Food-Induced “Dose-Dumping” from a Once-a-Day Theophylline Product as a Cause of Theophylline Toxicity

Hendeles, Leslie; Weinberger, Miles; Milavetz, Gary; Hill, Malcolm; Vaughan, Leigh M.

doi:10.1378/chest.87.6.758

Cited by 132 publications

(33 citation statements)

References 27 publications

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“…However, the substantial variations in profiles, which were found after food were in accordance with the steady state serum theophylline profiles in children treated with SRT (Uniphyllin) once a day in a recent clinical trial in which food intake in relation to dosing was not controlled (Nerminathan & McKenzie, 1984 Dose dumping has recently been reported to occur with the SRT product Theo-24 and pHdependent dissolution has been suggested as a possible explanation for this phenomenon (Hendeles et al, 1984(Hendeles et al, , 1985. Uniphyllin, however, shows pH-independent in vitro dissolution and yet pronounced dose dumping.…”

Section: Discussionmentioning

confidence: 64%

Food induced changes in theophylline absorption from a once‐a‐day theophylline product.

Steffensen¹,

Pedersen²

1986

Brit J Clinical Pharma

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1 Bioavailability and the absorption pattern of theophylline from the sustained release theophylline (SRT) product, Uniphyllin, were studied in eight adults and eight children under fasting conditions in the morning, after a standardised breakfast in the morning, and under fasting conditions in the evening (adults only). Theophylline given intravenously was used as a reference.2 The extent of absorption of theophylline was complete for all administrations of SRT both in adults and children.3 In adults the absorption profiles after the three administrations of SRT were very similar and at no time point was there any difference in serum theophylline concentration or fraction absorbed between the three regimens. In addition, inter and intra individual variations in absorption were small. 4 In children food caused a substantial change in the absorption pattern of theophylline so that the profiles became rather unpredictable with delays in absorption and periods of rapidly increasing serum drug concentrations. In three of the patients the dose dumping phenomenon resulted in toxic serum drug concentrations. Dumping of the dose could take place at any time interval between 3 and 15 h post dosing. Cmax was about 50% higher after fed than after fasting medication (P < 0.01). 5 It is concluded that children should not take SRT in large doses in combination with food.

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Section: Discussionmentioning

confidence: 64%

Food induced changes in theophylline absorption from a once‐a‐day theophylline product.

Steffensen¹,

Pedersen²

1986

Brit J Clinical Pharma

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“…Food effects may significantly alter the systemic availability of orally dosed drugs which can impact pharmacological responses or safety margins (3)(4)(5). Fleisher, Wu, and Benet used the Biopharmaceutics Classification System (BCS; 6) to predict the direction and change in the extent of drug exposure affected by food (1,7).…”

Section: Introductionmentioning

confidence: 99%

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Heimbach

Xia

Lin

et al. 2012

AAPS J

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Abstract. Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/ Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration-time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1-4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound's BCS/ BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions.

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“…This can represent a great risk for the patient, especially in cases when a large amount of the dose is dumped within a short period of time [100,101]. Fats, high concentrations of bile components and pH changes [101,102] are typical triggers for increased drug-release rates.…”

Section: Effect Of Food On Drug Relelasementioning

confidence: 99%

Drug release from matrix tablets: physiological parameters and the effect of food

Nokhodchi

Asare-Addo

2014

Expert Opinion on Drug Delivery

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Introduction: As dissolution plays an important and vital role in the drug-delivery process of oral solid dosage forms, it is, therefore, essential to critically evaluate the parameters that can affect this process. Areas covered:The consumption of food as well as the physiological environment and properties of the gastrointestinal tract, such as its volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pK a , diffusion coefficient, permeability and particle size, all affect drug dissolution and absorption rate. There are several dissolution approaches that have been developed to address the conditions as experienced in the in vivo environment, as the traditional dissolution being a quality control method is not biorelevant and as such do not always produce meaningful data. This review also describes the development of a systematic way that differentiates between robust and non-robust formulations by varying the effects of agitation and ionic strength through the use of the automated United States Pharmacopeia type III Bio-Dis apparatus. Expert opinion:With the improved understanding of the physiological parameters that can affect the oral bioperformance of dosage forms, strides have, therefore, been made in making dissolution testing methods more bio-logically based with the view of obtaining more in vitro--in vivo correlations.Keywords: agitation rate, biodissolution, drug release, effect of food, hydrophilic matrices, ionic strength Highlights -Understanding all the physiological parameters can serve as a basis for designing dissolution testing methods and systems that can more fully represent the gastrointestinal (GI) tract in humans and allow more in vitro-in vivo (IVIVC) correlations to be obtained thereby improving the oral bioperformance of dosage forms.-Simulation of GI conditions is essential to adequately predict the in vivo behaviour of drug formulations.-The choice of appropriate media for in vitro tests is crucial to their ability to correctly forecast the food effect in pharmacokinetic studies.-Several methods of dissolution testing have been conducted and are still ongoing that seek to further understand and develop media and dissolution methods to better represent the in vivo conditions and to aid in the better prediction of in vivo drug release.-Systematic change of agitation method and ionic strength evaluation may be used as additional tools in allowing for the identification of potential fed and fasted effects on drug release from hydrophilic matrices in the drive for developing dissolution methodologies that are more relevant in helping to achieve more IVIVC.

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Food-Induced “Dose-Dumping” from a Once-a-Day Theophylline Product as a Cause of Theophylline Toxicity

Cited by 132 publications

References 27 publications

Food induced changes in theophylline absorption from a once‐a‐day theophylline product.

Food induced changes in theophylline absorption from a once‐a‐day theophylline product.

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Drug release from matrix tablets: physiological parameters and the effect of food

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