.T.
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.237
Subject(s) - medicine , urology , population , pharmacokinetics , clearance , dosing , volume of distribution , pharmacology , covariate , body surface area , mathematics , statistics , environmental health
The aims of this population‐pharmacokinetic/pharmacodynamic (POP‐PKPD) analysis of voclosporin in renal allograft patients were to build a POP‐PKPD model for voclosporin and calcineurin activity (CNa) and identify clinically relevant covariates that could assist dosing of the drug. POP‐PKPD modeling was performed using a stochastic approximation of the standard expectation maximization (SAEM) algorithm for nonlinear mixed‐effects as implemented in Monolix™ 3.2. Voclosporin whole blood concentrations were obtained from de novo renal allograft patients and assayed using a validated LC/MS/MS assay. CNa was measured using a 32 P‐radiolabeled assay. A two‐compartment model with simultaneous sigmoid inhibitory E max model was used to describe the PKPD relationship between voclosporin concentration and CNa. The POP‐PKPD model was then utilized to simulate an optimal initial dosing strategy. Eighty‐seven patients were included in the POP‐PKPD study. Population mean estimates (relative standard error, rse) for oral clearance (CL/F) and first compartment volume of distribution (V1), were 717 mL min −1 (35%) and 2010 mL (17%), respectively. Maximum CNa Inhibition (I max ), effective concentration (C 50 ), and baseline immunosuppression (S 0 ) were 0.87 pmol/min/mg (8.0%), 123 ng/mL (10%), and 1.15 pmol/min/mg (4.0%), respectively. Covariate analyses demonstrated that age and body surface area significantly influenced CL/F: C L i = 717 ( Ag e i / 48.8 ) − 0.57( BS A i / 1.99 ) 1.1, while serum triglycerides significantly altered S 0 :S 0 i = 1.15 ( TRI G i / 1.97 ) 0.15.