Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters

The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled “Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers” (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73.


a b s t r a c t
The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled "Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers" (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET  Pharmacokinetic parameters were collected for GET 73 and MET 2 as reference data to evaluate the bioavailability of GET 73.
In Tables 1 and 2, timetables were set for the administration of GET 73 and the collection of data for the safety and tolerability of GET 73 in single and repeated ascending doses in healthy male volunteers.
In Tables 3 and 4, a procedure was documented for both single and repeated ascending doses with the goal of collecting preliminary pharmacokinetic data and monitor the safety of participants. Table 5 lists laboratory assessments for safety of GET 73 and potential factors that can affect its tolerability. Some tests were also used for inclusion/exclusion criteria (urine tests for drugs of abuse). Table 6 data shows the extent of exposure of GET 73 plasma concentration in a single ascending dose. C max and AUC 0-t are measures of these factors respectively with t max as a reference to the maximum concentration of GET 73 in the plasma.   Table 3 Experiment 1, assessments and procedures. Table 4 Experiment 2, assessments and procedures. 1 White blood cell count included differential white blood cell count. 2 Direct microscopy was performed if the sample was positive for any of these parameters.    Table 8, t max was collected in reference to when the C max was reached in the repeated ascending dose administration group for both Day 1 and Day 14. Table 9 measures the AUC 0-t for repeated ascending dose administration experiment. AUC 0-t ratio compares Day 14 to Day 1 levels. Table 10 shows the C min of GET 73 in the plasma over the repeated ascending dose administration. Data reported for Day 1 and Day 14. Table 11 goes into data about MET 2, the main metabolite of GET 73. Data reported for Day 1 and Day 14. Table 12 shows the t max of MET 2 in the repeated ascending dose administration of GET 73. Results reported as Median and minimum and maximum.    Data reported for Day 1 and Day 14. Table 13 collects data on the AUC 0-t of MET 2 in the plasma after repeated ascending dose administration of GET 73. Ratio compares Day 14 and Day 1 data are listed as well. Table 14 measures the C min of MET 2 in the plasma for repeated ascending dose administration of GET 73. Data was collected for Day 14 and Day

Experimental design, materials and methods
The method for collection of pharmacokinetic analytical data was validated at Quotient Bior- Blood samples for pharmacokinetic evaluation in plasma were collected into tubes containing lithium heparin prior to dosing and at various time points after dosing up to 48 h for Experiment 1 and up to 360 h for Experiment 2. The plasma samples were obtained from individuals from six single ascending dose groups in Experiment 1 (10-mg, 30-mg, 100-mg, 300-mg, 450-mg and 600-mg) and four multiple ascending dose groups in Experiment 2 (100-mg 300-mg, 450-mg and 450-mg twice a day). Results reported as Median and minimum and maximum.   Concentrations of GET 73 in human plasma samples were measured by LC-MS/MS after SLE þ (supported liquid extraction) over the calibration range of 2-1000 ng/ml according to the validated method and the relevant SOPs. Concentrations of MET 2 in human plasma samples were measured by LC-MS/MS after protein precipitation and dilution over the calibration range of 20-10,000 ng/ml. All instrument control, data collection, peak area integration and storage were performed using Analyst (versions 1.4.2 and 1.5.1, Applied Biosystems Inc., OA, US). Peak areas were then imported into Watson LIMS (version 7.2 Thermo Fisher Scientific Inc., MA, US) for regression and quantification. The mass spectrometer response (peak area ratio of analyte to internal standard) of each calibration standard was calculated by Watson LIMS and plotted against the nominal (prepared) concentration. A weighted linear regression analysis was used to calculate an equation of the calibration line. Concentrations of GET 73 and MET 2 in the plasma samples were back calculated from the calibration lines.
Values for the following pharmacokinetic parameters were estimated: 1) maximum plasma concentration (C max ), 2) the time to reach maximum plasma concentration (t max ) and 3) the area under the plasma concentration time curve over the dosing interval (AUC (0-t) ). Pharmacokinetic parameters were derived by noncompartmental analysis using WinNonlin (Version 4.1b, Pharshight Corporation, Mountain View, CA, US). Data in this article has not been published elsewhere.