Identification of Biowaivers Among Class II Drugs: Theoretical Justification and Practical Examples

Rinaki, Eleni; Dokoumetzidis, Aristides; Valsami, Georgia; Macheras, Panos

doi:10.1023/b:pham.0000041450.25106.c8

Cited by 71 publications

(47 citation statements)

References 14 publications

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“…According to Table 4, P app (AP→BL) was less than 2×10 -6 cm/s [32] due to the effl ux (P-gp, MRPs) function and high hydrophilicity paired with low lipid solubility, indicating that FTA might belonged to the class III of the biopharmaceutical classification system (BCS) [33] . The permeation through biomembranes is a rate-limiting process that results in low oral BA.…”

Section: Discussionmentioning

confidence: 99%

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Wang

Shan

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the mechanisms underlying the intestinal absorption of the major bioactive component forsythoside A (FTA) extracted from Forsythiae fructus. Methods: An in vitro Caco-2 cell model and a single-pass intestinal perfusion in situ model in SD rats were used. Results: In the in vitro Caco-2 cell model, the mean apparent permeability value (P app -value) was 4.15×10 -7 cm/s in the apical-tobasolateral (AP-BL) direction. At the concentrations of 2.6-10.4 μg/mL, the effl ux ratio of FTA in the bi-directional transport experiments was approximately 1.00. After the transport, >96% of the apically loaded FTA was retained on the apical side, while >97% of the basolaterally loaded FTA was retained on the basolateral side. The P app -values of FTA were inversely correlated with the transepithelial electrical resistance. The paracellular permeability enhancers sodium caprate and EDTA, the P-gp inhibitor verapamil and the multidrug resistance related protein (MRP) inhibitors cyclosporine and MK571 could concentration-dependently increase the Papp-values, while the uptake (OATP) transporter inhibitors diclofenac sodium and indomethacin could concentration-dependently decrease the P app -values. The intake transporter SGLT1 inhibitor mannitol did not cause signifi cant change in the P app -values. In the in situ intestinal perfusion model, both the absorption rate constant (K a ) and the effective permeability (P eff -values) following perfusion of FTA 2.6, 5.2, and 10.4 μg/mL via the duodenum, jejunum and ileum had no signifi cant difference, although the values were slightly higher for the duodenum as compared to those in the jejunum and ileum. The low, medium and high concentrations of verapamil caused the largest increase in the P eff -values for duodenum, jejunum and ileum, respectively. Sodium caprate, EDTA and cyclosporine resulted in concentration-dependent increase in the P eff -values. Diclofenac sodium and indomethacin caused concentration-dependent decrease in the Peff-values. Mannitol did not cause signifi cant change in the P app -values for the duodenum, jejunum or ileum. Conclusion:The results suggest that the intestinal absorption of FTA may occur through passive diffusion, and the predominant absorption site may be in the upper part of small intestine. Paracellular transport route is also involved. P-gp, MRPs and OATP may participate in the absorption of FTA in the intestine. The low permeability of FTA contributes to its low oral bioavailability.

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Section: Discussionmentioning

confidence: 99%

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Wang

Shan

et al. 2012

Acta Pharmacol Sin

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“…Yazdanian and collaborators (2004) investigated NSAID (non-steroidal anti-inflammatory drug) in a study and showed an increased drug solubility when FeSSIF and FaSSIF instead of buffers 0.1 N HCl (pH 1.2), 0.02 M citric acid (pH 5.0) and 0.02 M Na 2 HPO 4 , and 0.02 M NaH 2 PO4 (pH 7.4) were used (90). Rinaki et al developed a dynamic GI absorption model and showed that such solubility data generated in biorelevant media can be used as guidance for the formulation scientist in the development phase (92).…”

Section: Biorelevant Mediamentioning

confidence: 99%

Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System

Bou‐Chacra

Melo

Morales

et al. 2017

AAPS J

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Abstract.The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance's solubility or a drug product's in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today's different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.

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“…Over the past 25 years, mathematical models have been developed to estimate in vivo drug absorption from in vitro drug concentration-time data (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). These biopharmaceutical models base their prediction of drug absorption on physicochemical properties of the drug (solubility, pKa, physical state), physiological properties (absorption rate constant, local pH, transit time), and dosage form (17).…”

Section: Introductionmentioning

confidence: 99%

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Kleppe

Forney-Stevens

Haskell

et al. 2015

AAPS J

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Abstract. Poorly soluble drugs are increasingly formulated into supersaturating drug delivery systems which may precipitate during oral delivery. The link between in vitro drug concentration profiles and oral bioavailability is under intense investigation. The objective of the present work was to develop closedform analytical solutions that relate in vitro concentration profiles to the amount of drug absorbed using several alternate assumptions and only six parameters. Three parameters define the key features of the in vitro drug concentration-time profile. An additional three parameters focus on physiological parameters. Absorption models were developed based on alternate assumptions; the drug concentration in the intestinal fluid: (1) peaks at the same time and concentration as in vitro, (2) peaks at the same time as in vitro, or (3) reaches the same peak concentration as in vitro. The three assumptions provide very different calculated values of bioavailability. Using Case 2 assumptions, bioavailability enhancement was found to be less than proportional to in silico examples of dissolution enhancement. Case 3 assumptions lead to bioavailability enhancements that are more than proportional to dissolution enhancements. Using Case 1 predicts drug absorption amounts that fall in between Case 2 and 3. The equations developed based on the alternate assumptions can be used to quickly evaluate the potential improvement in bioavailability due to intentional alteration of the in vitro drug concentration vs. time curve by reformulation. These equations may be useful in making decisions as to whether reformulation is expected to provide sufficient bioavailability enhancement to justify the effort.

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Identification of Biowaivers Among Class II Drugs: Theoretical Justification and Practical Examples

Cited by 71 publications

References 14 publications

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

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