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Aim To assess the efficacy and safety of ertugliflozin in older patients with type 2 diabetes (T2D). Materials and methods This is a post hoc analysis of patients with T2D aged less than 65 years and those aged 65 years or older who participated in randomized, double-blind, phase III studies of ertugliflozin. Efficacy was evaluated in a pooled analysis of three placebo-controlled studies (ertugliflozin monotherapy and add-on therapy). Safety was evaluated in a pooled analysis of seven placebo- and active-controlled studies (including those used for efficacy). Least-squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs). Results In participants aged less than 65 years, the placebo-adjusted mean changes from baseline in HbA1c, BW and SBP with ertugliflozin 5 and 15 mg at week 26 were -0.9% and -1.0%, -1.9 and -1.8 kg, and -3.7 and -3.6 mmHg, respectively; in participants aged 65 years or older they were -0.6% and -0.8%, -1.9 and -2.2 kg, and -2.7 and -3.4 mmHg, respectively. The incidences of AEs, serious AEs, discontinuations and deaths in participants aged less than 65 years and those aged 65 years or older were generally similar across the treatment groups. In patients aged 65 years or older the incidences of volume depletion AEs and genital mycotic infection were higher with ertugliflozin than with non-ertugliflozin. Conclusions Ertugliflozin improved glycaemic control, BW and SBP in younger and older individuals with T2D and was generally well tolerated in both groups.

A fixed‐dose combination (FDC) of ertugliflozin, a selective sodium‐glucose cotransporter 2 inhibitor, and immediate‐release metformin is approved for the treatment of type 2 diabetes mellitus in the United States and European Union. Four open‐label, randomized, 2‐period, single‐dose, crossover studies were conducted under fasted conditions in healthy subjects to demonstrate bioequivalence of the ertugliflozin/metformin FDC tablets and coadministration of the individual components at respective strengths. In each study, 32 or 34 subjects received an ertugliflozin/metformin FDC tablet (2.5 mg/500 mg, 7.5 mg/850 mg, or 7.5 mg/1000 mg) and the respective doses of individual components (ertugliflozin with US‐ or EU‐sourced metformin [Glucophage]). Plasma samples for ertugliflozin and metformin concentrations were collected for 72 hours in each period. For both ertugliflozin and metformin, the 90% confidence intervals for the adjusted geometric mean ratio (FDC : coadministration) for area under the plasma concentration–time profile from time zero extrapolated to infinity and maximum observed plasma concentration were within acceptance criteria for bioequivalence. The majority of adverse events were mild in intensity. The studies demonstrated that each strength of FDC tablet is bioequivalent to respective doses of coadministered individual components, supporting that safety and efficacy can be bridged to the individual components used in phase 3 studies evaluating ertugliflozin in combination with metformin.

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 14 C 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. 14 C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14 C-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). 14 C-ertugliflozin plasma concentrations were determined using HPLC-accelerator mass spectrometry (AMS) and 14 C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o. /14 C-AUCi.v. )*(14 C-Dosei.v. /Dosep.o. )) and Fa ((14 C_Total_Urinep.o. /14 C_Total_Urinei.v. )* (14 C-Dosei.v. /14 C-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.

Ertugliflozin is a highly selective and potent inhibitor of the sodium-glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. The glycemic efficacy of sodium-glucose cotransporter 2 inhibitors such as ertugliflozin depends on glucose filtration through the kidney. This phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and tolerability of ertugliflozin (15 mg) in type 2 diabetes mellitus and healthy subjects with normal renal function (estimated glomerular filtration rate not normalized for body surface area ≥90 mL/min) and type 2 diabetes mellitus subjects with mild (60-89 mL/min), moderate (30-59 mL/min), or severe (

Aims To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes. Materials and methods This was a 52-week, double-blind, multicentre, randomized, parallel-group study with a 26-week, placebo-controlled treatment period (phase A), followed by a 26-week active-controlled treatment period (phase B) in 461 men and women, aged ≥18 years with inadequate glycaemic control (glycated haemoglobin [HbA1c] concentration 7.0% to 10.5% [53-91 mmol/mol], inclusive) despite diet and exercise. Results from phase A are reported in the present paper. The primary endpoint was the change in HbA1c from baseline to week 26. Results At week 26, the placebo-adjusted least squares mean HbA1c changes from baseline were −0.99% and −1.16% for the ertugliflozin 5 and 15 mg doses, respectively ( P

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Data demonstrating the pharmacokinetics (PK), efficacy and tolerability of PF-734200, a potent DPP-IV inhibitor in subjects with normal renal function, have been published or presented. WHAT THIS STUDY ADDS • This study provides better data on the PK of PF-734200 in subjects with varying degrees of renal insufficiency and in subjects with end-stage renal disease undergoing haemodialysis. In assessing the effects of renal impairment on the PK of PF-734200, this study provides evidence for potential dose adjustment of PF-734200 in patients with certain categories of renal impairment. AIMS PF-734200 is a potent, selective inhibitor of DPP-IV. This two-part study evaluated the pharmacokinetics (PK) of oral 20 mg PF-734200 in subjects with varying degrees of renal insufficiency or with end-stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF-734200 in ESRD. METHODS Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20 mg PF-734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1 h after HD, a single 20-mg dose was given to subjects with ESRD and serum samples were collected. After a 7-day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4 h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC-based method. RESULTS Systemic exposures of PF-734200 increased approximately 1.5-, 2.2-, 2.1- and 2.8-fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half-life increased from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD. Approximately, 29% of PF-734200 in the body after a single-dose administration was dialysed by 4 h HD. CONCLUSIONS Systemic exposure of PF-734200 increases with decreasing renal function. The effect of HD on drug removal is modest.

Diabet. Med. 28, 464–469 (2011) Abstract Aims PF-734200 is a potent and selective oral dipeptidyl peptidase-4 (DPP-4) inhibitor. This study assessed the efficacy and safety of PF-734200 at dose rates of 20 and 30 mg/day in subjects with Type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Methods This was a placebo-controlled, double-blind, randomized, multicentre, 12 week study. Subjects with Type 2 diabetes mellitus were eligible if screening glycosylated haemoglobin (HbA1c) was 7–11% (53.0–96.7 mmol/mol) and they had been receiving metformin monotherapy for ≥2 months. Subjects receiving metformin and an insulin secretagogue or metformin and thiazolidinedione needed to have a screening HbA1c of 6.5–9.5% (47.5–80.3 mmol/mol), measured prior to discontinuing the insulin secretagogue or thiazolidinedione. The primary end-point of the study was a change from baseline to week 12 in HbA1c levels. Results Baseline characteristics for 289 subjects randomized to PF-734200 or placebo groups were similar (mean age 56.5 years, mean body mass index 32.2 kg/m2 and mean HbA1c 8.2%, 66.1 mmol/mol). In the predefined per protocol data set, least-squares mean HbA1c at week 12 was reduced by 0.79 (8.6 mmol/mol 95% confidence interval –1.10 to –0.49, −12.0 to −5.4 mmol/mol) and 0.92% (10.1 mmol/mol; –1.23 to –0.61, −13.4 to −6.7 mmol/mol) in the 20 and 30 mg groups, respectively, compared with placebo. Differences from placebo were statistically significant (P

Pharmacogenomics is a rapidly expanding field aimed at understanding interpatient variability in drug response through the exploration and investigation of the human genome. It is an incontrovertible fact that large interpatient variability exists in response to medications. Variation in response has existed as long as medications have been used for the prevention and treatment of disease. In many ways, the field of pharmacogenomics began serendipitously in the 1950s after seminal observations describing variability in response to medications. Examples included peripheral neuropathy from isoniazid among slow acetylator, prolonged apnea from succinylcholine caused by pseudocholinesterase deficiency, and severe hypotension from debrisoquine among cytochrome P450 (CYP) 2D6 poor metabolizers. For the next 40 years, pharmacogenetic studies focused almost exclusively on the etiologies of altered variability in pharmacokinetic responses to medications. As we entered the 1990s, pharmacogenomic studies began to include studies that examined pharmacodynamic variability in drug response. Now instead of examining only differences in drug metabolizing enzymes, scientists began to focus on genes that encode drug transporters, drug targets, and ion channels. The ultimate goal of pharmacogenomics is to be able to accurately predict, based on an individual’s genomic information, which medications will provide the greatest benefit with the least harm, thus transforming medicine into an era of personalized therapeutics. This chapter provides a review of pharmacogenomics and how single nucleotide polymorphisms may impact pharmacotherapy and drug discovery. The chapter further explores the abundant recent literature as well as provides insight into some of the issues, limitations, and ethical considerations of pharmacogenomics. Keywords: pharmacogenomics; pharmacogenetics; single nucleotide polymorphisms; SNPs; individualized pharmacotherapy