Bioequivalence Study of Coated Cesol Tablet Formulation Versus Biltricide

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany36 enrolled

Overview

The purpose of this study is to assess the bioequivalence (BE) of new coated Cesol tablet (Test) versus Biltricide tablets (Comparator) in healthy male participants. Praziquantel (rac-PZQ) is the active ingredient for Cesol and Biltricide tablets.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

Cesol (Test)DRUG

Participant will receive coated cesol tablet in sequence 1 (Day 1 and Day 15) and in sequence 2 (Day 8 and Day 22). A washout period of 7 days will be maintained between 4 treatment periods.

Biltricide (Reference)DRUG

Participant will receive biltricide tablet in Sequence 1 (Day 8 and Day 22) and in sequence 2 (Day 1 and Day 15). A washout period of 7 days will be maintained between 4 treatment periods.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, and cardiac monitoring * Nonsmoker (=0 cigarettes, pipes, cigars or others) since at least 3 months * Have a body weight within 55.0 to 95.0 kilogram (kg) and body mass index within the range of 18.5 to 29.9 kilogram per meter squared (kg/m\^2) * Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in particular heart-rate corrected \[QTc\] (Bazett) \<450 milliseconds (ms) * Vital signs should be in normal range (systolic blood pressure: 90 to 140 millimeters of mercury \[mmHg\]; diastolic blood pressure: 50 to 90 mmHg; pulse rate: 50 to 90 beats per minute \[bpm\]; auricular body temperature between 35.9 degree centigrade \[°C\] to 37.6°C) * Are males agreeing to refrain from donating sperm, Use a male condom when having sexual intercourse with a woman of child-bearing potential, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of less than (\< )1 percent (%) per year * Other protocol defined inclusion criteria could apply Exclusion Criteria: * Any condition, including any clinically relevant abnormality in the safety laboratory parameters as judged by the Investigator, that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation * Have positive results from serology examination for Hepatitis B surface antigen (indicative of active Hepatitis B), Hepatitis C Virus or Human Immunodeficiency Virus (Human Immunodeficiency Virus 1/2 antibodies) * Participants who have used drugs that may affect the pharmacokinetics of rac-PZQ from 15 days before dosing until the last PK sample, example., phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole * Positive test for drugs of abuse (including alcohol) at Screening and prior to each dosing * Unlikely to comply with the protocol requirements, instructions and study-related restrictions; example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study * Participant is the Principal Investigator or any Sub investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study * Inability to communicate or cooperate with the Investigator (example. language problem, illiterates, poor mental status) or to comply with the requirements of the entire study, including dietary restrictions * Vulnerable participants (example., persons kept in detention). * Legal incapacity or limited legal capacity * Other protocol defined exclusion criteria could apply

Locations (1)

Nuvisan GmbH

Neu-Ulm, Germany

Outcomes

Primary Outcomes

Maximum Observed Plasma Concentration (Cmax) of Racemic-Praziquantel (Rac-PZQ)

Cmax was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Racemic-Praziquantel (Rac-PZQ)

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Secondary Outcomes

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Related TEAEs

Adverse event (AE): any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.

Time frame: Baseline up to Day 27

Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity According to Qualitative Toxicity Scale

Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported.

Data from ClinicalTrials.gov

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Time frame: Baseline up to Day 27

Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters

Laboratory investigation included hematology, biochemistry and urinalysis. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in laboratory parameters were reported.

Time frame: Baseline up to Day 27

Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs

Vital signs included body temperature, systolic and diastolic blood pressure and pulse rate. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in vital signs were reported.

Time frame: Baseline up to Day 27

Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings

12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-Lead ECG findings were reported.

Time frame: Baseline up to Day 27

Maximum Observed Plasma Concentration (Cmax) of Praziquantel (PZQ) Enantiomers: R-(-)-PZQ and S-(+) PZQ

Cmax was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Praziquantel (PZQ) Enantiomers: R-(-)-PZQ and S-(+)-PZQ

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Time to Reach Maximum Plasma Concentration (Tmax) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

Tmax was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

Time prior to the first measurable (non-zero) concentration; calculated as last time point at which the concentration is less than (\<) Lower Limit of Quantification (LLQ) before the occurrence of the first quantifiable concentration.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Terminal Elimination Half-Life (T1/2) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Terminal Rate Constant (Lambda z) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Apparent Clearance (CL/f) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period

Apparent Volume of Distribution During Terminal Phase (Vz/f) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ

Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period