Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Kalgutkar, Amit S.; Tugnait, Meera; Zhu, Tong; Kimoto, Emi; Miao, Zhuang; Mascitti, Vincent; Yang, Xin; Tan, Beijing; Walsky, Robert L.; Chupka, Jonathan; Feng, Bo; Robinson, Ralph P.

doi:10.1124/dmd.111.040675

Cited by 62 publications

(130 citation statements)

References 39 publications

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“…An example is ertugluflozin (PF-04971729), a selective inhibitor of the sodium-dependent glucose cotransporter 2. Reaction phenotyping studies indicated that both P450 (CYP3A4/3A5) and non-P450 pathways (UGT1A9 and UGT2B7) are involved in the metabolism of this compound (Kalgutkar et al, 2011). However, quantitative assignment of each of these pathways was not feasible because of low in vitro turnover in hepatic microsomes and hepatocytes.…”

Section: Special Considerations: Low Turnover Extrahepatic Metabolismentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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Section: Special Considerations: Low Turnover Extrahepatic Metabolismentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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“…In the ertugliflozin human mass balance study, ertugliflozin F a was estimated to be ≥50%,2 whereas in preclinical species, estimated F a was ∼75% and ∼100% in rats and dogs, respectively 1. In Caco‐2 cells, ertugliflozin permeability coefficient was 4.1 × 10 −6 cm/s in the apical (A) to basolateral (B) direction (BA/AB ratio of 2.1) 1. In light of these data, a clinical study was conducted to get a better understanding of permeability and obtain an estimate of the absolute bioavailability of ertugliflozin.…”

mentioning

confidence: 97%

“…Ertugliflozin, a highly selective and potent inhibitor of the sodium glucose cotransporter‐2,1, 2 has been approved in the United States for the treatment of type 2 diabetes mellitus at doses of 5 and 15 mg once daily. Recent phase III trials have demonstrated that ertugliflozin is associated with statistically significant reductions in hemoglobin A1c, fasting plasma glucose, and body weight when used as monotherapy (compared with placebo),3 and when added to sitagliptin4 or metformin plus sitagliptin 5.…”

mentioning

confidence: 99%

“…The mean urinary 14 C recovery suggested that the human fraction of ertugliflozin dose absorbed (F a ) is at least 50% 2. Metabolism of ertugliflozin is catalyzed mainly by uridine diphosphate‐glucuronosyltransferase‐1A9, with minor contributions from uridine diphosphate‐glucuronosyltransferase‐2B7 and cytochrome P450 isoenzymes 1, 2…”

mentioning

confidence: 99%

“…A compound is classified as having high permeability when (F a is determined to be ≥85% of an administered dose based on results from human mass balance or absolute bioavailability studies. In the ertugliflozin human mass balance study, ertugliflozin F a was estimated to be ≥50%,2 whereas in preclinical species, estimated F a was ∼75% and ∼100% in rats and dogs, respectively 1. In Caco‐2 cells, ertugliflozin permeability coefficient was 4.1 × 10 −6 cm/s in the apical (A) to basolateral (B) direction (BA/AB ratio of 2.1) 1.…”

mentioning

confidence: 99%

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Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Raje

Callegari

Sahasrabudhe

et al. 2018

Clinical Translational Sci

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Ertugliflozin, a sodium glucose cotransporter‐2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two‐period study design with 14C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin. Eight healthy adult men received 100‐μg i.v. 14C‐ertugliflozin (400 nCi) dose 1 h after a 15‐mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14C‐ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high‐performance liquid‐chromatography tandem mass spectrometry (HPLC‐MS/MS). 14C‐ertugliflozin plasma concentrations were determined using HPLC‐accelerator mass spectrometry (AMS) and 14C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o./14C‐AUCi.v.)*(14C‐Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C‐Dosei.v./14C‐Dosep.o.)) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

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Ertugliflozin

Zhong

2013

Handbook of Metabolic Pathways of Xenobiotics

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The metabolism of [ 14 C]‐ertugliflozin was studied in six healthy human subjects after a single oral dose of 25 mg. The major circulating radioactivity was attributed to ertugliflozin (50%). Hydroxylation products and glucuronide conjugates of the parent accounted for 3 and 46% of the circulating radioactivity, respectively. The total administered radioactivity recovered in urine and feces was 50 and 41%, respectively. Unchanged ertugliflozin was a minor component in urine accounting for only 1.5% of the administered dose. The primary urinary metabolites in urine were three ertugliflozin glucuronides. In feces, the unchanged drug was the most abundant component (accounting for about 34% of the dose), hydroxylation and oxidation metabolites were minor.

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Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Cited by 62 publications

References 39 publications

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

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