Dear all, thank you so. I think it is necessary to take into account all these explanations and suggestions as well before building the Pop PK model for this peptide. I don't have any dataset from previous IV administration, and, as I mentioned in my email, the current dataset is lacking in information of absorption phase.
Best, Niurys El mar, 13 sept 2022 a las 17:46, Leonid Gibiansky (< lgibian...@quantpharm.com>) escribió: > With flip-flop, we always can get 2 solutions (assuming 1-cmpt model > with absorption; 2-cpt case is similar but expressions may differ): > > ka1-CL-V1 and ka2-CL-V2 such that > > ka1=CL/V2 and ka2=CL/V1 > > Note that CL is the same, so info on CL will not help to distinguish > these cases. > > One cannot just fix the volume, as it should have one of the values V1 > or V2, but one can select the "more mechanistic" value if other > information (e.g., about similar compounds) is available, and push the > solution to the right place by providing the bounds on the range of > possible parameter estimates. > > Note that with SC dose, we cannot estimate CL and V, we have apparent CL > and apparent V (related to the underlying CLtrue and Vtrue as > CL=CLtrue/F and V= Vtrue/F, where F is the absolute bioavailability of > SC administration). When apparent CL and apparent V are compared with > parameters for other compounds, F should be taken into account. > > Thank you > Leonid > > > > > On 9/13/2022 10:54 AM, Bonate, Peter wrote: > > In comment to Shan’s statement: > > > > It's my understanding that this flip-flop phenomenon is fundamentally a > > mathematical problem -- that is, if we write down a PK model in its > > analytical form, it becomes rather easy to understand that swapping the > > values between ka and ke (CL/V) would lead to the same output. > > > > This is not true. The values do not swap out. V will be different. > > > > Consider a 1-compartment model with KA=0.1 per h, KEL=0.7 per h, and > > V1=125L. Suppose a 250 mg dose is given. This model has flip-flop > > kinetics. > > > > Now assume we build a model with KA=0.7 per h, KEL=0.1 per h, and V2 is > > unknown, same dose. This model does not have flip-flop. Using the > > simulated data from model 1 as the observed data for model 2, we can fit > > model 2 and find the optimum value of V2. In this case it is 875L. If > > you look at the profiles you will see that they are /exactly/ the same. > > > > So it’s not a matter of just changing the order of the exponents. > > > > If you want to estimate the parameters of a flip-flop model you need a > > data without absorption – IV. Or some other independent assessment of > > CL that does not depend on absorption. > > > > *Peter Bonate, PhD* > > > > Executive Director > > > > Pharmacokinetics, Modeling, and Simulation (PKMS) > > > > Clinical Pharmacology and Exploratory Development (CPED) > > > > Astellas > > > > 1 Astellas Way > > > > Northbrook, IL 60062 > > > > peter.bon...@astellas.com <mailto:peter.bon...@astellas.com> > > > > (224) 619-4901 > > > > Quote of the week – > > > > /“Dancing with the Stars” is not owned by Astellas.**/ > > > > *From:* owner-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> *On > > Behalf Of *Shan Pan > > *Sent:* Tuesday, September 13, 2022 3:42 AM > > *To:* Jakob Ribbing <jakob.ribb...@pharmetheus.com>; Niurys.CS > > <amaranth...@gmail.com> > > *Cc:* nmusers <nmusers@globomaxnm.com> > > *Subject:* Re: [NMusers] flip-flop without absorption information? > > > > This is an interesting discussion. At the same time I can't get my head > > around the assumption of any covariate on a flip-flop phenomenon. In > > other words, even if there is no information on covariates > > this phenomenon could still exist. > > > > It's my understanding that this flip-flop phenomenon is fundamentally a > > mathematical problem -- that is, if we write down a PK model in its > > analytical form, it becomes rather easy to understand that swapping the > > values between ka and ke (CL/V) would lead to the same output. > > > > In the absence of data on drug absorption as in your case, I think the > > solution could lie in fixing volume of distribution based on any prior > > information, e.g. a reported value in the literature. Otherwise, try to > > fix it to a reasonable estimate and see what happens. > > > > Hope it helps. > > > > Kind regards, > > > > Shan > > > > On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing > > <jakob.ribb...@pharmetheus.com <mailto:jakob.ribb...@pharmetheus.com>> > > wrote: > > > > Dear Niurys, > > > > It would be down to distributional assumptions in that case. > > > > For example if you have a very strong predictor (covariate) of > > either elimination or absorption rate (but not both) - data could be > > informative to discriminate between flip-flop or not. > > > > Had your therapeutic been IgG monoclonal antibody, albumin wold have > > been a predictor of the absolute CL that with a larger number of > > subjects may allow to discriminate (especially if a mix of both > > healthy, and patients with higher inflammation level and thereby > > lower albumin -> higher CL). > > > > On the other hand, for example body weight would not be helpful in > > this regard. > > > > Even if body weight would have an effect on CL and V, it would not > > have a major impact on terminal elimination (and in addition one > > could have a concern on body weight also affecting the absorption > rate). > > > > So you would need both the mechanistic knowledge on the covariate, > > for your therapeutic peptide in the RA population, and it would need > > to be a strong effect in sufficient number of subjects. > > > > On such obvious covariate would be different routes of > > administration, where nobody would question the mechanistic > > knowledge on that SC has a slower absorption that IV :>) > > > > In liu of IV dosing this becomes a more challenging task, however. > > > > Best wishes > > > > Jakob > > > > > > > > On 13 Sep 2022, at 05:05, Niurys.CS <amaranth...@gmail.com > > <mailto:amaranth...@gmail.com>> wrote: > > > > Niurys > > > > /This communication is confidential and is only intended for the use > > of the individual or entity to which it is directed. It may contain > > information that is privileged and exempt from disclosure under > > applicable law. If you are not the intended recipient please notify > > us immediately. Please do not copy it or disclose its contents to > > any other person./ > > > > /Any personal data will be processed in accordance with Pharmetheus' > > privacy notice, available //here/ > > <https://pharmetheus.com/privacy-policy/>/./ > > > > -- Niurys de Castro Suárez, PhD Assistant Professor of Pharmacometrics Associate Research Pharmacy Department Institute of Pharmacy and Food, University of Havana Cuba "Una estrella brilla en la hora de nuestro encuentro"
