Antony Simitopoulos!, Athanasios A. Tsekouras2,3, and Panos Macheras1,3
1Faculty of Pharmacy, Laboratory of Biopharmaceutics Pharmacokinetics, National and Kapodistrian University of Athens, Athens, Greece 2Department of Chemistry, Laboratory of Physical Chemistry, National and Kapodistrian University of Athens, Athens, Greece 3PharmaInformatics Unit, ATHENA Research Center, Athens, Greece
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: To develop software based on PBFTPK models for the estimation of absolute bioavailability, F for one- and two-compartment model drugs using oral data exclusively.
Methods: The calculation of F requires an initial fitting of PBFTPK model equations to the oral data to get estimates for the duration of drug absorption, τ, and the disposition parameters. For the one-compartment model drugs, linear regression analysis is applied to the logarithmically transformed elimination phase data beyond time τ, to get estimates for the intercept and slope, which are used to get an estimate for F as described in [5]. For two compartment model drugs each one of the absorption phase data up to time τ, is “corrected” in terms of the eliminated and reversibly distributed drug amount using the integrals from zero to the specific time point and the parameter estimates of the two-compartment model fitting. The two-compartment model equation for intravenous bolus administration is then fitted to the “corrected” absorption phase data; the parameter estimates for A, B, α, β are further used to estimate F based on classical pharmacokinetic equations.
Results:
For the one-compartment drugs, blood concentration-time curves from eight BCS Class I biowaiver immediate-release formulations, namely amoxicillin trihydrate [12], acetylsalicylic acid [14], bisoprolol fumarate [16], fluconazole [18], levetiracetam [20], moxifloxacin hydrochloride [22], ondansetron [24], and acetaminophen (paracetamol) [26], and four carbamazepine formulations B11, B12, B21 and B23 [27], were examined. The estimated F values generally aligned with reports in the literature [15,17,19,21,25], except for amoxicillin (0.66 compared to 0.72-0.77 in literature [11]), acetylsalicylic acid, and ondansetron (0.91 [13] and 0.97 [23], respectively, compared to literature-reported values of 0.68 and 0.50-0.70, respectively). The deviation for amoxicillin was attributed to its known variability and dose-dependency in absorption. Conversely, the notably higher F estimates for acetylsalicylic acid and ondansetron were linked to the first-pass effect, a common trait for both drugs. 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 [28].
Regarding the two-compartment drug venetoclax [29], our methodology yielded estimates for the fitting parameters A, B, α, and β at 0.14387 and 0.06029 (μg/mL) and 0.10547 and 0.02913 (h-1), respectively. The estimated F for venetoclax was 0.079, which closely matched the literature-reported value of 0.054 [30].
Conclusion: The enhanced analytical power of this software is due to the physiological notion of F.A.T., which is incorporated into all algorithms. Its use and its further development can lead to the abolishment of the laborious and expensive microdosing studies carried out in early drug development in big pharma for the estimation of F.
References
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Reference: PAGE 32 (2024) Abstr 11281 [www.page-meeting.org/?abstract=11281]
Poster: Software Demonstration