Relative Bioavailability Trial of Oral Dispersible Praziquantel Tablets in Healthy Volunteers

Merck KGaA, Darmstadt, Germany32 enrolled

Overview

This is a phase I, open-label, randomized, 4 period, crossover, single-center trial. The purpose of this trial is to assess the relative bio-availability of racemate Oral Dispersible Tablet praziquantel (ODT-PQZ) (MSC1028703A) 150 milligram (mg) versus the current marketed praziquantel (PZQ) (Cysticide® 500 mg) formulation in healthy male volunteers.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

Oral dispersible tablet of praziquantel (ODT-PZQ)DRUG

Treatment A (test): ODT-PZQ (MSC1028703A) at a single dose of 40 milligram per kilogram (mg/kg) orally dispersed in water after meal.

CysticideDRUG

Treatment B (reference): Cysticide tablet at a single dose of 40 mg/kg will be given with water orally after a meal.

ODT-PZQDRUG

Treatment C1 (test): ODT-PZQ (MSC1028703A) at a single dose of 20 mg/kg orally dispersed in water after a meal.

Eligibility

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

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy males 18-55 years of age (inclusive at screening) * Male subjects with partners of childbearing potential must have had a vasectomy or use acceptable methods of birth control (that is, condoms) and not donate sperm during, and until 90 days after the last dose of the trial medication * Provide written informed consent prior to any trial related procedure * Body weight of greater than or equal to (\>=)55.0 kg to less than (\<) 95.0 kg and a body mass index (BMI) between 18.5 and 29.9 kilogram per square meter (kg/m\^2) * Able to communicate well with the Investigator, understand the protocol requirements and restrictions, and willing to comply with the requirements of the entire trial * Non-smoker (= 0 cigarettes, pipes, cigars or other) from at least 3 months prior to start of trial * Electrocardiogram (ECG) recording (12-lead) without signs of clinically relevant pathology, in particular QTcB \< 450 milliseconds (ms) * Vital signs (systolic blood pressure, diastolic blood pressure and pulse) in supine position are within the normal range or show no clinically relevant deviation as judged by the Investigator 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 subject in the trial or that could interfere with the trial objectives, conduct or evaluation * History of gastrointestinal (GI) tract surgery, other GI tract diseases or acute GI tract infections within the last 2 weeks that could influence the GI absorption and/or motility according to the Investigator's opinion * Any clinically relevant abnormality in the safety laboratory parameters as judged by the Investigator * Positive results from serology examination for Hepatitis B surface antigen (HBsAg), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) * Have an ascertained or presumptive contraindication or hypersensitivity to the active drug substance and/or formulations' ingredients * Have any clinically significant history of allergic conditions which the Investigator considers may affect the outcome of the trial * History or presence of drug abuse or alcohol abuse (as defined by the assessment of the investigator) at screening and on each admission * Blood donation or loss of more than 400 mL of blood within 3 months before the first administration of the investigational product * Administration of any investigational product or use of any investigational device within 60 days prior to first dosing that may affect the pharmacokinetics of the investigational product * Subjects who have used drugs that may affect the pharmacokinetics (PK) of PZQ from 15 days before the first administration of the investigational product until the last PK sample * Consumption of substances known to be potent inhibitors or inducers of cytochrome P450s (CYPs) within 2 weeks before the first administration of the investigational product * Unlikely to comply with the protocol requirements, instructions and trial-related restrictions * Non-acceptance of the study breakfast * Excessive consumption of beverages containing xanthine (greater than \[\>\] 5 cups of coffee a day or equivalent) and the inability to refrain from the use of caffeine-containing beverages from 48 hours before the first administration of the investigational product until discharge from the clinic * Subject 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 subjects * Legal incapacity or limited legal capacity

Locations (1)

Please contact the Merck KGaA Communication Center

Darmstadt, Germany

Outcomes

Primary Outcomes

Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-inf) Adjusted for the Actual Administered Dose (AUC0-inf, Adj) of L-Praziquantel (L-PZQ)

AUC0-inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. AUC0-inf, adj was defined as the AUC0-inf adjusted for the actual administered dose of L-PZQ.

Time frame: Pre-dose,0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Secondary Outcomes

Maximum Observed Concentration in Plasma (Cmax) Adjusted for the Actual Administered Dose (Cmax, Adj) of L-PZQ, D-PZQ and Racemate PZQ

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Time to Reach Maximum Plasma Concentration (Tmax) of L-PZQ, D-PZQ, and Racemate PZQ

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Apparent Terminal Half-life (t1/2) of L-PZQ, D-PZQ, and Racemate PZQ

Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of L-PZQ, D-PZQ, and Racemate PZQ

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

AUC From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) Adjusted for the Actual Administered Dose (AUC0-t, Adj) of L-PZQ, D-PZQ, and Racemate PZQ

Data from ClinicalTrials.gov

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Treatment C2 (test): ODT-PZQ (MSC1028703A) at a single dose of 60 mg/kg orally dispersed in water after a meal.

ODT-PZQDRUG

Treatment D1 (test): ODT-PZQ (MSC1028703A) at a single dose of 40 mg/kg orally dispersed in water without a meal.

CysticideDRUG

Treatment D2 (reference): Cysticide crushed tablets at a single dose of 40 mg/kg will be given with water orally after a meal.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Extrapolated Area Under the Plasma Concentration Curve From Time Tlast to Infinity (AUCextra) of L-PZQ, D-PZQ, and Racemate PZQ

AUCextra was reported in terms of percentage of AUC0-inf.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Apparent Terminal Elimination Rate Constant (λz) of L-PZQ, D-PZQ, and Racemate PZQ

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

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Relative Bioavailability (Frel) of L-PZQ, D-PZQ, and Racemate PZQ

Frel was calculated for Treatment A versus Treatment B only. It was calculated by using AUC0-∞, with treatment A as the Test and treatment B as the Reference. Frel = AUC0-inf (test) / AUC0-inf (reference).

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Apparent Total Body Clearance of Drug From Plasma (CL/f) of L-PZQ, D-PZQ, and Racemate PZQ

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.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Apparent Volume of Distribution During the Terminal Phase (Vz/f) of L-PZQ, D-PZQ, and Racemate PZQ

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. Vz/f after oral dose was influenced by the fraction absorbed.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (AUC0-inf) Adjusted for the Actual Administered Dose (AUC0-inf, Adj) of D-PZQ and Racemate PZQ

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16 and 24 hours post-dose on Day 1 of each treatment

Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation

An adverse event (AE) was defined as any untoward medical occurrence in a subject 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 stud drug.

Time frame: Baseline up to end of treatment (up to Day 32)

Palatability Assessment Based on Visual Analog Scale (VAS) Score

Palatability was assessed in terms of Flavor, Smell, Sweetness, Overall liking of the medicine, Taste and Acceptability to swallow, each parameter assessed on a 0 to 100 millimeter (mm) visual analog scale (VAS), where 0 indicates "Did not like" and 100 indicates "very much liked". Flavor, Smell, Sweetness and Overall liking of the medicine were evaluated immediately after taking the medication (Day 1, 0 Hour) and Taste and Acceptability to swallow were assessed 2-5 minutes post administration of medication.

Time frame: Immediately and 2-5 minutes (min) after dosing on Day 1 of each treatment

Number of Subjects With Clinically Significant Change From Baseline in Vital Signs, Physical Examinations, Electrocardiogram (ECG) and Laboratory Parameters

Vital signs included oral body temperature, blood pressure and pulse rate. Body weight was recorded for physical examinations. The 12-lead ECGs were recorded after the subjects have rested for at least 5 minutes in supine position. The parameters heart rate (HR), RR, PR, QRS, QT and QTcB calculated by the Bazett formula. Laboratory investigation including chemistry, hematology and urinalysis.

Time frame: Baseline up to end of treatment (up to Day 32)