Relative Bioavailability Trial of L-Praziquantel in Healthy Volunteers

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: MSC2499550A
Drug: Cysticide

Registration Number: NCT02271984

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: This is a phase I, open-label, randomized, 5 period, crossover, single-center trial. The purpose of this trial is to assess the relative bio-availability of L-praziquantel (L-PZQ \[MSC2499550A\]) oral dispersible tablet (ODT) formulation (150 milligram \[mg\]) versus the current marketed racemate praziquantel (PZQ) (Cysticide® 500 mg) formulation in healthy male volunteers under fed conditions.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 36

Inclusion Criteria

Healthy males aged 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
Written informed consent prior to any trial related procedure
Have a body weight of greater than or equal to (>=) 55.0 kilogram (kg) to less than (<) 95.0 kg and a body mass index (BMI) of 18.5 to 29.9 kilogram per square meter (kg/m^2) (inclusive)
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 3 months
Electrocardiogram (ECG) recording (12-lead) without signs of clinically relevant pathology in particular corrected QT Interval (QTc) (Bazett) < 450 milliseconds (ms)
Vital signs (systolic and diastolic blood pressure, pulse) in supine position and body temperature within the normal range or showing no clinically relevant deviation as judged by the medical Investigator

Exclusion Criteria

Any surgical or medical condition, including findings in the medical history or in the prestudy 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 study or that could interfere with the study objectives, conduct or evaluation
History of surgery of the gastrointestinal tract (GI), history of other GI tract diseases, or acute GI tract infections in the last 2 weeks, which 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
Have positive results from serology examination for Hepatitis B surface antigen (HBsAg), 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 (amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine (phenylcyclohexalpiperidine), tetrahydrocannabinol, tricyclic antidepressants, methadone, methamphetamine, oxycodone and propoxyphene) or alcohol abuse at screening and on each admission as defined by 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 within 60 days prior to first PZQ administration
Subjects who have used drugs that may affect the pharmacokinetics (PK) of PZQ from 14 days before dosing until the last PK sample, for example, phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole, on discretion of the Investigator
Consumption of substances known to be potent inhibitors or inducers of cytochrome -P450 enzymes (CYP P450s) such as grapefruit juice, grapefruit juice containing products, and herbal remedies or dietary supplements containing St. John's Wort, in the 2 weeks before dosing
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 of study breakfast (for example, vegetarians, vegans and subjects 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
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 (for example, persons kept in detention)
Legal incapacity or limited legal capacity

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment A: MSC2499550A	MSC2499550A	MSC2499550A: 20 milligram per kilogram (mg/kg) under fed condition
Treatment B: Cysticide	Cysticide	Cysticide® 40 mg/kg under fed condition
Treatment C: MSC2499550A	MSC2499550A	C1:MSC2499550A :10 mg/kg under fed condition C2:MSC2499550A : 30 mg/kg under fed condition
Treatment E: MSC2499550A	MSC2499550A	MSC2499550A: 20 mg/kg directly disintegrated in mouth under fed condition
Treatment D: MSC2499550A	MSC2499550A	MSC2499550A 20 mg/kg under fasting condition

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-inf) Adj of L-Praziquantel (L-PZQ) After Dose Adjustment	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Secondary Outcome Measures

Name	Time	Method
Extrapolated Area Under the Concentration Time Curve (AUC) From Time Tlast to Infinity Given as Percentage From AUC0-inf (AUCextra) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	Extrapolated AUC from time tlast to infinity given as percentage from AUC0-inf. AUCextra =(last predicted concentration \[Clast pred\] divided by terminal elimination rate constant \[lambda z\]) divided by AUC0-inf., where Clast pred is the last predicted concentration.
Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of L-Praziquantel (L-PZQ) After Dose Adjustment	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	The AUC (0-t) was defined as the area under the plasma concentration versus time curve from time zero to time of last quantifiable concentration at or above the lower limit of quantification (AUC0-t) of L-PZQ.
Time to Reach the Maximum Plasma Concentration (Tmax) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose
Maximum Observed Concentration in Plasma (Cmax) of L-Praziquantel (L-PZQ) After Dose Adjustment	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose
Apparent Terminal Elimination Rate Constant (Lambda Z) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	The lambda z was calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Apparent Terminal Half-life (T1/2) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	The apparent terminal half-life was calculated by dividing natural log 2 with lambda z (ln2/lambda Z); where lambda Z is the terminal rate constant.
Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	Time prior to the first measurable (non-zero) concentration (tlag) of drug L-PZQ
Palatability Score	0 min for flavor, smell, sweetness, overall liking; 2-5 minutes post dose for taste in mouth and acceptability on Day 1	Each administration was assessed at 0 minutes on Day 1 for flavor, smell, sweetness, overall liking of the medicine and at 2-5 minutes on Day 1 for taste in mouth and acceptability to swallow using a modified 100 millimeter (mm), visual analog scale (VAS) incorporating a facial hedonic scale, where lower score (0) indicates "not acceptable/not liked at all" and higher score (100) indicates "very acceptable/liked very much".
Relative Bioavailability (Frel) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	Relative bioavailability (Frel) was calculated for L-PZQ only (treatment A versus treatment B) using the formula: Frel = (AUC0-inf (test or Treatment A)/AUC0-inf (reference or treatment B)) multiplied by 100.
Apparent Total Body Clearance of Drug From Plasma (CL/f) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	The CL/f of L-PZQ was a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F of L-PZQ from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf).
Apparent Volume of Distribution During the Terminal Phase (Vz/f) of L-Praziquantel (L-PZQ)	Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 12.0, 16 and 24 hours post-dose	The Vz/f was defined as the theoretical volume in which the total amount of L-PZQ required to uniformly distribute to produce the desired plasma concentration of L-PZQ. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant (lambda z) (Vz/f=Dose/( AUC0-inf\* lambda z).
Number of Subjects With Clinical Significant Laboratory Abnormalities, Electrocardiogram (ECG), Physical Examination and Vital Signs Reported as Treatment Emergent Adverse Events	From the first dose of study drug administration up to 3-10 days after the last dose of the study drug (up to a maximum of 7 weeks)	Any clinically significant changes in laboratory evaluations ECGs,physical examination (body weight) and vital signs (temperature, blood pressure, pulse rate) were recorded as treatment emergent adverse events. Following parameters were analyzed for laboratory examination: hematology (haemoglobin, hematocrit, red blood cell count, mean cell hemoglobin \[MCH\], MCH concentration, mean cell volume, white cell count, platelets, neutrophils, lymphocytes, monocytes, eosinophils, Basophils); serum chemistry (sodium, potassium, calcium, inorganic phosphate, creatinine, total protein, albumin, urea, uric acid, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\] gamma glutamyl transpeptidase, total bilirubin, alkaline phosphatase, glucose, triglycerides cholesterol); urinalysis (protein, glucose, ketones, pH, blood, leukocytes, nitrite); The 12-lead ECGs were recorded after the subjects had rested for at least 5 minutes in supine position.
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation	From the first dose of study drug administration up to 3-10 days after the last dose of the study drug (up to a maximum of 7 weeks)	An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. 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. TEAEs were adverse events that occurred between the first dose of study drug and up to 3-10 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. Subjects who discontinued and who died due to TEAEs were also reported.