A Semi-mechanistic Modeling Strategy to Link In Vitro and In Vivo Drug Release for Modified Release Formulations

Bergstrand, Martin; Söderlind, Erik; Eriksson, Ulf G.; Karlsson, Mats O.

doi:10.1007/s11095-011-0594-3

Cited by 18 publications

(28 citation statements)

References 42 publications

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“…However, we postulate that a more detailed mechanistic understanding of the influence of pH, food, and first-pass processes on the oral absorption of itraconazole will require using semiphysiological models of first-pass metabolite production (54) and the linking of in vitro dissolution profiles with in vivo kinetics (55). We are currently investigating such models.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

Abuhelwa

Foster

Mudge

et al. 2015

Antimicrob Agents Chemother

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bItraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose-and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies. Itraconazole is a broad-spectrum orally active triazole antifungal used for both prophylaxis and treatment of systemic fungal infections (1, 2). Itraconazole exerts antifungal activity through the inhibition of fungal cytochrome P450 (CYP) 3A isoenzymes, which mediate the synthesis of ergosterol, a vital component of the fungal cell membrane (3). Itraconazole undergoes extensive hepatic metabolism by human CYP3A4 isoenzymes. Both itraconazole and its major active metabolite, hydroxyitraconazole, inhibit mammalian CYP3A4, although to a lesser extent than that with the fungal CYP3A isoenzymes (4).Itraconazole is currently available as oral capsules in two marketed formulations: Sporanox, the brand product (Janssen Pharmaceuticals, Inc.[5]), and SUBA-itraconazole, the alternative product. SUBA-itraconazole is a novel formulation containing a solid dispersion of itraconazole in a pH-dependent polymeric matrix to enhance its dissolution and intestinal absorption; therefore, it exhibits greater bioavailability than the innovator product. As of 30 June 2015, SUBA-itraconazole has marketing approval in Australia, Spain, Germany, Sweden, and United Kingdom; currently, it is ava...

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

Abuhelwa

Foster

Mudge

et al. 2015

Antimicrob Agents Chemother

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“…Described in detail in the accompanying article A semimechanistic modeling strategy to link in vitro and in vivo drug release for modified release formulations (12).…”

Section: Magnetic Marker Monitoringmentioning

confidence: 99%

“…Drug model describing drug release rate has been described in detail elsewhere (12), the substance released from the tablet was directed into GI compartments representing the different observed GI positions based on the time varying covariate of observed GI position. The GI position of the tablet was typically monitored continuously for 10 min followed by a 20 min period without observations.…”

Section: Rate and Extent Of Absorptionmentioning

confidence: 99%

“…Drug model describing drug release rate (i.e. elimination from the tablet compartment) has been described in detail elsewhere (12), the substance released from the tablet is directed into GI compartments 2-8 depending on the observed tablet position. Gastric emptying from the stomach compartments (comp.…”

Section: Rate and Extent Of Absorptionmentioning

confidence: 99%

“…The work presented in this manuscript builds on a simultaneously submitted article "A mechanistic model to link in vitro and in vivo drug release for modified release formulations" (12). In that article a model describing in vitro drug release for a group of AZD0837 candidate formulations was described.…”

Section: Introductionmentioning

confidence: 99%

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A Semi-mechanistic Modeling Strategy for Characterization of Regional Absorption Properties and Prospective Prediction of Plasma Concentrations Following Administration of New Modified Release Formulations

et al. 2011

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A Model‐Based Approach to Predict Longitudinal HbA1c, Using Early Phase Glucose Data From Type 2 Diabetes Mellitus Patients After Anti‐Diabetic Treatment

Kjellsson

Cosson

Mazer

et al. 2013

The Journal of Clinical Pharma

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Predicting late phase outcomes from early-phase findings can help inform decisions in drug development. If the measurements in early-phase differ from those in late phase, forecasting is more challenging. In this paper, we present a model-based approach for predicting glycosylated hemoglobin (HbA1c) in late phase using glucose and insulin concentrations from an early-phase study, investigating an anti-diabetic treatment. Two previously published models were used; an integrated glucose and insulin (IGI) model for meal tolerance tests and an integrated glucose-red blood cell-HbA1c (IGRH) model predicting the formation of HbA1c from the average glucose concentration (Cg,av ). Output from the IGI model was used as input to the IGRH model. Parameters of the IGI model and drug effects were estimated using data from a phase1 study in 59 diabetic patients receiving various doses of a glucokinase activator. Cg,av values were simulated according to a Phase 2 study design and used in the IGRH model for predictions of HbA1c. The performance of the model-based approach was assessed by comparing the predicted to the actual outcome of the Phase 2 study. We have shown that this approach well predicts the longitudinal HbA1c response in a 12-week study using only information from a 1-week study where glucose and insulin concentrations were measured.

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A Semi-mechanistic Modeling Strategy to Link In Vitro and In Vivo Drug Release for Modified Release Formulations

Abstract: The paper outlines a modeling approach for predicting in vivo behavior from standard in vitro experiments and support formulation development and quality control.

Cited by 18 publications

References 42 publications

Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

A Semi-mechanistic Modeling Strategy for Characterization of Regional Absorption Properties and Prospective Prediction of Plasma Concentrations Following Administration of New Modified Release Formulations

A Model‐Based Approach to Predict Longitudinal HbA1c, Using Early Phase Glucose Data From Type 2 Diabetes Mellitus Patients After Anti‐Diabetic Treatment

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