Farmakokinetička ispitivanja mikofenolne kiseline kod pacijenata sa presađenim bubregom
Докторанд
Kundalić, Ana A.Ментор
Veličković-Radovanović, RadmilaЧланови комисије
Catić-Đorđević, AleksandraCvetković, Tatjana
Mitić, Branka
Pavlović, Radiša
Метаподаци
Приказ свих података о дисертацијиСажетак
Mycophenolic acid (MPA) is frequently prescribed as a part of
immuno suppressive protocols following kid ney transplantation.
Significant variability in MPA pharmacokinetics and the different
individual response emphasize the need for individualized dosing
regimens. The goals of this research were the development and
validat ion of HPLC method for the quantita tiv e analysis of MPA, the
identification of factors that contribute to the interindividual
variability of MPA, the assessment of the frequency and intensity of
adverse effects, the examine association of the salivary conc entration
(C SAL ) with the manifeste d a dverse effects, as well as the association
of the plasma and salivary concentration in relation to serum albumin
levels in kidney transplant patients.
This research included 102 adult kidney transplant patients. Plasma
and salivary MPA concentrations w ere determined by a validated
HPLC method and LC MS. The NONMEM® software was used for
the population an...alysis. The obtained model was further investigated
using Monte Carlo (MC) modeling. Adverse effects of the applied
t herapy were collected through a val ida ted questionnaire. A
correlation between plasma and salivary MPA concentrations was
established using the least squares method.
Population pharmacokinetic analysis identified patient age, MPA daily
dose, and nifedipine co therapy as significant factors in the variability
of MPA clearance. Using external validation method, the validity of
the obtained population model was confirmed. Furthermore, the
model was compared with similar models available in the literature
using the MC method, which confirmed its va lidity. A higher
frequency of adverse effects was recorded in female patients, with a
statistically significant difference in the occurrence of gastrointestinal
adverse effects and skin changes. Besides, gastrointestin al score was
significantly higher i n p atients using MMF compared to EC MPS.
Additionally, a relationship was established between C SAL and
aesthetic score in patients with lower albumin levels.
The obtained population pharmacokinetic model provides a basis
for
individualized MPA dosing in pa tie nts with the presence of variability
factors. Gender differences should be taken into account when
optimizing dosing regimens in order to achieve the efficacy and safety
of immunosuppressive therapy in kidney transplan t patients. The
results showed that C S AL MPA monitoring may contribute to
management of adverse effects.