• To determine the pharmacokinetics of posaconazole (new solid oral and IV) given as prophylaxis to patients who are at risk for developing fungal infections after receiving conditioning therapy (except strictly non myeloablative (NMA)) for…
ID
Source
Brief title
Condition
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Data will be analyzed using non-linear mixed effects modeling (NONMEM). NONMEM
is a one-stage analysis that simultaneously fixed (e.g. clearance, volume of
distribution, covariate effects)and random (e.g. inter- and intra-individual
variability and residual error) effects. Since allowance can be made for
individual differences, this method can be used with both intensive sampling
and sparse data (and in the occasion of missing values: an unbalanced number of
data points per patients).
Multiple compartment models with first-order or saturable elimination will be
tested. Between subject variability (BSV) and, when applicable, between
occasion variability (BOV) will be included on all pharmacokinetic parameters.
Residual unexplained variability (RUV) will be estimated with additive or
proportional error models. The first-order conditional estimation method with
interaction will be used. Citrulline will be tested as a binary covariate on
bioavailability. Dose linearity
Secondary outcome
not applicable
Background summary
Posaconazole is licensed for treatment of invasive fungal infections in
patients intolerant to first line therapy and for prophylaxis of invasive
fungal infections in patients receiving remission induction chemotherapy for
AML/MDS expected to have prolonged neutropenia and HSCT recipients undergoing
high-dose immunosuppression for GVHD.
Despite the proven clinical effectiveness of posaconazole in these patients;
low posaconazole plasma concentrations, possibly leading to breakthrough
infections, have been reported in literature . According to the ECIL
guidelines, posaconazole trough concentrations >0.5-0.7 mg/L for prophylaxis
and >1mg/L for treatment are related to higher efficacy.
Low plasma concentrations are due to very unpredictable bioavailability of the
oral suspension. Posaconazole is a highly lipophilic, weak base with low
solubility in water, all limiting the absorption. Furthermore, the
unpredictable bioavailability is attributed to underlying diseases (e.g.
diarrhea, neutropenia, mucositis) and used co-medication such as proton pump
inhibitors. This has limited the use of posaconazole, despite its extensive in
vitro spectrum potential.
The new oral formulation with a pH dependent polymer matrix shows more
consistent absorption compared to the oral solution. Doses of the new
formulations (IV and tablet) for both prophylaxis and treatment are 300mg BID
on day 1, followed by 300mg QD on following days. This dose regimen is
profoundly different compared to the dose regimens of the oral solution
(dependent on indication 200mg BID-QID).
The new formulations offer new treatment possibilities, specifically in
patients previously unable to attain adequate exposure to posaconazole.
Already some data are published on the pharmacokinetics; however strictly
selected to patients and healthy volunteers. However, important specific
aspects related to the pharmacokinetics remain unsolved, such as data on the
impact of different phases of mucositis on the pharmacokinetics, as it is
unknown whether mucosal barrier injury impacts the absorption of posaconazole
or alters presystemic clearance. Even though vanStraelen et al found that
posaconazole plasma concentrations remained >0.5mg/L in six allogeneic stem
cell transplant patients receiving posaconazole tablets as prophylaxis; it
remains unkown whether the pharmacokinetics will be impacted by mucositis and
adequate exposure will be attained in a larger group of patients or when given
as treatment where higher plasma concentrations are pursued (>1.0 mg/L).
With this trial we think we can resolve the pharmacokinetics of the new
formulations of posaconazole in a cohort of haematological patients. A
step-down in posaconazole dose will provide information on linearity of the
absorption. In theory, step-down from 300mg QD to consecutively 200mg QD and
100mg QD would provide rich information on linearity; however it remains
unknown if 100mg QD will ensure adequate exposure to ensure prophylaxis.
Therefore only step-down to 200mg QD will be performed.
Posaconazole can then serve as a model substrate to determine the impact of
mucositis on the pharmacokinetics of other drugs as well, allowing direct
translation of findings to the clinical practice and assists us in further
improving treatment of invasive fungal infections in this vulnerable group of
patients.
For the purpose of resolving our primary research question, we have selected a
group of patients that will experience a severe degree of mucositis either
induced by the conditioning regimen or severe GvHD and whom are a target
population for receiving posaconazole prophylaxis. As a general statement, we
hypothesize that altered absorption is more likely than altered clearance in
hematology patients. We expect that a difference in rate of absorption or
bioavailability or presystemic clearance is largest in patients with mucosal
barrier injury. A marker of mucosal damage (citrulline) will also be used to
identify the influence of mucositis on posaconazole pharmacokinetics. In order
to identify changes in absorption, this is the cohort best used to address the
question.
Study objective
• To determine the pharmacokinetics of posaconazole (new solid oral and IV)
given as prophylaxis to patients who are at risk for developing fungal
infections after receiving conditioning therapy (except strictly non
myeloablative (NMA)) for allogeneic stem cell transplant (SCT(, remission
induction chemotherapy for acute myeloid leukemia (AML)/ myelodysplastic
syndrome (MDS) or being treated for severe Graft versus Host Disease (GvHD).
• To determine the impact of mucositis on changes in drug absorption or
presystemic clearance.
Study design
Open-label, multi-centre, randomised, multiple-dose, multiple dose-level,
sequential therapy, phase IV trial
Intervention
- 10 subjects (group A) will start with posaconazole 300mg IV BID on day 1,
followed by 300mg IV QD on days 2-7, followed by 300mg PO QD on days 8-12,
followed by 200mg PO QD on days 13-16.
- 10 subjects (group B) will start with posaconazole 300mg PO BID on day 1,
followed by 300mg IV PO on days 2-7, followed by 300mg IV QD on days 8-12,
followed by 200mg IV QD on days 13-16.
Study burden and risks
The risk-classification is assessed as negligible to the patient population
receiving study drug at the current regimens. The drug is licensed for the use
investigated in this protocol. There is no attributable risk for the
application of the study protocol to the haematology patients at risk for
fungal infections.
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
2. Subject is at least 18 years of age on the day of providing informed consent.
3. Patient receives immunosuppressive therapy for acute GVHD, (non)myeloablative or reduced intensity conditioning regimens for SCT, or remission induction chemotherapy for AML/MDS.
4. In case of acute GVHD grade II-IV, patient has received less than 1 week of immunosuppressive therapy.
5. If a woman, is neither pregnant nor able to become pregnant and is not nursing an infant.
6. Has an ALAT <=200U/L, ALAT <=225U/L, alkaline phosphatase <=60 U/L and a bilirubin level <=50 µmol/L.
7. Subject is capable of receiving oral tablets.
8. Subject is managed with a central venous or arterial catheter.
Exclusion criteria
1. Documented history of sensitivity to medicinal products or excipients similar to those found in the posaconazole preparation.
2. Relevant history or presence of cardiovascular disorders (specific QTc time prolongation).
3. Inability to understand the nature of the trial and the procedures required.
4. Any sign or symptoms of invasive fungal disease or the use of antifungal drugs within the previous month.
5. Has previously participated in this trial.
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 | EUCTR2016-001182-87-NL |
| CCMO | NL58150.091.16 |