Antony Simitopoulos (1), Athanasios Tsekouras (2,3), and Panos Macheras (1,3)
(1) Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece, (2) Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece, (3) PharmaInformatics Unit, ATHENA Research Center, Athens, Greece.
Introduction: The introduction of the Finite Absorption Time (F.A.T.) [1,2] concept led to the development of PBFTPK models [3], successfully applied to various drug administration methods [3-6]. These models provided meaningful estimates for absorption stage durations and input rates. Recent advancements include the revamping of biopharmaceutics pharmacokinetics, introducing Finite Dissolution Time (F.D.T.) [7], the revising of In Vitro-In Vivo Correlations (IVIVC) [8], and the coupling of drug dissolution with the biopharmaceutic classification system [9]. This work connects FDA and ICH guidelines for biowaivers [10-11] with F.A.T. and F.D.T. concepts, particularly focusing on Class I drugs’ rapid dissolution and biowaiver acceptance criteria. PBFTPK models are utilized to analyze absorption duration and bioavailability in connection with high solubility and permeability, ensuring rapid and extensive absorption.
Objectives: The aim is to utilize PBFTPK models to assess Class I drugs and investigate whether the estimates for the bioavailable fraction (F) and absorption duration (τ) align with the rapid and complete absorption criteria typical of Class I drugs, where F>0.90.
Methods: Blood concentration-time datasets from eight BCS Class I biowaiver immediate-release formulations [12-27] were collected from relevant literature sources. The drugs examined were amoxicillin trihydrate, acetylsalicylic acid, bisoprolol fumarate, fluconazole, levetiracetam, moxifloxacin hydrochloride, ondansetron, and acetaminophen (paracetamol). Human pharmacokinetic data were analyzed, except for moxifloxacin hydrochloride, which was examined in buffalo calves. After data digitization, PBFTPK model equations were employed to fit the experimental data, facilitating the estimation of model parameters.
Results: Our analysis revealed that one-compartment models with either one or two input stages provided the best fits for all drugs examined. Estimates for τ ranged from 0.69 to 2.1 h, consistent with the rapid absorption characteristic of Class I drugs. Plotting solubility values against estimates for τ demonstrated that drugs with higher solubility exhibited shorter absorption periods. Furthermore, coupling the estimated τ with the corresponding estimate for the drug’s elimination rate constant elucidated that rapidly absorbing Class I drugs predominantly occupied a region with small τ values (τ < 1.5 h), while medium-absorbing drugs resided in the range of 1.5 ≤ τ < 5 h, thus validating the quantification of drug absorption with meaningful estimates for τ [3]. For the slowly absorbing drugs, only carbamazepine has been identified thus far [28]. The bioavailable fraction, F, was estimated using two distinct methodologies: one employed a theoretical method utilizing oral data exclusively, as previously described, while the other employed the classic trapezoidal rule. Elimination phase data beyond time τ were analyzed via semilogarithmic plots to indicate adherence to a one-compartment model of disposition for all examined drugs, rendering them suitable for further application of formulas developed in [5]. Estimates for F based on the two methodologies were generally congruent, with exceptions noted for fluconazole and levetiracetam. Notable discrepancies were observed for amoxicillin (0.66 compared to 0.72-0.77 reported in literature), acetylsalicylic acid, and ondansetron (0.91 and 0.97, respectively, compared to literature-reported values of 0.68 and 0.50-0.70, respectively). The slight discrepancy observed for amoxicillin was attributed to its variable and dose-dependent absorption as reported in the literature [12]. Conversely, the significantly higher estimates for F of acetylsalicylic acid and ondansetron compared to literature values were associated with the first-pass effect, a common characteristic for both drugs [14,24].
Conclusions: The estimates of the bioavailable fraction, F for five of the eight drugs studied were found in accord with the literature values. In all cases, calculated estimates for the bioavailable fraction, F, affirm the complete absorption (F > 0.90) previously reported in the literature for the examined drugs. This study thus lays the groundwork for evaluating bioavailability solely from oral data through modeling methodologies. A pharmacokinetic approach was developed, which can be used for granting the biowaiver status.
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Reference: PAGE 32 (2024) Abstr 11017 [www.page-meeting.org/?abstract=11017]
Poster: Methodology - New Modelling Approaches