Re: [Fwd: Simulations]

Date: Fri, 19 Nov 1999 10:10:51 -0800 From: Jeff Wald <jwald@pharsight.com> Subject: Re: [Fwd: Simulations] We have not noticed any differences between NONMEM and Pharsight Trial Designer (PTD) of the nature described in Eliane's e-mail. However, there are misconceptions that at times will lead to discrepant results. I have been given the opportunity to review the NONMEM and PTD models refrenced in Eliane's manuscript and have noticed 2 major differences between the two approaches. 1.) NONMEM always reports the variance of a normally-distributed eta. When using a parameter model of the form p=theta*exp(eta), then Var(eta) is APPROXIMATELY (CV(p))**2. That approximation is pretty good for small CV's. For example when sqrt(Var(eta)) = 0.1 then CV = 0.10025. However, when sqrt(Var(eta)) gets large the approximation isn't so good. This is illustrated here using the values from Eliane's manuscript: Parameter sqrt(Var(eta)) CV CL 0.56 0.607 V 0.604 0.664 ka 0.991 1.29 2.) The same model structure as NONMEM could have been used with normal distributions for log(p) and then translated to p. This approach is succinct in PTD through use of the exponentiated normal distribtion component. Alternately, a parameter modeled as p=theta*exp(eta) in NONMEM would be: mean(p) = theta*exp(Var(eta)/2) sd(p) = mean(p)*sqrt(exp(Var(eta))-1) In conclusion, NONMEM and PTD provide equivalent simulation results. If there are any questions as to formatting of population models in PTD, please send a note to support@pharsight.com. Regards, Jeff Wald Pharsight Corporation