Relative Bioavailability Trial of L-Praziquantel in Healthy Volunteers

A Phase I, Open-Label, Randomized, Single Dose, Five Period, Crossover, Single Center Trial To Assess The Relative Bioavailability Of The 150 mg ODT Formulation Of L PZQ (MSC2499550A) Versus The Current 500 mg PZQ Commercial Racemate Tablet Formulation In Healthy Male Volunteers

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: MSC2499550A; Drug: MSC2499550A; Drug: MSC2499550A; Drug: MSC2499550A; Drug: MSC2499550A; Drug: Cysticide

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Darmstadt, Germany
    • Please contact the Merck KGaA Communication Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment A: MSC2499550A; MSC2499550A: 20 milligram per kilogram (mg/kg) under fed condition	Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 10 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 30 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water in fasted condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg directly disintegrated in the mouth without water under fed conditions in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ
Experimental: Treatment B: Cysticide; Cysticide® 40 mg/kg under fed condition	Drug: Cysticide; Subjects will receive a single oral dose of current PZQ formulation (Cysticide®) at 40 mg/kg with water, under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: Praziquantel
Experimental: Treatment C: MSC2499550A; C1:MSC2499550A :10 mg/kg under fed condition C2:MSC2499550A : 30 mg/kg under fed condition	Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 10 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 30 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water in fasted condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg directly disintegrated in the mouth without water under fed conditions in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ
Experimental: Treatment D: MSC2499550A; MSC2499550A 20 mg/kg under fasting condition	Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 10 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 30 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water in fasted condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg directly disintegrated in the mouth without water under fed conditions in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ
Experimental: Treatment E: MSC2499550A; MSC2499550A: 20 mg/kg directly disintegrated in mouth under fed condition	Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 10 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 30 mg/kg dispersed in water under fed condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg dispersed in water in fasted condition in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ; Drug: MSC2499550A; Subjects will receive a single oral dose of MSC2499550A formulation at 20 mg/kg directly disintegrated in the mouth without water under fed conditions in one of the intervention periods. There will be a wash-out period of at least 7 days between each of the intervention period.; Other Names: L-PZQ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC0-inf) Adj of L-Praziquantel (L-PZQ) After Dose Adjustment	The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of L-Praziquantel (L-PZQ)	Time prior to the first measurable (non-zero) concentration (tlag) of drug 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
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	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.	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 Area Under the Concentration Time Curve (AUC) From Time Tlast to Infinity Given as Percentage From AUC0-inf (AUCextra) of L-Praziquantel (L-PZQ)	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.	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 Half-life (T1/2) of L-Praziquantel (L-PZQ)	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.	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) of L-Praziquantel (L-PZQ)	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.	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)	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.	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 Total Body Clearance of Drug From Plasma (CL/f) of L-Praziquantel (L-PZQ)	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).	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 Volume of Distribution During the Terminal Phase (Vz/f) of L-Praziquantel (L-PZQ)	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).	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
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation	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.	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)
Palatability Score	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".	0 min for flavor, smell, sweetness, overall liking; 2-5 minutes post dose for taste in mouth and acceptability on Day 1
Number of Subjects With Clinical Significant Laboratory Abnormalities, Electrocardiogram (ECG), Physical Examination and Vital Signs Reported as Treatment Emergent Adverse Events	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.	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)

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Bagchus WM, Bezuidenhout D, Harrison-Moench E, Kourany-Lefoll E, Wolna P, Yalkinoglu O. Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo- and Racemic Praziquantel: Two Phase I Studies. Clin Transl Sci. 2019 Jan;12(1):66-76. doi: 10.1111/cts.12601. Epub 2018 Dec 21.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2014
• Primary Completion (Actual): December 31, 2014
• Study Completion (Actual): December 31, 2014

Study Registration Dates

• First Submitted: October 20, 2014
• First Submitted That Met QC Criteria: October 20, 2014
• First Posted (Estimate): October 22, 2014

Study Record Updates

• Last Update Posted (Actual): January 3, 2018
• Last Update Submitted That Met QC Criteria: May 28, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Healthy; Pharmacokinetics; Bioavailability; L-PZQ; PZQ; MSC2499550A; Praziquantel
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiparasitic Agents; Anthelmintics; Praziquantel
• Other Study ID Numbers: 200661-001