(W1030-04-25) The Estimates for the Absorption Rate Constant in Pharmacokinetics and Pharmacometrics Are Wrong: A New Era Based on the Finite Absorption Time Concept Rises

Purpose: To show the potential impact the concept of Finite Absorption Time (F.A.T.) can have across many fields pertaining to drugs/formulations, from inception to in vitro and in vivo studies, to clinical trials and approval, to development of generics, to in vitro-in vivo correlations and PBPK studies

Methods: We incorporated custom written software modules describing various scenarios of one- and two-compartment disposition models with as many as five successive zero-order absorption stages in commercial non-linear regression analysis software (Igor by Wavemetrics). We have analyzed many sets of pharmacokinetic data for drugs administered mostly orally, with immediate or modified release, but the set also included pulmonary, intramuscular, intranasal and transdermal drugs. These fits primarily determined the model that described the data best, at an adequate level of parameter uncertainty and parameter cross correlation, F.A.T. being the most interesting quantity found. Fits to classical models with first-order, infinite duration for absorption stage were attempted in all cases. Subsequently, the parameters determined with the FBFTPK models allowed further calculation of partial or total AUCs for performing comparisons among formulations. Furthermore, relying on the elimination rate constant parameters that resulted from the fits, the percent of drug absorbed could be established as a function of time. This processing allowed an independent determination of the F.A.T.

Results: In most data sets analyzed the FBFTPK models performed better than the corresponding classical models, providing meaningful estimates both for input rate constants and the F.A.T. (τ) of the absorption stage or stages. Oftentimes, τ was found to be extremely short and of the order of tmax. In cases of multiple successive absorption stages, τ could be greater than tmax. Drugs with complex absorption kinetics (e.g., oxybutynin, mavoglurant) could be described successfully by these models [3]. Besides orally administered drugs, we analyzed pulmonary (e.g., budesonide, formoterol), intramuscular (e.g., naloxone), intranasal (e.g., naloxone, amiloride), and transdermal (e.g., oxybutynin) drugs [3,7]. Comparisons of partial AUCs up to the time of absorption termination rather than to infinite time showed that the bioequivalence of formulations can be assessed based solely on sampling limited up to time τ (e.g., salmeterol, fluticasone) [7-9]. Consequently, bioequivalence trials do not need to be extended beyond τ, thus saving in time, resources, cost and increasing volunteer availability. Similarly, the percent of drug absorbed (e.g., paracetamol, niraparib) showed a distinct change in slope at τ indicating that IVIV correlation studies need to be extended only for the time that is realistic to expect drug dissolution and absorption. From comparisons between PBPK simulations and corresponding PBFTPK fits for immediate release formulations (e.g., etoricoxib, gaboxadol) a clear relationship between the absorption rate and the product of permeability and luminal concentration was observed [10].

Conclusion: A new library of PBFTPK models is at the disposal of pharmacometricians for population analyses. Furthermore, the concept of F.A.T. is set to sweep many aspects of how formulations are developed, studied, how they function, how they are tested and how different formulations are compared.

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Ljubljana, Slovenia, 28 June-1 July 2022
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