Application of the Finite Absorption Time (F.A.T.) Concept in the Assessment of Bioequivalence.

PURPOSE: Το formulate a methodology for the assessment of bioequivalence using metrics, which are based on the physiologically sound F.A.T. METHODS: 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. Simulated data were used to study the proper way for the estimation of metrics. A bioequivalence study was analyzed using these metrics. RESULTS: The rate of drug absorption was found to be equal to the slope of the amount absorbed versus 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. The plot of the ratio test/reference of the simulated data for the amount absorbed as a function of time becomes constant beyond the end of drug absorption from the formulation exhibiting the longer absorption. The assessment of the bioequivalence study was based on the slope of the amount absorbed versus time curve for the rate of absorption, while the estimate for the constant ratio test/reference for the amount absorbed was used for the assessment of extent of absorption. CONCLUSIONS: 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 for the amount of drug absorbed is an indicator of the extent of absorption.

IVIVC Revised.

PURPOSE: To revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts. METHODS: The estimates τ and τd for F.A.T. and F.D.T., respectively are constrained by the inequality τd ≤ τ; their relative magnitude is dependent on drug's BCS classification. A modified Levy plot, which includes the time estimates for τ and τd was developed. IVIVC were also considered in the light of τ and τd estimates. The modified Levy plot of theophylline, a class I drug, coupled with the rapid (30 min) and very rapid (15 min) dissolution time limits showed that drug dissolution/absorption of Class I drugs takes place in less than an hour. We reanalyzed a carbamazepine (Tegretol) bioequivalence study using PBFTPK models to reveal its complex absorption kinetics with two or three stages. RESULTS: The modified Levy plot unveiled the short time span (~ 2 h) of the in vitro dissolution data in comparison with the duration of in vivo dissolution/absorption processes (~ 17 h). Similar results were observed with the modified IVIVC plots. Analysis of another set of carbamazepine data, using PBFTPK models, confirmed a three stages absorption process. Analysis of steady-state (Tegretol) data from a paediatric study using PBFTPK models, revealed a single input stage of duration 3.3 h. The corresponding modified Levy and IVIVC plots were found to be nonlinear. CONCLUSIONS: The consideration of Levy plots and IVIVC in the light of the F.A.T. and F.D.T. concepts allows a better physiological insight of the in vitro and in vivo drug dissolution/absorption processes.

Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption.

PURPOSE: The Wagner-Nelson and Loo-Riegelman methods developed in the 1960s and used since for the construction of percent of drug absorbed as a function of time as well as in in vitro in vivo correlations are re-considered in the light of the physiologically sound Finite Absorption Time (F.A.T.) concept developed recently. METHODS: The classical equations for the percentage of drug absorption as a function of time were modified by taking into account the termination of drug absorption at F.A.T., replacing the parameters associated with the assumption of infinite drug absorption. RESULTS: Mathematical analysis using the relevant Physiologically Based Pharmacokinetic Finite Time (PBFTK) models assuming one- or two-compartment drug disposition, revealed that the modified %absorbed versus time curves are of bilinear type with an ascending limb intersecting the horizontal line at F.A.T. A computer-based methodology is described for the estimation of F.A.T. from experimental data. More than one linear ascending limb is found when more than one absorption phase is operating. Experimental data were analyzed and the estimates for F.A.T were found to be similar to those derived from nonlinear regression analysis using PBFTPK models. CONCLUSION: These results place an end to the routinely reported exponential %absorbed versus time curves prevailing in biopharmaceutics-pharmacokinetics since their inception in the'60 s. These findings point to the use of the F.A.T. concept in drug absorption research and regulatory guidelines such as deconvolution techniques for the assessment of drug input rate, stochastic mean absorption time calculations, population analyses, in vitro in vivo correlations and bioequivalence guidelines.

Physiologically based Pharmacokinetic Models under the Prism of the Finite Absorption Time Concept.

To date, mechanistic modeling of oral drug absorption has been achieved via the use of physiologically based pharmacokinetic (PBPK) modeling, and more specifically, physiologically based biopharmaceutics model (PBBM). The concept of finite absorption time (FAT) has been developed recently and the application of the relevant physiologically based finite time pharmacokinetic (PBFTPK) models to experimental data provides explicit evidence that drug absorption terminates at a specific time point. In this manuscript, we explored how PBBM and PBFTPK models compare when applied to the same dataset. A set of six compounds with clinical data from immediate-release formulation were selected. Both models resulted in absorption time estimates within the small intestinal transit time, with PBFTPK models generally providing shorter time estimates. A clear relationship between the absorption rate and the product of permeability and luminal concentration was observed, in concurrence with the fundamental assumptions of PBFTPK models. We propose that future research on the synergy between the two modeling approaches can lead to both improvements in the initial parameterization of PBPK/PBBM models but to also expand mechanistic oral absorption concepts to more traditional pharmacometrics applications.

The Finite Absorption Time (FAT) concept en route to PBPK modeling and pharmacometrics.

The concept of Finite Absorption Time (FAT) for oral drug administration is set to affect pharmacokinetic analyses, Physiologically-based Pharmacokinetics simulations, and Pharmacometrics.

Re-writing Oral Pharmacokinetics Using Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models.

PURPOSE: To develop physiologically based finite time pharmacokinetic (PBFTPK) models for the analysis of oral pharmacokinetic data. METHODS: The models are based on the passive drug diffusion mechanism under the sink conditions principle. Up to three drug successive input functions of constant rate operating for a total time τ are considered. Differential equations were written for all these models assuming linear one- or two-compartment-model disposition. The differential equations were solved and functions describing the concentration of drug as a function of time for the central and the peripheral compartment were derived. The equations were used to generate simulated data and they were also fitted to a variety of experimental literature oral pharmacokinetic data. RESULTS: The simulated curves resemble real life data. The end of the absorption processes τ is either equal to tmax or longer than tmax at the descending portion of the concentration time curve. Literature oral pharmacokinetic data of paracetamol, ibuprofen, almotriptan, cyclosporine (a total of four sets of data), and niraparib were analyzed using the PBFTPK models. Estimates for τ corresponding to a single or two or three different in magnitude input rates were derived along with the other model parameters for all data analyzed. CONCLUSIONS: The PBFTPK models are a powerful tool for the analysis of oral pharmacokinetic data since they rely on the physiologically sound concept of finite absorption time.

Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations.

PURPOSE: To explore the application of the parameters of the physiologically based finite time pharmacokinetic (PBFTPK) models subdivided in first-order (PBFTPK)1 and zero-order (PBFTPK)0 models to bioavailability and bioequivalence. To develop a methodology for the estimation of absolute bioavailability, F, from oral data exclusively. METHODS: Simulated concentration time data were generated from the Bateman equation and compared with data generated from the (PBFTPK)1 and (PBFTPK)0 models. The blood concentration Cb(τ) at the end of the absorption process τ, was compared to Cmax; the utility of [Formula: see text] and [Formula: see text] in bioequivalence assessment was also explored. Equations for the calculation of F from oral data were derived for the (PBFTPK)1 and (PBFTPK)0 models. An estimate for F was also derived from an areas proportionality using oral data exclusively. RESULTS: The simulated data of the (PBFTPK)0 models exhibit rich dynamics encountered in complex drug absorption phenomena. Both (PBFTPK)1 and (PBFTPK)0 models result either in Cmax = Cb(τ) or Cmax > Cb(τ) for rapidly- and not rapidly-absorbed drugs, respectively; in the latter case, Cb(τ) and τ are meaningful parameters for drug's rate of exposure. For both (PBFTPK)1 and (PBFTPK)0 models, [Formula: see text] or portions of it cannot be used as early exposure rate indicators. [Formula: see text] is a useful parameter for the assessment of extent of absorption for very rapidly absorbed drugs. An estimate for F for theophylline formulations was found close to unity. CONCLUSION: The (PBFTPK)1 and (PBFTPK)0 models are more akin to in vivo conditions. Estimates for F can be derived from oral data exclusively.

Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept.

BACKGROUND AND OBJECTIVES: Naloxone for opioid overdose treatment can be administered by intravenous injection, intramuscular injection, or intranasal administration. Published data indicate differences in naloxone pharmacokinetics depending on the route of administration. The aim of this study was to analyze pharmacokinetic data in the same way that we recently successfully applied the concept of the finite absorption time in orally administered drug formulations. METHODS: Using the model equations already derived, we performed least squares analysis on 24 sets of naloxone concentration in the blood as a function of time. RESULTS: We found that intramuscular and intranasal administration can be described more accurately when considering zero-order absorption kinetics for finite time compared with classical first order absorption kinetics for infinite time. CONCLUSIONS: One-compartment models work well for most cases. Two-compartment models provide better details, but have higher parameter uncertainties. The absorption duration can be determined directly from the model parameters and thus allow an easy comparison between the ways of administration. Furthermore, the precise site of injection for intramuscular delivery appears to make a difference in terms of the duration of the drug absorption.

Interpreting airborne pandemics spreading using fractal kinetics' principles.

Introduction  The reaction between susceptible and infected subjects has been studied under the well-mixed hypothesis for almost a century. Here, we present a consistent analysis for a not well-mixed system using fractal kinetics' principles.  Methods  We analyzed COVID-19 data to get insights on the disease spreading in absence/presence of preventive measures. We derived a three-parameter model and show that the "fractal" exponent h of time larger than unity can capture the impact of preventive measures affecting population mobility.  Results  The h=1 case, which is a power of time model, accurately describes the situation without such measures in line with a herd immunity policy. The pandemic spread in four model countries (France, Greece, Italy and Spain) for the first 10 months has gone through four stages: stages 1 and 3 with limited to no measures, stages 2 and 4 with varying lockdown conditions. For each stage and country two or three model parameters have been determined using appropriate fitting procedures. The fractal kinetics model was found to be more akin to real life.  Conclusion  Model predictions and their implications lead to the conclusion that the fractal kinetics model can be used as a prototype for the analysis of all contagious airborne pandemics.

Significant modification of the I(-)3 Lewis base character in the ß-cyclodextrin polyiodide inclusion complex with Co2+ ion: an FT-Raman investigation.

The ß-cyclodextrin (ß-CD) polyiodide inclusion complex (ß-CD)(2)·Co(0.5)·I(7)·21H(2)O has been synthesized, characterized and further investigated via FT-Raman spectroscopy in the temperature range of 30-120°C. The experimental results point to the coexistence of I(-)(7) units (I(2)·I(-)(3)·I(2)) that seem not to interact with the Co(2+) ions and I(-)(7) units that display such interactions. The former units exhibit a disorder-order transition of both their I(2) molecules above 60°C due to a symmetric charge-transfer interaction with the central I(-)(3) [I(2)←I(-)(3)→I(2)], whereas in the latter units only one of the two I(2) molecules becomes well-ordered above 30°C. The other I(2) molecule remains disordered presenting no charge-transfer phenomena. The Co(2+) ion induces a considerable asymmetry on the geometry of the I(-)(3) anion and a significant modification of its Lewis base character. Complementary dielectric measurements suggest no important involvement of H···I contacts in the observed modification of the I(-)(3) electron-transfer properties.

All-electron first principles calculations of the ground and some low-lying excited states of BaI.

The electronic structure of the heavy diatomic molecule BaI has been examined for the first time by ab initio multiconfigurational configuration interaction (MRCI) and coupled cluster (RCCSD(T)) methods. The effects of special relativity have been taken into account through the second-order Douglas-Kroll-Hess approximation. The construction of Omega(omega,omega) potential energy curves allows for the estimation of "experimental" dissociation energies (De) of the first few excited states by exploiting the accurately known De experimental value of the X2Sigma+ ground state. All states examined are of ionic character with a Mulliken charge transfer of 0.5 e- from Ba to I, and this is reflected to large dipole moments ranging from 6 to 11 D. Despite the inherent difficulties of a heavy system like BaI, our results are encouraging. With the exception of bond distances that on the average are calculated 0.05 A longer than the experimental ones, common spectroscopic parameters are in fair agreement with experiment, whereas De values are on the average 10 kcal/mol smaller.