Non-linear Increases in Danazol Exposure with Dose in Older vs. Younger Beagle Dogs: The Potential Role of Differences in Bile Salt Concentration, Thermodynamic Activity, and Formulation Digestion

Anby, Mette Uhre; Williams, Hywel David; Feeney, Orlagh M.; Edwards, Glenn A.; Benameur, Hassan; Pouton, Colin W.; Porter, Christopher John

doi:10.1007/s11095-013-1260-8

Cited by 8 publications

(10 citation statements)

References 57 publications

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“…The polymers E 100, HPMCAS:HF, and HPMC E4M were therefore employed in initial experiments to determine whether drug loading significantly affected PPI performance. The in vitro concentration profiles of fenofibrate after dispersion and digestion of the three formulations (Type IIIA-MC, IIIB-MC, and IV) at high drug load (85% saturation), resulted in more precipitation than those obtained at low (40% saturation) drug load, in agreement with previous studies using fenofibrate 38,39,43,68 and other PWSDs 17,53,69 in LBFs. This can be attributed to the higher AP MAX reached at higher drug load, which increases the maximum supersaturation ratio (S M ) and therefore the pressure applied on the formulation to maintain supersaturation without drug precipitation.…”

Section: Molecular Pharmaceuticssupporting

confidence: 89%

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

et al. 2018

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The ability of lipid-based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastrointestinal (GI) fluids has generated significant interest in the past decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs) to the formulation. In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid-soluble polymers Eudragit (EU) RL100 and poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water-soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure, and a good correlation was found between the degree of in vitro supersaturation and in vivo drug exposure. An improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

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Section: Molecular Pharmaceuticssupporting

confidence: 89%

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

et al. 2018

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“…19 This was suggested to reflect either saturation of first pass metabolism or an increase in thermodynamic activity at higher doses. Interestingly, the dose-dependent increase in bioavailability was evident in only one cohort of (older) animals, and not in another (younger) group.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Previous studies of danazol absorption from SEDDS revealed nonlinear increases in exposure (bioavailability) with increasing drug dose in dogs. 19 This was suggested to reflect either saturation of first pass metabolism or an increase in thermodynamic activity at higher doses. Interestingly, the dose-dependent increase in bioavailability was evident in only one cohort of (older) animals, and not in another (younger) group.…”

Section: ■ Discussionmentioning

confidence: 99%

“…16 −18 In a previous study from our laboratories, the impact of increasing drug dose on danazol bioavailability from SEDDS formulations in beagle dogs was explored in an attempt to delineate the potentially opposing effects of increasing dose leading to supersaturation (and an increase in thermodynamic activity and absorption) versus an increase in precipitation (and a reduction in absorption). 19 Interestingly, the data obtained varied as a function of the animal cohort. 19 In older animals increasing dose resulted in increases in bioavailability up to a critical point (consistent with increases in supersaturation and thermodynamic activity), above which further increases resulted in a reduction in bioavailability (consistent with increased precipitation).…”

Section: ■ Introductionmentioning

confidence: 99%

“…19 Interestingly, the data obtained varied as a function of the animal cohort. 19 In older animals increasing dose resulted in increases in bioavailability up to a critical point (consistent with increases in supersaturation and thermodynamic activity), above which further increases resulted in a reduction in bioavailability (consistent with increased precipitation). In contrast, in a younger animal cohort linear increases in danazol exposure were evident with increases in dose and bioavailability was unchanged.…”

Section: ■ Introductionmentioning

confidence: 99%

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An in Vitro Digestion Test That Reflects Rat Intestinal Conditions To Probe the Importance of Formulation Digestion vs First Pass Metabolism in Danazol Bioavailability from Lipid Based Formulations

et al. 2014

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The impact of gastrointestinal (GI) processing and first pass metabolism on danazol oral bioavailability (BA) was evaluated after administration of self-emulsifying drug delivery systems (SEDDS) in the rat. Danazol absolute BA was determined following oral and intraduodenal (ID) administration of LFCS class IIIA medium chain (MC) formulations at high (SEDDSH-III) and low (SEDDSL-III) drug loading and a lipid free LFCS class IV formulation (SEDDS-IV). Experiments were conducted in the presence and absence of ABT (1-aminobenzotriazole) to evaluate the effect of first pass metabolism. A series of modified in vitro lipolysis tests were developed to better understand the in vivo processing of SEDDS in the rat. Danazol BA was low (<13%) following oral and ID administration of either SEDDS. Increasing drug loading, ID rather than oral administration, and administration of SEDDS-IV rather than SEDDS-III led to higher oral BA. After pretreatment with ABT, however, danazol oral BA significantly increased (e.g., 60% compared to 2% after administration of SEDDSL-III), no effect was observed on increasing drug loading, and differences between SEDDS-III and -IV were minimal. In vitro digestion models based on the lower enzyme activity and lower dilution conditions expected in the rat resulted in significantly reduced danazol precipitation from SEDDS-III or SEDDS-IV on initiation of digestion. At the doses administered here (4-8 mg/kg), the primary limitation to danazol oral BA in the rat was first pass metabolism, and the fraction absorbed was >45% after oral administration of SEDDS-III or SEDDS-IV. In contrast, previous studies in dogs suggest that danazol BA is less dependent on first pass metabolism and more sensitive to changes in formulation processing. In vitro digestion models based on likely rat GI conditions suggest less drug precipitation on formulation digestion when compared to equivalent dog models, consistent with the increases in in vivo exposure (fraction absorbed) seen here in ABT-pretreated rats.

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Route-Specific Challenges in the Delivery of Poorly Water-Soluble Drugs

Warnken¹,

Smyth²,

Williams³

2022

AAPS Advances in the Pharmaceutical Sciences Series

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Non-linear Increases in Danazol Exposure with Dose in Older vs. Younger Beagle Dogs: The Potential Role of Differences in Bile Salt Concentration, Thermodynamic Activity, and Formulation Digestion

Cited by 8 publications

References 57 publications

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

An in Vitro Digestion Test That Reflects Rat Intestinal Conditions To Probe the Importance of Formulation Digestion vs First Pass Metabolism in Danazol Bioavailability from Lipid Based Formulations

Route-Specific Challenges in the Delivery of Poorly Water-Soluble Drugs

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