Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes.

Danuglipron (PF-06882961) is an oral, small-molecule glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log-linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function.

Metabolic disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and skin administration in rats.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone have shown a synergistic percutaneous enhancement when applied concurrently. Both compounds are extensively metabolized in vivo into a series of potentially toxic metabolites: 2 metabolites of DEET, N,N-diethyl-m-hydroxymethylbenzamide (DHMB) and N-ethyl-m-toluamide (ET), and 3 metabolites of oxybenzone, 2,4-dihydroxybenzophenone (DHB), 2,2-dihydroxy-4-methoxybenzophenone (DMB), and 2,3,4-trihydroxybenzophenone (THB). In this study, the metabolites were extensively distributed following intravenous and topical skin administration of DEET and oxybenzone in rats. Combined application enhanced the disposition of all DEET metabolites in the liver but did not consistently affect the distribution of oxybenzone metabolites. The DHMB appeared to be the major metabolite for DEET, while THB and its precursor DHB were the main metabolites for oxybenzone. Repeated once-daily topical application for 30 days led to higher concentrations of DEET metabolites in the liver. Hepatoma cell studies revealed a decrease in cellular proliferation from all metabolites as single and combined treatments, most notably at 72 hours. Increased accumulation of DHMB and ET in the liver together with an ability to reduce cellular proliferation at achievable plasma concentrations indicated that simultaneous exposure to DEET and oxybenzone might have the potential to precipitate adverse effects in a rat animal model.

Tissue disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and topical administration in rats.

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.

Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Healthy Japanese and Western Subjects.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. This randomized, double-blind (sponsor-open) study in healthy Japanese subjects and open-label study in Western subjects assessed ertugliflozin pharmacokinetics and pharmacodynamics. Cohort A received 3 ascending single doses of ertugliflozin (1, 5, and 25 mg; n = 6 Japanese, n = 6 Western) or placebo (n = 3 Japanese) under fasted conditions. Cohort B received multiple once-daily doses of ertugliflozin 25 mg (n = 6 Japanese) or placebo (n = 3 Japanese) for 7 days under fed conditions. For Japanese subjects in Cohort A, maximum plasma concentrations (Cmax ) were observed 1 to 1.5 hours after dosing, and apparent mean terminal half-life was 12.4 to 13.6 hours. The ratios of the geometric means (Japanese/Western) for ertugliflozin 1-, 5-, and 25-mg single doses were 95.94%, 99.66%, and 90.32%, respectively, for area under the plasma concentration-time curve and 107.59%, 97.47%, and 80.04%, respectively, for Cmax . Area under the plasma concentration-time curve and Cmax increased in a dose-proportional manner. For Cohort B, Cmax was observed 2.5 hours after dosing (days 1 and 7), and steady state was reached by day 4. The 24-hour urinary glucose excretion was dose dependent. Ertugliflozin was generally well tolerated. There were no meaningful differences in exposure, urinary glucose excretion, and safety between Japanese and Western subjects.

Population pharmacokinetics and exposure-response analyses of varenicline in adolescent smokers.

Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12 and nausea/vomiting incidence) for varenicline in adolescent smokers were characterized using data from two phase 1 and one phase 4 studies. A one-compartment popPK model with first-order absorption and elimination adequately fitted the observed data. The effect of female sex on apparent clearance was significant. Apparent volume of distribution increased with body weight and decreased by 24%, 15%, and 14% for black race, "other" race, and female sex, respectively. The observed range of exposure in the phase 4 study was consistent with that expected for each dose and body-weight group from the results obtained in adolescent PK studies, supporting that varenicline dose and administration were appropriate in the study. The relationship between CAR9-12 and varenicline area under the concentration-time curve (AUC) from 0 to 24 hours (AUC24 ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC24 (p < 0.001) and was higher in females. Varenicline PK and ER for tolerability in adolescent smokers were comparable with adults, while ER for efficacy confirmed the negative results reported in the phase 4 study.

Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non-E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects. A 2-compartment model with first-order absorption, lag time, and first-order elimination was fitted to the observed data. For the E/SE Asian vs non-E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non-E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non-Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non-Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration-time curve. Therefore, the differences in CL/F (area under the concentration-time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

Population Pharmacokinetic Model for Ertugliflozin in Healthy Subjects and Patients With Type 2 Diabetes Mellitus.

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.

End-to-end application of model-informed drug development for ertugliflozin, a novel sodium-glucose cotransporter 2 inhibitor.

Model-informed drug development (MIDD) is critical in all stages of the drug-development process and almost all regulatory submissions for new agents incorporate some form of modeling and simulation. This review describes the MIDD approaches used in the end-to-end development of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes mellitus. Approaches included (1) quantitative systems pharmacology modeling to predict dose-response relationships, (2) dose-response modeling and model-based meta-analysis for dose selection and efficacy comparisons, (3) population pharmacokinetics (PKs) modeling to characterize PKs and quantify population variability in PK parameters, (4) regression modeling to evaluate ertugliflozin dose-proportionality and the impact of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 genotype on ertugliflozin PKs, and (5) physiologically-based PK modeling to assess the risk of UGT-mediated drug-drug interactions. These end-to-end MIDD approaches for ertugliflozin facilitated decision making, resulted in time/cost savings, and supported registration and labeling.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta-analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration-time curve (AUC) or maximum observed plasma concentration (Cmax ) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9-2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose-proportional manner over the dose range of 0.5-300 mg, and population-predicted AUC and Cmax values for the 5- and 15-mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population-predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild-type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study.

Tissue deposition of the insect repellent DEET and the sunscreen oxybenzone from repeated topical skin applications in rats.

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.

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor.

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 (Tmax) 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 (Cmax) by 29%. The effect on Cmax 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 Cmax 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.

Effect of Food on the Pharmacokinetics of Ertugliflozin and Its Fixed-Dose Combinations Ertugliflozin/Sitagliptin and Ertugliflozin/Metformin.

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.

Bioequivalence of Ertugliflozin/Sitagliptin Fixed-Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components.

A fixed-dose combination (FDC) tablet of ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, was developed for the treatment of patients with type 2 diabetes mellitus. Four studies were conducted under fasted conditions to demonstrate bioequivalence of ertugliflozin/sitagliptin FDC tablets and individual components at respective strengths when coadministered in healthy subjects. All studies had open-label, randomized, 2-period, 2-sequence, single-dose crossover designs. In each study 18 or 19 subjects were enrolled and received an ertugliflozin/sitagliptin FDC tablet (5 mg/50 mg, 5 mg/100 mg, 15 mg/50 mg, or 15 mg/100 mg) and corresponding strengths of ertugliflozin and sitagliptin coadministered as individual components. For both ertugliflozin and sitagliptin, the 90%CIs for the ratio (FDC:coadministration) of geometric means for area under the plasma concentration-time profile from time 0 extrapolated to infinite time, and maximum observed plasma concentration, were within acceptance criteria for bioequivalence (80% to 125%). All adverse events were mild in intensity. The 4 studies demonstrated that each strength of FDC tablet is bioequivalent to the respective dose of coadministered individual components. This indicates that the known efficacy and tolerability of ertugliflozin and sitagliptin when coadministered can be translated to the use of a FDC formulation.

In-vitro permeation of the insect repellent N,N-diethyl-m-toluamide (DEET) and the sunscreen oxybenzone.

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.

Evaluation and comparison of five matrix excipients for the controlled release of acrivastine and pseudoephedrine.

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.