March 17th 2011

1. Version PFIM Interface 3.1

PFIM Interface 3.1 is an extension of the version PFIM Interface 2.1 and is based on an extension of the R script version PFIM 3.0 dedicated to design evaluation and optimisation for multiple response models.
This interface version is extended for multiple response models. It can also be used for single response models instead of PFIM interface 2.1 to compute the Fisher information matrix for nonlinear mixed effects models. In addition to this extension, options have been added for model specification and development of the expression of the Fisher information matrix (MF). Regarding model specification, the library of standard PK models has been completed with three compartment models with linear elimination and models with Michaelis-Menten elimination (one, two and three compartment models). Furthermore, a library of pharmacodynamic (PD) models is now available. Concerning the expression of the Fisher information matrix, PFIM Interface 3.1 can handle either a block diagonal Fisher information matrix or a full one.

2. Version PFIM 3.2.2 (Release of new library documentation + bug correction for PFIM with inter-occasion variability in case of 4 occasions or more + with discrete covariates on several parameters)

This new update includes a new documentation of the library of models implemented in PFIM 3.2, presenting mathematical expressions for one, two and three compartment pharmacokinetic models with linear elimination or with Michaelis-Menten elimination as well as for pharmacodynamic models. 
Furthermore, an error in the previous version concerning the implementation of the block of variance terms for inter-occasion variability (IOV) in the Fisher information matrix, which leads to under-predict the standard errors of IOV in case of 4 occasions or more, has been fixed. A bug concerning discrete covariates when considering the same covariate effect on several parameters has also been corrected. This was an output problem for covariates only and did not impact the criterion.

July 12th 2010

Version PFIM 3.2.1 (change of the file libFED.dll + bug correction in the call of the Fedorov-Wynn algorithm + bug correction in the PD libraries)

A bug in the call of the Fedorov-Wynn algorithm has also been corrected. The bug concerned the generation of the list of possible elementary designs in the initial step of design optimisation, when the user constrained PFIM to choose one sampling time from a sampling window composed of this sampling time only. The implementation in the file algofedorov3.2.r has been modified to take into account this error.

Furthermore, a bug in the previous version of PFIM 3.2 concerning the implementation of the Imax models has been fixed. The bug concerns the three library files LibraryPD_PDdesign.r, LibraryPD_PKPDdesign.r and CreateModel_PKPDdesign.r.

January 23th 2010

Version PFIM 3.2

PFIM 3.2 is an extension of the version PFIM 3.0. This version incorporates new features in terms of model specification and expression of the Fisher information matrix. Regarding model specification, the library of standard pharmacokinetic (PK) models has been completed by the three compartment models with linear elimination and models with Michaelis-Menten elimination (one, two and three compartment models). Furthermore, a library of pharmacodynamic (PD) models is now available. Concerning the expression of the Fisher information matrix, PFIM 3.2 can handle either a block diagonal Fisher information matrix or the complete one. It is now also possible in PFIM 3.2 to use models including inter-occasion variability (IOV) with replicated designs at each occasion. Last, a new feature of PFIM 3.2 is the computation of the Fisher information matrix for models including fixed effects for the influence of discrete covariates on the parameters. It can be specified if covariates change or not through the different occasions. The computation of the predicted power of the Wald test for comparison or equivalence test for a given distribution of a discrete covariate as well as the number of subjects needed to achieve a given power can be computed.

May 20th 2008

Update of version PFIM Interface 2.1 (bug correction)

A bug in the previous version of the Fedorov-Wynn algorithm has been corrected.
The bug concerns the computation of the number of subjects in the optimised designs using the Fedorov-Wynn algorithm (designs optimised with the Simplex algorithm are unaffected by the bug).
The only results affected are population designs combining elementary designs with unequal number of sampling times. eg :

• if the final design is for instance ((1,2,3),(1,3,5)) with frequencies (alpha1, alpha2) it is unaffected by the bug
• if the final design is for instance ((1,2,3),(1,3)) with frequencies (alpha1, alpha2), it is affected by the bug, and the frequencies will not be correct. In this case the correct frequencies should be respectively (alpha1/3)/sum and (alpha2/2)/sum where sum=(alpha1/3)+(alpha2/2) to normalise the sum of the frequencies to 1. ("frequencies" refer to the frequencies reported by the bugged version of the algorithm)

Because of this bug, the final criterion and estimates of SE for the parameters in the model, being computed with the wrong frequencies, is also incorrect, but differences should be small and unlikely to be clinically significant. The new version of the Fedorov-Wynn outputs the correct frequencies and we encourage users to update PFIM interface 2.1 with the new version.