Population PKPD of voclosporin in renal allograft patients.
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 Emax 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 (Imax), effective concentration (C50), and baseline immunosuppression (S0) 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: CLi=717(Agei/48.8)-0.57(BSAi/1.99)1.1, while serum triglycerides significantly altered S0: S0i=1.15(TRIGi/1.97)0.15.
Isotechnika Pharma Inc., Edmonton, AB, Canada.
P R
PR
Mayo
Isotechnika Pharma Inc., Edmonton, AB, Canada.
S Y
SY
Ling
Isotechnika Pharma Inc., Edmonton, AB, Canada.
R B
RB
Huizinga
Isotechnika Pharma Inc., Edmonton, AB, Canada.
D G
DG
Freitag
Isotechnika Pharma Inc., Edmonton, AB, Canada.
L J
LJ
Aspeslet
Isotechnika Pharma Inc., Edmonton, AB, Canada.
R T
RT
Foster
D000328:Adult; D019703:Calcineurin / Q000097:blood; D065095:Calcineurin Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D014184:Transplantation, Homologous
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C484071:voclosporin; D016572:Cyclosporine; D019703:Calcineurin
calcineurin inhibition; pharmacodynamics; population pharmacokinetics; transplantation; voclosporin