Elucidating the Role of Dose in the Biopharmaceutics Classification of Drugs: The Concepts of Critical Dose, Effective In Vivo Solubility, and Dose-Dependent BCS

Charkoftaki, Georgia; Dokoumetzidis, Aristides; Valsami, Georgia; Macheras, Panos

doi:10.1007/s11095-012-0815-4

Cited by 23 publications

(8 citation statements)

References 61 publications

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“…This approach has been applied to the study of the intestinal precipitation of a basic BCS class II drug in the presence or absence of omeprazole 73. It is interesting to note that this type of analysis (AUC vs. dose plots) has been used for the development of dose‐dependent BCS (DDBCS) 32. Finally, the third approach relies on human aspirates 70.…”

Section: Scientific Aspects Of Oral Drug Absorptionmentioning

confidence: 99%

“…A very interesting result of both studies is that the solubility–dose ratio is an important parameter for BDDCS classification. Prompted by these advances,30,31 an in‐depth study of the role of the solubility–dose ratio in the biopharmaceutics classification of drugs was performed 32. The original model24 used for the development of BCS was modified27 and used to examine in detail the effect of dose on the fraction of dose absorbed for each one of the four BCS drug classes.…”

Section: Regulatory Aspects Of Oral Drug Absorptionmentioning

confidence: 99%

“…The original model24 used for the development of BCS was modified27 and used to examine in detail the effect of dose on the fraction of dose absorbed for each one of the four BCS drug classes. Based on this modeling work, the concepts of the critical dose and effective in vivo solubility were developed 32. Moreover, real data were analyzed to derive estimates of effective in vivo solubility.…”

Section: Regulatory Aspects Of Oral Drug Absorptionmentioning

confidence: 99%

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Antituberculosis Therapy–Induced Acute Liver Failure: Magnitude, Profile, Prognosis, and Predictors of Outcome

et al. 2010

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Antituberculosis therapy (ATT)–associated acute liver failure (ATT-ALF) is the commonest drug-induced ALF in South Asia. Prospective studies on ATT-ALF are lacking. The current study prospectively evaluated the magnitude, clinical course, outcome, and prognostic factors in ATT-ALF. From January 1986 to January 2009, 1223 consecutive ALF patients were evaluated: ATT alone was the cause in 70 (5.7%) patients. Another 15 (1.2%) had ATT and simultaneous hepatitis virus infection. In 44 (62.8%) patients, ATT was prescribed empirically without definitive evidence of tuberculosis. ATT-ALF patients were younger (32.87 [±15.8] years), and 49 (70%) of them were women. Most had hyperacute presentation; the median icterus encephalopathy interval was 4.5 (0-30) days. The median duration of ATT before ALF was 30 (7-350) days. At presentation, advanced encephalopathy and cerebral edema were present in 51 (76%) and 29 (41.4%) patients, respectively. Gastrointestinal bleed, seizures, infection, and acute renal failure were documented in seven (10%), five (7.1%), 26 (37.1%), and seven (10%) patients, respectively. Compared with hepatitis E virus (HEV) and non-A non-E–induced ALF, ATT-ALF patients had nearly similar presentations except for older age and less elevation of liver enzymes. The mortality rate among patients with ATT-ALF was high (67.1%, n = 47), and only 23 (32.9%) patients recovered with medical treatment. In multivariate analysis, three factors independently predicted mortality: serum bilirubin (≥10.8 mg/dL), prothrombin time (PT) prolongation (≥26 seconds), and grade III/IV encephalopathy at presentation. Conclusion: ATT-ALF constituted 5.7% of ALF at our center and had a high mortality rate. Because the mortality rate is so high, determining which factors are predictors is less important. A high proportion of patients had consumed ATT empirically, which could have been prevented. Hepatology 2010

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Section: Scientific Aspects Of Oral Drug Absorptionmentioning

confidence: 99%

Section: Regulatory Aspects Of Oral Drug Absorptionmentioning

confidence: 99%

Section: Regulatory Aspects Of Oral Drug Absorptionmentioning

confidence: 99%

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Antituberculosis Therapy–Induced Acute Liver Failure: Magnitude, Profile, Prognosis, and Predictors of Outcome

et al. 2010

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“…Precipitation is a function of both concentration and time; the peak concentration and its duration depend on the drug, drug form, dose, and formulation components (the exact dependence of which is the focus of intense current investigation) (5,28,29,(38)(39)(40)(41)(42)(43). If both the peak drug concentration and duration of that peak in vivo were equal to the values determined from the in vitro dissolution profile (Fig.…”

Section: Relationship Between In Vitro Drug Concentration Profile Andmentioning

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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“…For example, obvious maturation changes are related to the volume increase of luminal fluids, intestinal surface area, and intestinal permeability (12)(13)(14)(15). Administered dose is also fundamentally important, and therefore, there may be a need for a more quantitative, dose-dependent approach to pediatric BCS (16,17). Wu and Benet (18) have proposed an alternative Biopharmaceutics Drug Disposition Classification System which includes the role of metabolism in classifying drugs.…”

Section: Challenges In the Development Of Pediatric Dosage Forms Frommentioning

confidence: 99%

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

Zajicek

Fossler

Barrett

et al. 2013

AAPS J

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Abstract. Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

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Elucidating the Role of Dose in the Biopharmaceutics Classification of Drugs: The Concepts of Critical Dose, Effective In Vivo Solubility, and Dose-Dependent BCS

Cited by 23 publications

References 61 publications

Antituberculosis Therapy–Induced Acute Liver Failure: Magnitude, Profile, Prognosis, and Predictors of Outcome

Antituberculosis Therapy–Induced Acute Liver Failure: Magnitude, Profile, Prognosis, and Predictors of Outcome

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

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

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