Nikos Alimpertis, Athanasios A. Tsekouras, and Panos Macheras
ATHENA Research Center and National and Kapodistrian University of Athens
Introduction: The introduction of the finite absorption time (F.A.T.) concept [1,2] was followed by the development of the pertinent PBFTPK models [3]. These models were applied successfully to orally, nasally, intramuscularly, and pulmonary inhaled administered drugs [3-6]. In all cases, meaningful parameter estimates for the duration of absorption stage(s) and the input rate(s) were derived. In the course of these studies, we recently i) revamped the foundations of biopharmaceutics pharmacokinetics developing modified, in terms of F.A.T., %absorbed versus time plots [7], ii) introduced the concept of finite dissolution time (F.D.T.) and accordingly revised the in vitro – in vivo correlations (IVIVC) [8] iii) coupled dissolution with the biopharmaceutic classification system [9] and iv) applied the PBFTPK models in studies dealing with PBPK modeling [4,10] and pharmacometrics [4].
Objectives: a. To develop modeling methodologies for the assessment of bioequivalence using novel metrics and to estimate absolute bioavailability F from oral data exclusively b. To demonstrate the wrong and shifted to the right exponential % absorbed versus time curves generated in all PBPK absorption models. c. To replace the wrong and routinely used first-order absorption models of either one- or two-or multi-compartment model disposition with the physiologically sound PBFTPK models in pharmacometrics.
Methods: a. The equations of the physiologically based finite time pharmacokinetic models for the one- and two-compartment model with one and two input stages of absorption were solved to derive metrics for the extent and rate of absorption. Oral data from BCS Class I & II drugs were analyzed by conducting PBFTPK model fits to estimate the duration of the absorption phase, τ and the input rate(s) for each one of the drugs studied. Estimates for the bioavailable fraction, F for all drugs were derived using a published relationship for one-compartment model drugs [5] and a new one for two-compartment model drugs. b. Published PBPK data [10] were analyzed using PBFTPK models and the relevant % absorbed-time bilinear curves were constructed [7]. The simulated-generated in vivo absorption data were compared with the in vivo observed % absorbed-time bilinear curves derived from the PBFTPK fitting. c. First-order absorption rate constants estimates derived from pharmacometrics studies dealing with pulmonary inhalers published in the literature were analyzed; mean and median estimates and their uncertainty for the absorption rate constant were compared with the relevant estimates for the duration of input and the input rates derived from PBFTPK fittings to mean concentration, time data.
Results: a. The rate of drug absorption was found to be equal to the slope of the amount absorbed vs time curve. The amount of drug absorbed at the end of the absorption process, corresponding to the blood concentration at F.A.T. is an indicator of the extent of absorption. Best fits were observed using either one- or two-compartment model with one or two input stages for the drugs examined. The estimates for the total duration of the absorption phase(s) of the studied drugs were found to be in the range 0.69-2.21 h. F estimates for Class I drugs were very close to those reported in the literature and all of them close to unity. Acetylsalicylic acid and ondansetron exhibited much higher F estimates than literature values; this deviation was attributed to first-pass effect. For the carbamazepine formulations, F estimates were found to be 0.85, 0.51, 0.79 and 0.73, respectively, closely resembling the literature value of 0.78 [11]. Regarding the two-compartment drug venetoclax, the estimated F was 0.079, which closely matched the literature-reported value of 0.054 [12]. b. All the simulated % absorbed generated from PBPK models [10] were exponential, while the observed profiles derived from the PBFTPK models were bilinear exhibiting a shorter absorption period estimate, τ, i.e., 0.61, 0.29, 0.62, 0.43, 0.77, and 1.68 h for etoricoxib, gaboxadol, dipyridamole pioglitazone, compound C, and losartan, respectively. c. Our analysis showed that the drug absorption duration was a more meaningful estimate than the absorption rate constants reported in the literature. In all cases, the duration of drug absorption derived from the PBFTPK fittings was shorter than five minutes which rules out the first-order notion of drug absorption applied in all pharmacometric studies.
Conclusions: a. The assessment of rate in bioequivalence studies can be based on the estimation of slope of the percent absorbed versus time curve while the constant ratio test/reference of the amount of drug absorbed is an indicator of the extent of absorption. The estimates for F were found in accord with the literature reported values. These findings pave the way for the assessment of bioequivalence and the estimation of F with minimal modeling pharmacokinetic approaches, which enhance the MIDD towards MIDDA initiative. b. The analysis of PBPK models call for model informed dissolution-absorption in vitro results, which provide bilinear concentration -time plots relevant to those observed in vivo concentration-time profiles justified in our analysis using the PBFTPK models. Dissolution functions in PBPK modeling should be replaced with equations relevant to the F.A.T. and F.D.T. concepts such as modified versions of Noyes Whitney equation and Weibull function for simulating drug dissolution in vivo for a certain period of time [13]. c. The absorption structural models in pharmacometrics should be replaced with the physiologically sound PBFTPK models. This will allow the description of drug absorption stage(s) with meaningful parameters for the duration and the input rate for each one of the absorption stages [14]. Accordingly, the development of a pharmacometric computational framework which integrates finite-time absorption principles into novel PBFTPK structural models, along with the respective error models is required.
References:
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[4] Macheras P, Tsekouras AA. The Finite Absorption Time (FAT) concept en route to PBPK modeling and pharmacometrics. J Pharmacokinet Pharmacodyn. 2023 Feb;50(1):5-10. https://doi.org/10.1007/s10928-022-09832-w.
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[6] Tsekouras AA, Macheras P. Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept. Eur J Drug Metab Pharmacokinet. 2023;48:455–462. https://doi.org/10.1007/s13318-023-00831-x
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[8] Alimpertis N, Simitopoulos A, Tsekouras AA, Macheras P. IVIVC Revised. Pharm Res. 2024 Feb;41(2):235-246. https://doi.org/10.1007/s11095-024-03653-x.
[9] Simitopoulos A, Tsekouras A, Macheras P. Coupling Drug Dissolution with BCS. Pharm Res. 2024 Jan 30. https://doi.org/10.1007/s11095-024-03661-x.
[10] Wu D, Tsekouras AA, Macheras P, Kesisoglou F. Physiologically based Pharmacokinetic Models under the Prism of the Finite Absorption Time Concept. Pharm Res. 2023 Feb;40(2):419-429. https://doi.org/10.1007/s11095-022-03357-0.
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[12] Alaarg A, Menon R, Rizzo D, Liu Y, Bien J, Elkinton T, Grieme T, Asmus LR, Salem AH. A microdosing framework for absolute bioavailability assessment of poorly soluble drugs: A case study on cold-labeled venetoclax, from chemistry to the clinic. Clin Transl Sci. 2022 Jan;15(1):244-254. https://doi.org/10.1111/cts.13144.
[13] Dokoumetzidis A, Papadopoulou V, Macheras P. Analysis of dissolution data using modified versions of Noyes-Whitney equation and the Weibull function. Pharm Res. 2006 Feb;23(2):256-61. doi: 10.1007/s11095-006-9093-3. Epub 2006 Jan 25. PMID: 16421665.
[14] Macheras P., Tsekouras A.A. Revising Oral Pharmacokinetics, Bioavailability and Bioequivalence Based on the Finite Absorption Time Concept, Springer, Berlin. (2023)
Reference: PAGE 32 (2024) Abstr 11178 [www.page-meeting.org/?abstract=11178]
Poster: Methodology - Other topics