Fed and fasted gastric pH and gastric residence time in conscious beagle dogs

Sagawa, Kazuko; Li, Fasheng; Liese, Ryan; Sutton, Steven C.

doi:10.1002/jps.21602

Cited by 105 publications

(105 citation statements)

References 13 publications

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“…Given the chiral nature of SB-823094, the formation of each enantiomer was also confirmed, with no marked differences between rats, dogs, and humans. Safety margins for SB-554008 were attained in the dog only (;1.5-fold), whereas in the rat this metabolite was present at lower concentrations than in humans, which is consistent with the physiologic pH of the stomach in rats being higher than dogs in both fed and fasted states (McConnell et al, 2008;Sagawa et al, 2009). Interestingly, SB-554008 was not observed at all systemically after a single oral dose of the enteric coated tablet in humans (LLQ 0.1 ng/ml), whereas after a single oral solution dose of [ 14 C]darapladib, the mean individual pooled plasma concentration of SB-554008 was up to 4.5 nanogram equivalents/milliliter, clearly demonstrating that SB-554008 concentrations are substantially greater after oral dosing of solution than an enteric coated tablet, which protects darapladib from the low pH environment in the stomach.…”

Section: Following IV and Oral Administration Of [supporting

confidence: 65%

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

et al. 2013

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The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A 2 , was investigated in healthy male subjects using [14 C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acidcatalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

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Section: Following IV and Oral Administration Of [supporting

confidence: 65%

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

et al. 2013

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“…Specific pH for the GI compartments were set at pH values presented for the Beagle Model in GastroPlus as follows: SI1, pH 6.2; SI2, pH 6.2; SI3, pH 6.2; SI4, pH 6.4; SI5, pH 6.6; SI6, pH 6.68; SI7, pH 6.75; colon, pH 6.45. The exception was the stomach compartment, which was set to be similar to human gastric pH (pH 1.2) because our studies involved either pentagastrin-pretreated dogs or fed dogs, which have stomach pH similar to humans (Sagawa et al, 2009). Solubility of the stomach compartment was set at 0.49 mg/ml, the solubility of GDC-0449 in simulated gastric fluid at the stomach pH.…”

Section: Methodsmentioning

confidence: 99%

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

Wong¹,

Theil²,

Cui³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (ϳ19% of systemic clearance). Likewise, in vitro studies using sandwichcultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior.The hedgehog (Hh) signaling pathway regulates proliferation and differentiation during embryogenesis. Hh ligands bind to Patched (PTCH1), a transmembrane protein on target cells. In the absence of Hh, the role of PTCH1 is to inhibit the activity of Smoothened (SMO), a seven-transmembrane protein that serves as the signaling component of the pathway. Binding of Hh proteins to PTCH1 relieves this inhibition and initiates activation of SMO. The increase in SMO activity causes increases in activated forms of Gli, transcriptional factors that serve to regulate the expression of Hh target genes. Activation of the Hh pathway has been implicated in a number of cancers (Scales and de Sauvage, 2009). Mutations in the Hh receptor components, PTCH1 or SMO, result in constitutive pathway activation and have been identified in basal cell carcinoma (Hahn et al., 1996;Johnson et al., 1996) and medulloblastoma (Pietsch et al., 1997;Raffel et al., 1997;Vorechovský et al., 1997). It has also been observed that aberrant Hh ligand production can contribute to the growth of other tumor types, such as colorectal and pancreatic cancer (Yauch et al., 2008), prostate cancer (Fan et al., 2004), and B cell lymphoma (Dierks et al., 2007), through paracrine activation of the Hh pathway. Paracrine signaling typically involves ligand expressed on the cancer cells ...

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“…Pentagastrin (6 μg/kg, intramuscular) was administered 30 min prior to drug dose to control gastric pH in the range pH 1-3 (15). The fasted-state gastric pH has been reported to span a wide range between 1.6 and 8.5 and can vary between dog colonies (15,21,22). To reduce this inherent gastric pH variability and control it in a range more typical of human stomach pH, pentagastrin, a synthetic peptide that simulates the secretion of gastric acid secretion in a dose and time-dependent manner in dog and man was used (15,23).…”

Section: Dog Pk Model For Food Effectmentioning

confidence: 99%

“…These are likely to stem from differences in physiology that are exemplified for certain drugs. For example, in dogs, drugs that are susceptible to a narrow window of absorption tend to show enhanced absorption in the fed state as longer gastric emptying compared to humans prolongs the window of absorption (21). BMS-G and BMS-P are examples of drugs that show such distinctive behavior in dogs with FE ratios of 5.2 and 5.5.…”

Section: Dog-to-human Fe Predictionmentioning

confidence: 99%

“…Consequently, BMS-G benefits from delayed gastric emptying in the dog fed state that enhances its overall bioavailability and FE ratio. Another possible scenario for mechanistic differences stems from fed-state gastric pH being 3-4 units lower than in humans (21). Ionizable weak base drug, such as BMS-D that show strong pH-dependent dissolution at low fed-state gastric pH drives up the exposure and FE ratio to 2.65 compared to human FE ratio of 1.7.…”

Section: Dog-to-human Fe Predictionmentioning

confidence: 99%

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Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Mathias

Yang

Vig

et al. 2015

AAPS J

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Abstract. In vitro and in vivo experimental models are frequently used to assess a new chemical entity's (NCE) biopharmaceutical performance risk for food effect (FE) in humans. Their ability to predict human FE hinges on replicating key features of clinical FE studies and building an in vitro-in vivo relationship (IVIVR). In this study, 22 compounds that span a wide range of physicochemical properties, Biopharmaceutics Classification System (BCS) classes, and food sensitivity were evaluated for biorelevant dissolution in fasted-and fed-state intestinal media and the dog fed/fasted-state pharmacokinetic model. Using the area under the curve (AUC) as a performance measure, the ratio of the fed-to-fasted AUC (FE ratio) was used to correlate each experimental model to FE ratio in humans. A linear correlation was observed for the in vitro dissolution-human IVIVR (R 2 =0.66, % mean square error 20.7%). Similarly, the dog FE ratio correlated linearly with the FE ratio in humans (R 2 =0.74, % mean square error 16.25%) for 15 compounds. Data points near the correlation line indicate dissolution-driven mechanism for food effect, while deviations from the correlation line shed light on unique mechanisms that can come into play such as GI physiology or unusual physicochemical properties. In summary, fed/fasted dissolution studies and dog PK studies show a reasonable correlation to human FE, hence are useful tools to flag high-risk NCEs entering clinical development. Combining kinetic dissolution, dog FE model and in silico modeling one can study FE mechanism and formulation strategies to mitigate the FE risk.KEY WORDS: biorelevant dissolution; dog food effect model; food effect; in vitro-in vivo relationship.

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Fed and fasted gastric pH and gastric residence time in conscious beagle dogs

Cited by 105 publications

References 13 publications

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

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