Nikolaos Alimpertis1, Kosmas Kosmidis2, Athanasios A Tsekouras3, Panos Macheras1
1Faculty of Pharmacy, National & Kapodistrian University of Athens, 2Department of Physics, Aristotle University of Thessaloniki, 3Department of Chemistry, National & Kapodistrian University of Athens
Introduction: Pharmacokinetic (PK) analyses, data evaluation, and simulations assume that absorption of drugs administered orally or otherwise lasts forever. This erroneous practice has been pointed out in several recent publications [1-4]. The Finite Absorption Time (F.A.T.) concept [2] applied in the Physiologically Based Finite Time Pharmacokinetic (PBFTPK) models [3-6] with one or more absorption stages provide meaningful parameter estimates for the duration, t, of absorption stage(s) and rate(s). Zero-order absorption kinetics are applied given the rapid blood flow [7] in the portal vein. Bioavailability (BA) and bioequivalence (BE) assessment is affected [5,8,9], because no information is to be gained from prolonged sampling once absorption ceases. Traditional analysis of percent of drug absorbed was shown to be in full agreement with the more or less abrupt termination of drug absorption [10]. In all, we revamped the foundations of biopharmaceutics-PK developing, modified in terms of F.A.T., %absorbed versus time plots [10]; introduced the concept of finite dissolution time and revised the in vitro-in vivo correlations (IVIVC) [11]; coupled dissolution with the biopharmaceutic classification system [12]; applied the PBFTPK models in studies dealing with PBPK modeling [4,13] and pharmacometrics (PM) [4]. Objectives: a. Use the F.A.T. concept to uncover the true meaning of Cmax and [AUC](0 to inf) parameters used in PK, pharmacodynamics (PD), PM, BA and BE. b. Develop F.A.T. driven MIDD approaches used in all phases of drug and generics development. Methods: a. We used a PBFTPK model with one absorption stage, first-order elimination and one-compartment model disposition. We calculated the amount of drug eliminated from the body up to time t, Qel (t). b. We reconsidered all MIDD approaches applied in PK, PD and PM in all phases of drug and generics development in the light of F.A.T. concept, the analytical power of PBFTPK models and the true meaning of Cmax and [AUC](0 to inf). Results: a. We found that Ct, which is the blood drug concentration at the end of the absorption process, is proportional to the fraction, F of dose D absorbed minus the quantity Qel (t). An adjusted concentration value (Cadj)t, which is proportional to FD is derived using (Cadj)t= Ct+Qel(t)/Vd where Vd is the volume of distribution. Thus Ct is misconceived as Cmax since its inception in 1953 [14,15] and, most importantly, since its adoption as a rate of absorption metric by FDA in 1977 [16]. We found that [AUC](0 to inf) for extravascularly administered drugs is equal to [AUC](t to inf) = (Cadj)t/kel where kel is the elimination rate constant. We realized that the use of [AUC](0 to inf) as the most appropriate extent of exposure metric must be continued, but [AUC](0 to t) is the most appropriate as an extent of absorption metric. b. Accordingly, drug development strategy and MIDD approaches must be modified in all phases of drug development. In early phases and Phase I studies absolute bioavailability should be estimated using a semi-simultaneous approach [17] adapted to the F.A.T. concept. Analysis of LiCl data reported in [17], applying the PBFTPK software [3], yielded estimates for the absolute BA of LiCl formulation given intraperitoneally, by using the “concentration maxima” FD/Vd of the two formulations, which were found to be in full agreement with those reported in [17] based on the classical estimation. This methodology can reduce drug sampling scheme. Estimates for absolute BA, duration, t, of absorption stage(s) and corresponding input rate(s) in the early phase of drug development will facilitate PBPK modeling work for the development of formulation; only the influence of dose and drug’s particle size on drug absorption have to be studied using finite time dissolution functions [18] running for time t. In phases II and III, PBFTPK models should be employed in PK, PM studies as shown in the superiority of PBFTPK models versus the classical first-order absorption models [2,3,6]. Questioning flip flop kinetics, which is incompatible with the F.A.T. concept in oral drug absorption, we analyzed published data using PBFTPK and fractal kinetics models. Doxycycline data [19] were described nicely with a PBFTPK model with one input stage (t=0.44±0.06 h) and one compartment model disposition, while two sets of long-acting injectable data [20] were best described with input rates driven by time-depended coefficients (229t-0.48, R2=0.964 and 14.36t-0.44, R2=0.958) and one-compartment model disposition. All these models were superior to the flip-flop models. The strategy of the development of generics should be modified: analysis of the reference in vivo data using PBFTPK models should be followed by the establishment, if any, IVIVC for the reference product. This strategy was applied to mesalazine data [21]; the analysis using PBFTPK models revealed that the duration of mesalazine absorption coincides with the colon targeting, while the best IVIVC correlations were established when dissolution was carried out under sink conditions, similar to the conditions prevailing in the gastrointestinal tract [22]. The latter finding was verified by applying the same methodology to in vivo and in vitro data of efonidipine HCl [23]. The following strategy was formulated for the development of generics: i) Analysis of the in vivo reference formulation data using the PBFTPK models [3] ii) Construction of the percent absorbed versus time plot for the reference formulation [10] iii) In vitro dissolution studies of the reference formulation in a flowthrough system ensuring sink conditions iv) Correlation based on % absorbed and % in vitro dissolved curves of the reference formulation [11] v) Dissolution experiments for the generic formulation based on step (iv) best results. Finally, a model-depended approach for BE assessment was developed and applied to cyclosporine [3] and carbamazepine [10] BE data. Input rates and duration of absorption, derived from PBFTPK model fittings to the data, are used as rate metrics, while the area [AUC](0 to t) is used for assessment of the extent of absorption. Conclusions: The uncovered meaning of Cmax and [AUC](0 to inf) induces revolutionary changes in the MIDD approaches applied in the development of drugs and generics. The estimation of absolute BA in the early phase of drug development using the semi-simultaneous approach coupled with the PBFTPK modeling will abolish complex microdosing studies [24]. The PBPK modeling work will be focused only on the formulation characteristics, dose and drug’s particle size. PBFTPK models used as structural models in PK, PK-PD and PM of phase II and III studies will enhance the validity of the estimates derived and the overall modeling-prediction exercise. The development of generics will rely on real IVIVC of the reference product. The estimate of dissolution/absorption duration for the reference formulation of Class II drugs will guide the in vitro dissolution work for predictive absorption purposes of the test product.
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Reference: PAGE 33 (2025) Abstr 11322 [www.page-meeting.org/?abstract=11322]
Poster: Drug/Disease Modelling - Absorption & PBPK