Praziquantel Bioequivalence Study

• Cisticid (Drug), also known as Praziquantel: Participants received single oral dose of 1200 mg (two 600 mg tablets) Cisticid (Test) on Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2) or Day 15 (Treatment Period 3).
• Biltricide (Drug), also known as Praziquantel: Participants received 600 mg of Biltricide (Reference) tablet at a dose of 1200 mg on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).

Primary outcomes

• Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of L-Praziquantel (L-PZQ) [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 12.0 hours post-dose]: Area under the plasma concentration-time curve from 0 to the time of the last quantifiable concentration.
• Maximum Observed Plasma Concentration (Cmax) of L-Praziquantel (L-PZQ) [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 12.0 hours post-dose]: The maximum observed plasma concentration of L-Praziquantel (L-PZQ).

Secondary outcomes

• Time to Reach Maximum Plasma Concentration (Tmax) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: Time of the maximum drug concentration.
• Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: 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 (LLOQ) before the occurrence of the first quantifiable concentration.
• Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: AUC0-inf is defined as the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
• Extrapolated Area Under the Plasma Concentration Curve From Time Tlast to Infinity (AUCextra) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: AUCextra was reported in terms of percentage of AUC0-inf.
• Terminal Elimination Half-Life (t1/2) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: 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.
• Terminal Elimination Rate Constant (Lambda Z) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: Lambda Z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
• Apparent Clearance (CL/f) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
• Apparent Volume of Distribution During Terminal Phase (Vd/f) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vd/f after oral dose was influenced by the fraction absorbed.
• Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: Area under the drug plasma concentration-time curve from time zero to the time last measurable concentration.
• Maximum Observed Plasma Concentration (Cmax) of Racemate PZQ (Rac-PZQ) [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 12.0 hours post-dose]: The maximum observed plasma concentration of rac-Praziquantel (rac-PZQ).
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [Baseline up to Day 29]: An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.
• Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters [Baseline up to Day 29]: Number of participants with clinically significant abnormalities in laboratory parameters were reported. Laboratory investigation included hematology, biochemistry, urinalysis and coagulation.
• Number of Participants With Clinically Significant Abnormalities in Vital Signs [Baseline up to Day 29]: Number of participants with clinically significant abnormalities in vital signs were reported. Vital signs included body temperature, systolic / diastolic blood pressure, and pulse rate.
• Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings [Baseline up to Day 29]: Number of participants with clinically significant abnormalities in 12-lead electrocardiogram (ECG) were reported. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position.

Sex: Male, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

* A male participant must agree to use and to have their female partners willing to use additional non-hormonal contraception (for example, condoms or occlusive cap with spermicide, non-hormonal intra-uterine device \[IUD\], previous sterilization of participant or his partner, being sexually inactive) from Day of randomization up to final end of treatment (EOT) visit
* Gave written informed consent prior to any trial related procedure
* Have a body weight (BW) of greater than (>) 55.0 kilogram (kg) to less than (<) 95 kg and a body mass index (BMI) between 18.0 and 27.0 kg/meter square (m\^2)
* Able to communicate well with the Investigator, understanding the protocol requirements and restrictions, and willing to comply with the requirements of the entire trial
* Non-smoker (= 0 cigarettes, pipes, cigars or others) since at least three months
* 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: 45 to 90 beats per minute \[bpm\]; oral body temperature between 35.0 degree centigrade \[°C\] to 37.5°C)
* All values for biochemistry, liver function test and hematology tests of blood and urine within the normal range or showing no clinically relevant deviation as judged by the Investigator. Hematocrit and hemoglobin must be above the lower limit; upper limit may range up to 15 percent (%). Remaining results, including white blood cells may range +/- 15%, if participant is asymptomatic
* Negative screen for alcohol and drugs of abuse (opiate class, barbiturates, cocaine and metabolites, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) at screening and on each admission
* Negative screen for Hepatitis B surface (HBs) antigens, Hepatitis C Virus (HCV) antibodies, Hepatitis A Virus (HAV) antibodies and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies
* Other protocol defined inclusion criteria could apply

Exclusion Criteria:

* Any surgical or medical condition, including findings in the medical history or in the pre-study assessments, or any other significant disease, that in the opinion of the Investigator, constitutes a risk or a contraindication for the participation of the participant in the study or that could interfere with the study objectives, conduct or evaluation
* History of surgery of the gastrointestinal (GI) tract, history of other GI tract diseases, or acute GI tract infections in the last 2 weeks, which could influence the gastrointestinal absorption and/or motility according to the Investigator's opinion
* Any clinically relevant abnormality in the safety laboratory parameters as judged by the Investigator
* Have positive results from serology examination for Hepatitis B surface (HBs) antigen, Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV)
* Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the Investigator considers may affect the outcome of the trial
* History or presence of drug abuse (opiate class, barbiturates, cocaine and its main metabolite, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) or alcohol abuse at screening and on each admission. Alcohol abuse is defined by the assessment of the Investigator
* Loss or donation of more than 400 milliliter (mL) of blood within 90 days prior to first Praziquantel (PZQ) administration
* Administration of any investigational product or use of any investigational device in any clinical study within 30 days prior to first PZQ administration. Participants who have used drugs that may affect the pharmacokinetics of PZQ from 14 days before dosing until the last pharmacokinetic (PK) sample, for example, phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole
* Consumption of substances known to be potent inhibitors or inducers of Cytochrome P450s (CYP P450s) such as grapefruit, orange, cranberry or juices of these fruits, herbal remedies or dietary supplements containing St. John's Wort, poppy seeds, cruciferic vegetables, in the two weeks before dosing until last PK sample
* Unlikely to comply with the protocol requirements, instructions and trial-related restrictions, for example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the trial
* Non-acceptance or non-compliance with the study breakfast (for example, vegetarians, vegans and participants who follow special diets)
* Excessive consumption of beverages containing xanthine (>5 cups of coffee a day or equivalent) or inability to stop consuming caffeine from 48 hours prior to drug administration until discharge from the clinic
* Participant is the Investigator or any Sub-Investigator, research assistant, pharmacist, trial coordinator, other staff or relative thereof directly involved in the conduct of the trial
* Vulnerable participants (for example, persons kept in detention)
* Legal incapacity or limited legal capacity
* Other protocol defined exclusion criteria could apply

Participant flow

Outcome results

• Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of L-Praziquantel (L-PZQ) (Primary), Mean, Hour*nanogram per milliliter (h*ng/ml): Cisticid 441.53 +/- 345.70; Biltricide First Administration 547.41 +/- 384.82; Biltricide Second Administration 460.25 +/- 343.37
• Maximum Observed Plasma Concentration (Cmax) of L-Praziquantel (L-PZQ) (Primary), Mean, ng/mL: Cisticid 310.87 +/- 249.02; Biltricide First Administration 426.42 +/- 324.01; Biltricide Second Administration 363.20 +/- 333.50
• Time to Reach Maximum Plasma Concentration (Tmax) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Median, hours: Cisticid 2.5 (1.5 to 5.5); Biltricide First Administration 2 (1 to 3.5); Biltricide Second Administration 2.5 (1 to 4.5)
• Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Median, hours: Cisticid 1 (0.25 to 3); Biltricide First Administration 1 (0.25 to 2.5); Biltricide Second Administration 1 (0.25 to 3.5)
• Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Mean, h*ng/ml: Cisticid 468.52 +/- 352.29; Biltricide First Administration 584.23 +/- 410.05; Biltricide Second Administration 497.89 +/- 348.81
• Extrapolated Area Under the Plasma Concentration Curve From Time Tlast to Infinity (AUCextra) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Mean, Percentage of AUC0-inf: Cisticid 5.36 +/- 3.73; Biltricide First Administration 5.49 +/- 6.47; Biltricide Second Administration 5.74 +/- 4.02
• Terminal Elimination Half-Life (t1/2) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Mean, hours: Cisticid 1.87 +/- 1.12; Biltricide First Administration 2.59 +/- 3.01; Biltricide Second Administration 2.32 +/- 1.65
• Terminal Elimination Rate Constant (Lambda Z) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Median, Per hour: Cisticid 0.452927 (0.103378 to 1.120808); Biltricide First Administration 0.383267 (0.032567 to 0.721124); Biltricide Second Administration 0.370854 (0.073375 to 0.944209)
• Apparent Clearance (CL/f) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Mean, Milliliter per hour: Cisticid 749261.50 +/- 744206.88; Biltricide First Administration 585260.42 +/- 541013.95; Biltricide Second Administration 673193.51 +/- 531848.19
• Apparent Volume of Distribution During Terminal Phase (Vd/f) of L-Praziquantel (L-PZQ) and Racemate PZQ (Rac-PZQ) (Secondary), Mean, Milliliter: Cisticid 1540237.10 +/- 1069504.21; Biltricide First Administration 1660474.33 +/- 1619772.26; Biltricide Second Administration 1800582.47 +/- 1385707.17
• Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Racemate PZQ (Rac-PZQ) (Secondary), Mean, h*ng/ml: Cisticid 2071.35 +/- 1370.58; Biltricide First Administration 2421.73 +/- 1518.94; Biltricide Second Administration 2131.01 +/- 1353.64
• Maximum Observed Plasma Concentration (Cmax) of Racemate PZQ (Rac-PZQ) (Secondary), Mean, ng/mL: Cisticid 1209.15 +/- 803.20; Biltricide First Administration 1530.23 +/- 944.12; Biltricide Second Administration 1356.18 +/- 1011.46
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs (Secondary), Count of participants, Participants: Cisticid 2; Biltricide First Administration 5; Biltricide Second Administration 6
• Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Secondary), Count of participants, Participants: Cisticid 0; Biltricide First Administration 0; Biltricide Second Administration 0
• Number of Participants With Clinically Significant Abnormalities in Vital Signs (Secondary), Count of participants, Participants: Cisticid 0; Biltricide First Administration 0; Biltricide Second Administration 0
• Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings (Secondary), Count of participants, Participants: Cisticid 0; Biltricide First Administration 0; Biltricide Second Administration 0

Adverse events

Time frame: Baseline up to Day 29

Other adverse events by term

• Study Protocol (PDF, 2017-10-27)
• Statistical Analysis Plan (PDF, 2019-05-30)

• Medical Responsible, Study director, Merck KGaA, Darmstadt, Germany