Primary objective:To assess pharmacokinetic similarity of EBR/GZR as a crushed (test) Zepatier tablet compared to a whole (reference) tablet.Secondary objective:To assess Cmax similarity of EBR/GZR as a crushed (test) Zepatier tablet compared to a…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Geometric Mean Ratios and the 90% confidence interval of the AUC0-72h and
AUC0-inf of a crushed tablet (test) compared to a whole tablet (reference).
AUC0-72h/ AUC0-inf GMR with a 90% CI falling entirely within the range of 0.7
to 1.43 are considered pharmacokinetic similar.
Secondary outcome
Geometric Mean Ratios and the 90% confidence interval of the AUC0-72h and
AUC0-inf of a crushed tablet (test) compared to a whole tablet (reference).
AUC0-72h/ AUC0-inf GMR with a 90% CI falling entirely within the range of 0.7
to 1.43 are considered pharmacokinetic similar
Background summary
For patients with swallowing difficulties, administration of whole tablets can
be problematic and might lead to noncompliance. Studies indicate that between
10% and 40% of adults have difficulties swallowing solid oral medication, while
general practitioners underestimated these problems.
In addition, HCV patients that are hospitalized (at intensive care units) due
to severe illness (co-infections/ liver failure) might not be able to swallow
medication. Therefore it is useful to know whether it is possible to administer
Zepatier through alternative methods, like crushed with water or through a
feeding tube. MSD showed that at least 92% recovery of both components (EBR and
GZR) was achieved through three types of tube. However, information about the
safety and efficacy of crushed tablets is lacking which might result in
interruption or discontinuation of expensive HCV therapy. However, it is not
recommended to interrupt treatment because there is no evidence about the
efficacy of the therapy after discontinuation (and restarting).
Currently, patients and healthcare professionals are crushing tablets without
information about efficacy and safety. Depending on the biopharmaceutical
characteristics of a drug formulation, crushing tablets can lead to altered
pharmacokinetics of drugs. Therefore, it is important to know whether
pharmacokinetic parameters are influenced by crushing of tablets; both a
decrease and an increase in exposure may occur. A decrease of the plasma
concentrations of EBR and/or GZR potentially reduces the therapeutic effect of
the drugs. Higher doses or switching to other HCV-drugs might be needed. In
contrast, in case a higher Cmax and/or AUC occur there might be an increased
risk of toxicity.
As a result, crushing of EBR/GZR is contraindicated.
This study will be conducted to investigate whether a crushed EBR/GZR tablet is
pharmacokinetic similar to EBR/GZR as a whole tablet.
Study objective
Primary objective:
To assess pharmacokinetic similarity of EBR/GZR as a crushed (test) Zepatier
tablet compared to a whole (reference) tablet.
Secondary objective:
To assess Cmax similarity of EBR/GZR as a crushed (test) Zepatier tablet
compared to a whole (reference) tablet.
To evaluate the safety and tolerability of crushed Zepatier tablets in healthy
volunteers.
Study design
12 healthy volunteers will be divided into one of the following treatment
sequences: RT:TR.
Treatment period
* R: Single-dose EBR/GZR as a whole tablet administered with 250 milliliters of
water in a fasted state.
* T: Single-dose crushed EBR/GZR tablet administered with 250 milliliters of
water in a fasted state.
Between the different treatment periods a wash-out period of 14 days is
scheduled. Blood samples for a pharmacokinetic curve will be collected up to 72
hours after observed intake of the study medication on days 1, 2 and 3, and 15,
16 and 17.
The by MSD recommended procedure will be followed including the use of a
specified tablet crusher.
Intervention
Administration of a crushed tablet
Study burden and risks
Geometric Mean Ratios and the 90% confidence interval of the Cmax a crushed
tablet (test) compared to a whole tablet (reference). Cmax GMR with a 90% CI
falling entirely within the range of 0.7 to 1.43 are considered pharmacokinetic
similar.
Median of t* and tmax of elbasvir and grazoprevir of a crushed tablet (test)
compared to a whole tablet (reference).
Adverse events after administration of (crushed) EBR/GZR will be described and
compared (including clinically relevant laboratory abnormalities).
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is at least 18 and not older than 55 years at screening.
2. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1.
3. Subject weighs at least 40 kg.
4. Subject has a Quetelet Index (Body Mass Index) of 18 to 35 kg/m2, extremes included.
5. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
6. Subject is in good age-appropriate health condition as established by medical history, physical examination, and electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges. If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
7. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgment.
Exclusion criteria
1. Creatinine clearance below 60 mL/min.
2. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
3. Positive hepatitis B or C test
4. Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the study.
5. Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (max 2 gram/day), intrauterine device.
6. Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders (clinically relevant increased ALAT/ASAT or hyperbilirubinemia), hormonal disorders (especially diabetes mellitus), coagulation disorders.
7. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
8. History of or current abuse of drugs, alcohol or solvents (positive drugs of abuse test).
9. Inability to understand the nature and extent of the study and the procedures required.
10. Participation in a drug study within 60 days prior to Day 1.
11. Donation of blood within 60 days prior to Day 1.
12. Febrile illness within 3 days before Day 1.
13. Co-worker of Radboud university medical center.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000415-17-NL |
| CCMO | NL61215.091.17 |