This study aims to evaluate the PK profile and IIV of drug exposure in plasma in children (aged 6-17 years) receiving (elexacaftor-)tezacaftor-ivacaftor. Secondary objectives are to evaluate the relationship between covariates and PK parameters that…
ID
Source
Brief title
Condition
- Other condition
- Respiratory disorders congenital
- Congenital respiratory tract disorders
Synonym
Health condition
cystische fibrose
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is to determine the exposure (area under the curve (AUC)
and maximum plasma concentration (Cmax)) of elexacaftor, tezacaftor and
ivacaftor.
Secondary outcome
1) To evaluate the relationship between covariates and PK parameters in order
to explain inter-patient variability
2) To evaluate the relationship between AUC and through levels
3) To compare drug exposure in children of different age groups and compare
with that in adults
4) To explore if there is a correlation between drug concentrations and
clinical outcome measures (efficacy like exacerbation frequency, increase in
weight, lung function parameters and safety like side effects.
Background summary
There are novel medicines in CF that target the CF transmembrane conductance
regulator (CFTR) and increase its activity. These drugs improve the lung
function, quality of life and body mass index in patients with specific
mutations and might decrease pulmonary exacerbations. The combination of
tezacaftor-ivacaftor (Symkevi®) is already being used by patients >= 12 years
old and was approved by the European Medicine Agency (EMA) in September 2020
for children from the age of 6 years. The combination of
elexacaftor-tezacaftor-ivacaftor (Kaftrio ®) will be available from January
2022 for patients >= 12 years old and was approved by the EMA in November 2021
for children from the age of 6 years. The clinical efficacy of these drugs is
limited, some patients respond, while others do not or have side effects. The
inter-individual variability (IIV) seems large and therefore this study
hypothesizes that we might be over- or undertreating specific groups of
patients, which can affect efficacy, side effects and costs of these expensive
drugs. Very little is known about the pharmacokinetics (PK) of
(elexacaftor-)tezacaftor-ivacaftor, especially in the paediatric population.
Better knowledge of the PK may provide more insight into the exposure-response
relationships and IIV.
Study objective
This study aims to evaluate the PK profile and IIV of drug exposure in plasma
in children (aged 6-17 years) receiving (elexacaftor-)tezacaftor-ivacaftor.
Secondary objectives are to evaluate the relationship between covariates and PK
parameters that explain the IIV, to compare drug exposure in children with that
in adult, and to explore the correlation between drug concentrations and
clinical outcome parameters.
Study design
National multi-center, observational with interventional sampling,
pharmacokinetic study.
Study burden and risks
During the regular visits to the hospital (every three months) blood samples
are taken for clinical routine purposes. For this study a small extra volume (1
ml) will be obtained when the regular sample is taken. Children will not
receive extra venapunctures for this study. In addition to the blood obtained
by venapuncture, dried blood spot (DBS) samples will be collected. One full
curve of 3 time points (t=0, t=4 and t=8) will be collected at home after DBS
instruction during the year visit, and will be sent to the hospital. If during
a regular visit no venous blood sample is taken for routine care, a DBS sample
will be taken at a random time point. Furthermore, leftover material from blood
samples taken during routine patient care will be collected as well. Patients
will be followed during a maximum of 12 months (4-5 visits) per intervention
(Symkevi and/or Kaftrio). If patients already participated in the trial during
Symkevi treatment, new informed consent will be asked for another follow-up
period during Kaftrio treatment.
The patient will not have direct benefit from participation in this study. We
aim for improved treatment of CF patients and in that respect the results of
the study may improve treatment in the future for the patients participating in
the study or any patient with similar characteristics.
Clinical data regarding the pharmacokinetics in children are limited. Better
knowledge of the PK may provide more insight into the exposure-response
relationships and its inter-patient variability. This knowledge may result in
more insight in the efficacy of the drugs and contribute to the possible
development of individualized dosing schemes.
Meibergdreeg 9
Amsterdam 1105AZ
NL
Meibergdreeg 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
- Use a combination therapy of (elexacaftor-)tezacaftor-ivacaftor for a minimum
period of 8 days in regular care or compassionate use
- CF patients aged 6 years and older
- Signed informed consent from the patient when >=16 years, from the patient and
both parents for patients aged 12-15 years, from both parents aged 6-11 years
Exclusion criteria
- History of poor compliance deemed by the physician
- Concomitant use of drugs that have an inhibitory or inducing effect on the
CYP3A4 enzyme metabolism 14 days before the blood collection, if the patient
uses one or more of these medicines the blood collection of the upcoming visit
will be skipped:
o Inducers of CYP3A: rifampicin, rifabutin, phenobarbital, carbamazepine,
phenytoin and St. John*s wort
o Inhibitors of CYP3A: ketoconazole, itraconazole, posaconazole, voriconazole,
telithromycin, clarithromycin, fluconazole, erythromycin and grapefruit juice
- Patient or parent refusal
Design
Recruitment
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 |
|---|---|
| CCMO | NL75811.018.21 |