Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (T max) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concentrations were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an absolute bioavailability of ~ 100% under fasted conditions. Administration of the ertugliflozin 15 mg commercial tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concentration-time curve (AUC), but decreased peak concentrations (C max) by 29%. The effect on C max is not clinically relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were associated with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was observed and not considered clinically relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clinically meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and C max by 39% and 15%, respectively, and is not expected to affect efficacy in a clinically meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.

Ertugliflozin, an inhibitor of sodium‐glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed‐dose combination (FDC) therapies with either sitagliptin or immediate‐release metformin. The effect of a standard, high‐fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15‐/100‐mg), and ertugliflozin/metformin FDC (7.5‐/1000‐mg) tablets was evaluated. In 3 separate open‐label, 2‐period, 2‐sequence, single‐dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone are capable of enhancing skin permeation of each other when applied simultaneously. We carried out a cellular study in rat astrocytes and neurons to assess cell toxicity of DEET and oxybenzone and a 30-day study in Sprague-Dawley rats to characterize skin permeation and tissue disposition of the compounds. Cellular toxicity occurred at 1 µg/mL for neurons and 7-day treatment for astrocytes and neurons. DEET and oxybenzone permeated across the skin to accumulate in blood, liver, and brain after repeated topical applications. DEET disappeared from the application site faster than oxybenzone. Combined application enhanced the disposition of DEET in liver. No overt sign of behavioral toxicity was observed from several behavioral testing protocols. It was concluded that despite measurable disposition of the study compounds in vivo, there was no evidence of neurotoxicological deficits from repeated topical applications of DEET, oxybenzone, or both.

Ertugliflozin is a selective sodium‐glucose cotransporter 2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). A population pharmacokinetic (popPK) model was developed to characterize the pharmacokinetics (PK) of ertugliflozin and quantify the influence of intrinsic (eg, body weight, age, sex, race, estimated glomerular filtration rate [eGFR], T2DM) and extrinsic (eg, food) covariates on the PK parameters of ertugliflozin. The analysis was conducted using data from 15 clinical studies (phases 1‐3) enrolling healthy subjects and patients with T2DM, which included 13,691 PK observations from 2276 subjects and was performed using nonlinear mixed‐effects modeling. A 2‐compartment popPK model with first‐order absorption and a lag time and first‐order elimination, described the plasma concentration–time profile of ertugliflozin after single and multiple dosing in healthy subjects and in patients with T2DM. Apparent clearance increased with increasing body weight and eGFR, was slightly lower in patients with T2DM and females, and was slightly higher in Asians. Apparent central volume of distribution increased with increasing body weight and was higher in females and Asians. Administration of ertugliflozin with food decreased the absorption rate constant (ka) and relative bioavailability (F1) compared with fasted. When ertugliflozin was administered without regard to food, estimates of ka and F1 were similar to those for administration with food. The popPK model successfully characterized ertugliflozin exposure in healthy subjects and patients with T2DM. None of the covariates evaluated had a clinically relevant effect on ertugliflozin PK.

The permeation behaviours of the insect repellent N,N-diethyl-m-toluamide (DEET) and the sunscreen oxybenzone were assessed in a series of in-vitro diffusion studies, using piglet skin and poly (dimethylsiloxane) (PDMS) membrane. The transmembrane permeability of DEET and oxybenzone across piglet skin and PDMS membrane was dependent on dissolving vehicles and test concentrations. An enhanced permeation increase across piglet skin was found for DEET and oxybenzone when both compounds were present in the same medium (DEET: 289% in propylene glycol, 243% in ethanol and 112% in poly(ethylene glycol) (PEG-400); oxybenzone: 139% in PEG-400, 120% in propylene glycol and 112% in ethanol). Permeation enhancement was also observed in PDMS membrane (DEET: 207% in ethanol, 124% in PEG-400 and 107% in propylene glycol; oxybenzone: 254% in PEG-400, 154% in ethanol and 105% in propylene glycol). PDMS membrane was found to be a suitable candidate for in-vitro diffusion evaluations. This study shows that the permeations of the insect repellent DEET and the sunscreen oxybenzone were synergistically enhanced when they were applied simultaneously.

A fixed-dose combination (FDC) of ertugliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and immediaterelease 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.

The insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone (OBZ) have been shown to produce synergistic permeation enhancement when applied concurrently in vitro and in vivo. The disposition of both compounds following intravenous administration (2 mg/kg of DEET or OBZ) and topical skin application (100 mg/kg of DEET and 40 mg/kg of OBZ) was determined in male Sprague-Dawley rats. Pharmacokinetic analysis was also conducted using compartmental and non-compartmental methods. A two-compartment model was deemed the best fit for intravenous administration. The DEET and oxybenzone permeated across the skin to accumulate in blood, liver and kidney following topical skin application. Combined use of DEET and oxybenzone accelerated the disappearance of both compounds from the application site, increased their distribution in the liver and significantly decreased the apparent elimination half-lives of both compounds (p < 0.05). Hepatoma cell studies revealed toxicity from exposure to all treatment concentrations, most notably at 72 h. Although DEET and oxybenzone were capable of mutually enhancing their percutaneous permeation and systemic distribution from topical skin application, there was no evidence of increased hepatotoxic deficits from concurrent application.

For treatment of allergic rhinitis, acrivastine with pseudoephedrine in Semprex-D conventional capsules requires dosing every 6-8 hours. This study was designed to develop a controlled release matrix tablet of acrivastine and pseudoephedrine and evaluate 5 different matrix excipients for their in vitro controlled-release profiles. Compritol 888ATO, Eudragit RS, Methocel K100M, Polyox WSR301 and Precirol ATO5 were used alone or in varying combinations for the formulation of controlled release matrix tablets. In vitro drug dissolution and mathematical modeling were used to characterize drug release rate and extent. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. Due to the aqueous solubility of pseudoephedrine and the size of the dose, none of the matrix excipients used alone prolonged drug release significantly to meet the desired twice-daily administration frequency. The use of two excipients in combination, however, significantly decreased the dissolution rate of both active ingredients. A combined lipid-based Compritol and hydrophilic Methocel produced optimal controlled drug release for longer than 8 hours for both acrivastine and pseudoephedrine.