Penyesuaian Dosis Regimen

pada Pasien dengan

Gangguan Fungsi Ginjal

Ana Hulliyyatul
Jannah
1706096701
Ethical approval This study was approved by the Ethics Review Board of
Kagoshima University Hospital (Kagoshima, Japan)

Funding Financial support for this study was provided by the Japan
Society for the Promotion of Science (21928024).
 Background

The threshold Cmin

Linezolid and AUC24 to
(oxazolidinone class minimise linezolid-
Impaired renal
of synthetic induced
The incidence of function increased
antibacterial agents) thrombocytopenia as
linezolid -induced the trough plasma
 exhibits a broad well as the dosage to
thrombocytopenia  concentration (Cmin)
spectrum of activity achieve AUC24/MIC
The main adverse significantly higher in and AUC24 of
against of
event  patients with linezolid, with the
Gram-positive ≥100 for a
thrombocytopenia impaired renal result  exposure to
bacteria (meticillin- therapeutic response
function than in higher drug
resistant in patients with
patients with normal concentrations
Staphylococcus impaired renal
renal function induced
aureus (MRSA) & function have yet to
thrombocytopenia
vancomycin-resistant be determined.
enterococci).
The Aim of The Study

To define PD thresholds that could minimize linezolid-induced thrombocytopenia

To define PD thresholds that could minimize linezolid-induced thrombocytopenia
by assessing the relationship between exposure to linezolid and decreases in
by assessing the relationship between exposure to linezolid and decreases in
the platelet count in adult patients.
the platelet count in adult patients.

To conduct population PK analysis to identify factors influencing linezolid

To conduct population PK analysis to identify factors influencing linezolid
pharmacokinetics
pharmacokinetics

To confirm the need for dosage adjustment based on linezolid plasma levels.
To confirm the need for dosage adjustment based on linezolid plasma levels.
Patients

Written informed consent was obtained from 44 adult patients who

were administered linezolid between October 2008 and March 2013 at
Kagoshima University Hospital.
Methods
1. Drug administration and sample collection

On Days 3–14 [mean

± standard deviation
(S.D.) 5.8 ± 2.2 days]
after the initial
administration (under
steady-state
Linezolid plasma
All patients were conditions), venous
concentrations were
administered 300 mg blood samples were
measured by high
or 600 mg of linezolid drawn
performance liquid
twice daily just before the next
chromatography
intravenously or orally. administration (Cmin)
(HPLC)
and just after the end
of the 1-, 1.5- or 2-h
infusion or 2 h after
the oral administration
(approximately the
peak concentration).
2. Population pharmacokinetic modelling

› All PK data were modelled with a one-compartment PK model with a first-order absorption
process

› The structural parameters used were the volume of distribution (V; in L) and drug clearance
(CL; in L/h)

› Interindividual variability was modelled exponentially: i = × exp(i)

› Residual (intra-individual) variability was modelled proportionally: Cobs,ij = Cpred,ij × (1 +

εij)

› The first-order absorption rate constant (ka) for oral administration was fixed at 0.583 h−1

› The fraction of the absorbed drug (bioavailability) was assumed to be 100%

› AUC24/MIC ratio of ≥ 100

› Age, body weight, serum creatinine, CLCr estimated using the Cockcroft–Gault formula

› The significance levels for forward inclusion and backward elimination were set at P < 0.05
and P < 0.01, respectively.
3. Assessment of thrombocytopenia

Platelet counts
Thrombocytopeni were measured:
a  decrease to once a day
≤70% in the ratio Ratio of minimum
The effects of (n = 17),
of platelet counts platelet counts
drug exposure on
during treatment during treatment once every 2 days
thrombocytopenia
with linezolid to to the baseline (n = 7),
were investigated
the baseline levels was also once every 3 days
in 44 patients.
levels (pre- calculated. (n = 8) and
treatment with
linezolid). once a week
(n = 12).
4. Determination of Minimum Inhibitory Concentration

The MICs of linezolid for a total of 444 MRSA strains from hospitalized patients were
determined by the broth microdilution method as described by the Clinical and
Laboratory Standards Institute (CLSI).
5. Statistical analysis

A linear regression analysis was performed to examine the PK relationship

between the linezolid Cmin and AUC24. All statistical analyses were performed using
SPSS software v.15.0J (SPSS Japan Inc., Tokyo Japan), with a two-sided P-value of
<0.05 being considered significant.
Results
CONCLUSION

 Analyzing the population pharmacokinetics

and thrombocytopenic effects of linezolid in
adult patients proposed a dosage strategy
based on the Cmin target and renal
function in order to avoid adverse events
and to enable effective linezolid therapies
to be continued.

 Further studies involving a large number of

patients are needed to confirm the current
findings and to clarify their therapeutic
implications.