TAK-438 - Safety, Blood Levels & Effects of Repeated Doses

(AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration (AUC[0-tlqc]).

AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.

AUC(0-tau) is a measure of the area under the plasma concentration-time curve from time 0 to time tau over a dosing interval, where tau is the length of the dosing interval.

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

(Cmax-Cmin)/Cavg, where Cmin is the minimum observed plasma concentration and Cavg is the average plasma concentration at steady state.

Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body.

Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-24), expressed in L/hr.

Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by λz.

Ae(0-t) is the total amount of drug excreted in urine from time 0 to t, where t is 24 hours on Day 1 and 48 hours on Day 7.

Ae(0-tau) is the total amount of drug excreted in urine from time 0 to tau, where tau equals 24 hours.

CLr is a measure of apparent clearance of the drug from the urine calculated as total amount excreted in the urine from time 0 to 24 hours postdose / plasma area under the curve from time 0 to 24 hours post-dose.

Fe is a measure of the fraction of drug excreted in urine and is calculated as Fe = (total amount excreted in the urine from time 0 to 24 hours post-dose / dose)×100.

A baseline physical examination (defined as the pretreatment assessment immediately prior to the start of study drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) genitourinary system; and (12) other. All subsequent physical examinations should assess clinically significant changes from the baseline examination.

Participants with at least one potentially clinically significant post-baseline vital sign finding. Vital signs will include body temperature (oral temperature), sitting blood pressure (after sitting for 5 minutes), and pulse (bpm).

Full 12-lead ECGs will be recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (using Bazett correction; QTcB) intervals. The investigator or other qualified physician will interpret each ECG using one of the following categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically significant.

Laboratory tests for hematology, serum chemistries, coagulation tests, and urinalysis will be performed.

Treatment-emergent adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 7 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.

Assessed by physical examination, ECG, and safety tests of blood/urine

Assessed by adverse events

Primary pharmacokinetic parameters (AUC (0-tlqc), AUC (0-inf), Cmax) for TAK-438 and its metabolites M-I, M-II, M-III and M-IV-Sul will be subject to statistical analysis

Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 24-hour period at Baseline and over a 24-hour period following the administration of study on Days 1, 4 and 7.

Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 48-hour period following the administration of study drug on Day 7.

Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 12-hour period from 8 PM to 8 AM to assess nocturnal pH.