ABSTRACT
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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Fasting/blood , Sitagliptin Phosphate/administration & dosage , Adult , Area Under Curve , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cross-Over Studies , Drug Combinations , Female , Healthy Volunteers , Humans , Male , Sitagliptin Phosphate/pharmacokinetics , Tablets , Therapeutic Equivalency , Young AdultABSTRACT
There are many sources of analytical variability in ligand binding assays (LBA). One strategy to reduce variability has been duplicate analyses. With recent advances in LBA technologies, it is conceivable that singlet analysis is possible. We retrospectively evaluated singlet analysis using Gyrolab data. Relative precision of duplicates compared to singlets was evaluated using 60 datasets from toxicokinetic (TK) or pharmacokinetic (PK) studies which contained over 23,000 replicate pairs composed of standards, quality control (QC), and animal samples measured with 23 different bioanalytical assays. The comparison was first done with standard curve and QCs followed by PK parameters (i.e., Cmax and AUC). Statistical analyses were performed on combined duplicate versus singlets using a concordance correlation coefficient (CCC), a measurement used to assess agreement. Variance component analyses were conducted on PK estimates to assess the relative analytical and biological variability. Overall, 97.5% of replicate pairs had a %CV of <11% and 50% of the results had a %CV of ≤1.38%. There was no observable bias in concentration comparing the first replicate with the second (CCC of 0.99746 and accuracy value of 1). The comparison of AUC and Cmax showed no observable difference between singlet and duplicate (CCC for AUC and Cmax >0.99999). Analysis of variance indicated an AUC inter-subject variability 35.3-fold greater than replicate variability and 8.5-fold greater for Cmax. Running replicates from the same sample will not significantly reduce variation or change PK parameters. These analyses indicated the majority of variance was inter-subject and supported the use of a singlet strategy.
