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 [email protected]<mailto:[email protected]> (224) 619-4901 Quote of the week – “Dancing with the Stars” is not owned by Astellas. From: [email protected] <[email protected]> On Behalf Of Shan Pan Sent: Tuesday, September 13, 2022 3:42 AM To: Jakob Ribbing <[email protected]>; Niurys.CS <[email protected]> Cc: nmusers <[email protected]> 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 <[email protected]<mailto:[email protected]>> 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 <[email protected]<mailto:[email protected]>> 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/>.
