Natural disease course modeling of achondroplasia to evaluate the efficacy of recifercept in the absence of a placebo control arm in phase II study.

While randomized, placebo-controlled, double-blinded clinical studies are the gold standard for evaluating the efficacy of investigational drugs, the use of placebo in children with achondroplasia should be limited because it provides no clinical benefit while exhausting study participants' treatment window. Recifercept is an investigational drug for treating children with achondroplasia aged 2-10 years. An alternative efficacy evaluation method, instead of a placebo control arm, was employed in the phase II study. Prior to participating in the phase II study, participants completed a natural history (NH) study. Based on the NH data, a multi-variate linear mixed effects natural disease course model of three anthropometric end points (standing height, sitting height, and arm span) was developed. The model was validated using published growth charts of children with achondroplasia. Subsequently, the model was used to simulate the natural growth trajectories (without any treatment) of the three anthropometric end points for the individuals enrolled in the phase II study. To quantify the efficacy of recifercept, the simulations were compared with the observations post-recifercept treatment in the phase II study. For all the tested doses of recifercept, at the individual level, the observations were comparable to the simulations at 6 and 12 months post-recifercept treatment, suggesting no treatment effect. The results contributed to the decision of terminating recifercept clinical development. This work delivers a framework that could eliminate the need for placebo in clinical trials yet provide sufficient evidence for evaluating the efficacy of an investigational drug.

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.

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.

Bioequivalence of Metformin in Ertugliflozin/Metformin Fixed-Dose Combination Tablets to Canadian-Sourced Metformin Coadministered With Ertugliflozin Under Fasted and Fed States.

A fixed-dose combination (FDC) product of a selective sodium-glucose cotransporter 2 inhibitor ertugliflozin and immediate-release metformin is approved for type 2 diabetes mellitus in the United States, European Union countries, Canada, and other countries. Two studies were conducted to assess the bioequivalence of metformin in the ertugliflozin/metformin FDC tablets to the corresponding doses of Canadian-sourced metformin (Glucophage) coadministered with ertugliflozin. Both studies were phase 1 randomized, open-label, 2-period, single-dose crossover studies (n = 32) in which healthy subjects received an ertugliflozin/metformin FDC tablet (2.5/500 mg or 7.5/850 mg) and the respective doses of the individual components (ertugliflozin coadministered with Canadian-sourced metformin) under fasted (n = 18) or fed (n = 14) conditions. Blood samples were collected 72 hours postdose to determine metformin concentrations. The 90% confidence intervals were within the bioequivalence acceptance criteria for the adjusted geometric mean ratios (FDC:coadministered) for metformin area under the plasma concentration-time curve from time zero to time t, where t is the last point with a measurable concentration and peak observed plasma concentration for both dose strengths under fasted and fed conditions. All study medications were well tolerated. Bioequivalence was demonstrated for the metformin component of the ertugliflozin/metformin FDC tablets and the corresponding doses of the Canadian-sourced metformin coadministered with 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.

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.

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

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.

Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia.

BACKGROUND: Current treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia. METHODS: The efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18-65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability. RESULTS: At day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively. CONCLUSIONS: Neither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.

A PK/PD study comparing twice-daily to once-daily dosing regimens of ertugliflozin in healthy subjects
.

OBJECTIVE: Ertugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing. The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID). This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC24)) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE24)) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD. MATERIALS AND METHODS: In this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days. Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period. RESULTS: The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC24 was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD. GMR (90% CI) of UGE24 for BID vs. QD administration was 110.2% (103.0%, 117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg. The 90% CIs of the GMR of AUC24 and UGE24 for BID vs. QD dosing were within the acceptance range for equivalence (80 - 125%) and the prespecified criterion for similarity (70 - 143%), respectively. All treatments were well tolerated. CONCLUSION: There are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.

Assessment of the Drug Interaction Potential of Ertugliflozin With Sitagliptin, Metformin, Glimepiride, or Simvastatin in Healthy Subjects.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of adults with type 2 diabetes mellitus, is expected to be coadministered with sitagliptin, metformin, glimepiride, and/or simvastatin. Four separate open-label, randomized, single-dose, crossover studies were conducted in healthy adults to assess the potential pharmacokinetic interactions between ertugliflozin 15 mg and sitagliptin 100 mg (n = 12), metformin 1000 mg (n = 18), glimepiride 1 mg (n = 18), or simvastatin 40 mg (n = 18). Noncompartmental pharmacokinetic parameters derived from plasma concentration-time data were analyzed using mixed-effects models to assess interactions. Coadministration of sitagliptin, metformin, glimepiride, or simvastatin with ertugliflozin had no effect on area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) or maximum observed plasma concentration (Cmax ) of ertugliflozin (per standard bioequivalence boundaries, 80% to 125%). Similarly, ertugliflozin did not have any impact on AUCinf or Cmax of sitagliptin, metformin, or glimepiride. AUCinf for simvastatin (24%) and simvastatin acid (30%) increased slightly after coadministration with ertugliflozin and was not considered clinically relevant. All treatments were well tolerated. The lack of clinically meaningful pharmacokinetic interactions demonstrates that ertugliflozin can be coadministered safely with sitagliptin, metformin, glimepiride, or simvastatin without any need for dose adjustment.

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.

Effect of Rifampin on the Pharmacokinetics of Ertugliflozin in Healthy Subjects.

PURPOSE: Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor being developed for the treatment of type 2 diabetes mellitus. The primary enzyme involved in the metabolism of ertugliflozin is uridine diphosphate-glucuronosyltransferase (UGT) 1A9, with minor contributions from UGT2B7 and cytochrome P450 (CYP) isoenzymes 3A4, 3A5, and 2C8. Rifampin induces UGT1A9, UGT2B7, CYP3A4, and CYP3A5. Because concurrent induction of these enzymes could affect ertugliflozin exposure, this study assessed the effect of multiple doses of rifampin on the pharmacokinetic properties of single-dose ertugliflozin. METHODS: Twelve healthy adult subjects were enrolled in this open-label, 2-period, fixed-sequence study and received ertugliflozin 15mg on day 1 of period 1, followed by rifampin 600mg once daily on days 1 to 10 in period 2. On day 8 of period 2, ertugliflozin 15mg was coadministered with rifampin 600mg. Plasma samples for ertugliflozin pharmacokinetic analysis were collected during 72hours after dosing on day 1 of period 1 and day 8 of period 2 and analyzed using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis of concentration-time data. Natural log transformed AUC0-∞ and Cmax of ertugliflozin were analyzed using a mixed-effects model with treatment as a fixed effect and subject as a random effect. FINDINGS: After administration of ertugliflozin 15mg alone or with rifampin, the Tmax was 1hour. The mean t½ was 12.3hours for ertugliflozin alone and 9.2hours with steady-state rifampin. Geometric mean ratios for AUC0-∞ and Cmax were 61.2% (90% CI, 57.2%-65.4%) and 84.6% (90% CI, 74.2%-96.5%), respectively. Ertugliflozin was well tolerated when administered alone or with rifampin. IMPLICATIONS: Coadministration of ertugliflozin with rifampin decreased ertugliflozin AUC0-∞ and Cmax by 39% and 15%, respectively. The effect of the reduced exposure was evaluated using the ertugliflozin dose-response model. The model predicted that a 5-mg ertugliflozin dose after coadministration with rifampin is expected to maintain clinically meaningful glycemic efficacy. Therefore, no dose adjustment of ertugliflozin is recommended when ertugliflozin is coadministered with a UGT and CYP inducer, such as rifampin.