Majid Vakilynejad

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Properties of the GPR40 Agonist TAK-875: Results From a Double-Blind, Placebo-Controlled Single Oral Dose Rising Study in Healthy Volunteers

TAK‐875 is a selective G‐protein‐coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double‐blind, placebo‐controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK‐875 following administration of a single oral dose of TAK‐875 (25–800 mg) in 60 healthy volunteers. TAK‐875 was eliminated slowly with a mean terminal elimination t1/2 of approximately 28.1 to 36.6 hours. Systemic exposure of TAK‐875 did not exhibit dose‐proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that coadministration of TAK‐875 with a high‐fat meal decreased Cmax of TAK‐875 by 40% and AUC by 17%. Clinical adverse experiences were generally mild and transient. No dose‐dependent pattern was observed. In healthy volunteers, no glucose‐lowering effect and no increase in insulin or c‐peptide secretion were evident following administration of TAK‐875; the frequency of plasma glucose concentrations <70 mg/dL was similar in the TAK‐875 and pooled placebo groups. TAK‐875 was well tolerated in the study and has pharmacokinetic characteristics suitable for a once‐daily regimen. The pharmacodynamic data support the notion that TAK‐875, if effective in diabetic patients, may bear a low risk of hypoglycemia.

A Multiple‐Ascending‐Dose Study to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of a Novel GPR40 Agonist, TAK‐875, in Subjects With Type 2 Diabetes

G‐protein‐coupled receptor 40 (GPR40), highly expressed in pancreatic β‐cells, mediates free fatty acid (FFA)‐induced insulin secretion. This phase I, double‐blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose‐lowering GPR40 agonist, TAK‐875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose‐proportional increases in AUC0−24 and Cmax occurred. TAK‐875 showed good tolerability with no dose‐limiting side effects. Two subjects (on TAK‐875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK‐875 showed reductions from baseline in fasting (2 to −93 mg/dl) and post‐OGTT glucose (26 to −172 mg/dl), with an apparent dose‐dependent increase in post‐OGTT C‐peptide over 14 days. Consistent with preclinical data, TAK‐875 apparently acts as a glucose‐dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once‐daily oral administration.

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury.

&NA; Fasiglifam (TAK‐875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK‐875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK‐875 caused a dose‐dependent increase in serum total BA in rats and dogs. Additionally, there were dose‐dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK‐875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose‐dependent manner following TAK‐875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK‐875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK‐875‐mediated liver injury in dogs.

Pharmacometric Approaches to Guide Dose Selection of the Novel GPR40 Agonist TAK-875 in Subjects With Type 2 Diabetes Mellitus

The G‐protein‐coupled receptor 40 agonist (GPR40) TAK‐875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pharmacometric approaches such as model‐based exposure‐response and meta‐analyses were applied to (i) characterize exposure/dose–efficacy responses of TAK‐875, (ii) characterize the time course of glycosylated hemoglobin A1c (HbA1c) response with TAK‐875 6.25 to 200 mg q.d. doses for 12 weeks, (iii) project and compare HbA1c response with dipeptidyl peptidase 4 (DPP‐4) inhibitors and TAK‐875 up to 24 weeks, and (iv) provide a quantitative rationale for dose selection in phase 3. On the basis of phase 2 data, relationships between TAK‐875 concentrations and HbA1c were well characterized by exposure–response models. EC50 and Emax of TAK‐875 were estimated to be 3.16 µg/ml and 0.366, respectively. Model‐based simulations over 24 weeks indicated that the 25‐ and 50‐mg q.d. doses of TAK‐875 achieve efficacy as comparable with or better than that of commonly used antidiabetic agents.

A Population Pharmacokinetic–Pharmacodynamic Meta-Analysis of Vortioxetine in Patients with Major Depressive Disorder

Vortioxetine is approved for the treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure–response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and two generalized anxiety disorder studies of vortioxetine (3160 patients), and efficacy data [Montgomery–Åsberg Depression Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the development of PK and PK/Efficacy models. One‐ and two‐compartment models were evaluated as structural PK models, and linear and nonlinear (Emax) models were used to describe the relationship between average vortioxetine concentration at steady‐state (Cav) and change in MADRS score from baseline (ΔMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterized by a two‐compartment model with first‐order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/hr and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F, but the effect of each of these covariates was not considered clinically relevant, as they lead to ±26% change in area under the curve or Cmax of vortioxetine. An Emax model best described the relationship between ΔMADRS and Cav. Half‐maximal effective concentration (EC50) and Emax estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterized the vortioxetine exposure–response relationship.

Population Pharmacokinetics and Exposure‐Response of a Fixed‐Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With Stage 2 Hypertension

Population pharmacokinetic and exposure‐response models for azilsartan medoxomil (AZL‐M) and chlorthalidone (CLD) were developed using data from an 8‐week placebo‐controlled phase 3, factorial study of 20, 40, and 80 mg AZL‐M every day (QD) and 12.5 and 25 mg CLD QD in fixed‐dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2‐compartment model with first‐order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure‐response analysis evaluated AZL‐M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (±20% change). Predicted maximal SBP responses (Emax) were –15.6 and –23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL‐M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL‐M/CLD combination therapy is comparable in black and nonblack subjects.

A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis

Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.

Model-Based Approach to Predict Adherence to Protocol During Antiobesity Trials

Development of antiobesity drugs is continuously challenged by high dropout rates during clinical trials. The objective was to develop a population pharmacodynamic model that describes the temporal changes in body weight, considering disease progression, lifestyle intervention, and drug effects. Markov modeling (MM) was applied for quantification and characterization of responder and nonresponder as key drivers of dropout rates, to ultimately support the clinical trial simulations and the outcome in terms of trial adherence. Subjects (n = 4591) from 6 Contrave® trials were included in this analysis. An indirect‐response model developed by van Wart et al was used as a starting point. Inclusion of drug effect was dose driven using a population dose‐ and time‐dependent pharmacodynamic (DTPD) model. Additionally, a population‐pharmacokinetic parameter‐ and data (PPPD)‐driven model was developed using the final DTPD model structure and final parameter estimates from a previously developed population pharmacokinetic model based on available Contrave® pharmacokinetic concentrations. Last, MM was developed to predict transition rate probabilities among responder, nonresponder, and dropout states driven by the pharmacodynamic effect resulting from the DTPD or PPPD model. Covariates included in the models and parameters were diabetes mellitus and race. The linked DTPD‐MM and PPPD‐MM was able to predict transition rates among responder, nonresponder, and dropout states well. The analysis concluded that body‐weight change is an important factor influencing dropout rates, and the MM depicted that overall a DTPD model‐driven approach provides a reasonable prediction of clinical trial outcome probabilities similar to a pharmacokinetic‐driven approach.

Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin

AIMS The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure. METHODS Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments. RESULTS A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively. CONCLUSIONS The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight.