Pavlos Chrysafidis1,2, Panos Macheras1,2
1Department of Pharmacy, National and Kapodistrian University of Athens, 2PharmaInformatics Unit, ATHENA Research Center, Athens, Greece
Objectives: This work aims to i) abolish the current assumption of infinite time of oral drug absorption [1] and ii) develop new models based on biopharmaceutical, physiological and finite absorption time concepts.
Methods: Drugs pass through the gastrointestinal membranes by passive diffusion; we consider the rate of penetration of the simplest system of transport under sink conditions
Rate of Penetration=P·(SA)·(CGI) (1)
where P is the permeability of drug, SA is the surface area of the membrane, and CGI is the drug concentration at the absorption site; the blood flow in the hepatic portal vein (20-40cm/sec) impose sink conditions.
We reconsidered gastrointestinal drug absorption taking into account drug’s transit times. For Class I drugs [2], the completion of absorption (fraction of dose absorbed, F>0.90) ceases in a shorter time than the duration of the gastrointestinal transit 4.86 h [3]. For Class II, III and IV drugs [2], the limited overall absorption ( F<0.90) can be continued beyond the ileocecal valve and lasts not more than the whole gut transit time e.g. 29.81 h [3]. For each one of the four drug classes the rate of penetration in the stomach/small intestine and the colon was expressed separately taking into account the rate limiting step for the drug Class considered e.g. saturations solubility Cs for Class II drugs. e.g.
(Rate of Penetration in the stomach/small intestine, Class II drug)=
P ·(SA)i ·(CS) = ki= FiD/ τi (2)
(Rate of Penetration in the colon, Class II drug)=
P ·(SA)C ·(CS) = kC =[ (1−Fi)D/( τc –τi)] ·λ (3)
where D is the dose, Fi is the fraction of dose absorbed in the stomach and small intestine, τi is the duration of the absorption in the stomach and small intestine, τc corresponds to the termination of drug absorption in the colon and λ is a coeffcient (0<λ<1) associated with the reduction of the penetration rate due to small surface area (SA)C value, ki and kC denote the zero-order rate constants in the two regions.
These equations were further coupled with the pharmacokinetic equations, assuming one compartment model disposition e.g. Eqs 4 and 5 are linked with Eqs 2 and 3, respectively
Vd(dCb /dt)= ki −kelCbVd for 0<t<τi (4)
Vd(dCb/ dt)= kC − kelCbVd for τi<t<τc (5)
where Cb is the drug blood concentration, Vd is the volume of drug distribution and kel is the elimination rate constant. For the following equation applies :
(dCb/ dt)= −kelCb for t>τc (6)
Depending on the gut transit time duration of all four classes (I, II, III, IV) the change of drug blood concentration is followed through the sets of branched equations applied for three time periods [0- τi], [τi– τC ], [τC, ∞]. A great number of simulations were field-tested considering physiological gut transit times. For all drug class cases, the respective differential equations were coupled in algorithms implemented in SciPy’s computational environment.
Results: Simulated data for Class I drugs exhibited a sharp peak at τi, followed by an elimination phase. The sharp peak indicates drug’s full absorption. Contrary to the classical Cmax, tmax steady-state considerations, the Cb, t profiles exhibit discontinuity at the observed peak which is in accord with drug’s complete absorption at τi . For Class II, III, and IV drugs assuming absorption beyond the small intestine, the Cb, t profiles during the time interval [τi , τc] are heavily dependent on the relative magnitude of the prevailing input and output rates during this time interval. Thus, the classical monotonic decrease of drug concentration beyond τi is observed while profiles with a gradually declining phase are observed too. The elimination phase beyond time τC can be distinguished from the late phases of drug absorption in the colon apart from the cases when the elimination rate constant is similar to the one prevailing at the late stages of drug absorption.
Conclusion: These findings suggest that the false hypothesis of infinite absorption [1], can be replaced with biopharmaceutically- physiologically based finite absorption time pharmacokinetic (PBFTPK) concepts. The PBFTPK models lead to re-consideration of the meaning of the important parameters Cmax, AUC and flip-flop kinetics; these models can be applied to bioequivalence, in vitro-in vivo correlations, paediatric scaling studies, interspecies pharmacokinetic scaling and pharmacometrics.
References:
[1] Macheras.P. On an Unphysical Hypothesis of Bateman Equation and its Implications for Pharmacokinetics (2019). Pharmaceutical Research 36, 94.
[2] Gl. Amidon H. Lennernas Vp. Shah Jr. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.(1995). Pharmaceutical Research 12 413–20.
[3] Abuhelwa AY ,Foster DJR, Upton RN. A Quantitative Review and Meta-models of the Variability and Factors Affecting Oral Drug Absorption-Part II: Gastrointestinal Transit Time. ( 2016). AAPS J 18. 1322–1333. DOI: 10.1208/s12248-016-9953-7.
Reference: PAGE () Abstr 9319 [www.page-meeting.org/?abstract=9319]
Poster: Oral: Methodology - New Modelling Approaches