لخّصلي

This open-label, single-dose, parallel-group study (September 2008-April 2009) investigated bilastine pharmacokinetics in renal insufficiency. Four groups (n=6 each) received a single 20mg oral dose: healthy subjects (GFR >80 mL/min/1.73 m²) and those with mild (50-80), moderate (30-50), and severe (≤30) renal insufficiency (GFR assessed by iothalamate clearance). Strict inclusion/exclusion criteria were applied, ensuring participants were either infertile or using double-barrier contraception. Blood and urine samples were collected at various time points post-dose, with bilastine quantified using LC/MS/MS. The study adhered to Declaration of Helsinki, FDA, EMA, ICH, and GCP guidelines.

Methods
2.1 Study Design and Population
This study was conducted in accordance with the provisions of the Declaration of Helsinki and its amendments, US FDA and European Medicines Agency (EMA) guide-lines, and the guidelines of the International Conference on Harmonization (ICH) and Good Clinical Practice (GCP) that were in place at the time of the study.
Male and female volunteers were enrolled in this open-label, single-dose, parallel-group study, undertaken at the
Bilastine Pharmacokinetic in Renal Insufficiency
facilities of Clinical Pharmacology of Miami, Inc., Miami, FL, USA, between September 2008 and April 2009.
The protocol and informed consent form were reviewed and approved by The Independent Investigational Review Board, Plantation, FL, USA, prior to the screening or enrolment of any study participants. All subjects gave their informed, written consent prior to undergoing any study-related procedures.
A bilastine 20 mg single oral dose was administered to
four groups (n = 6 each) of subjects either healthy or with
various degrees of renal insufficiency. Subjects were assigned to groups according to their glomerular filtration rate (GFR) during initial screening assessed by iothalamate clearance, as follows:
Group 1: healthy (GFR >80 mL/min/1.73 m})
Group 2: mild renal insufficiency (GFR 50-80 mL/min/ 1.73 m3)
Group 3: moderate renal insufficiency (GFR 30-50 mL/ min/1.73 m*)
Group 4: severe renal insufficiency (GFR ≤30 mL/min/
1.73 m)
It is recommended that renal function in pharmacoki-
netic studies is determined by
GFR using
accurate and well established methods [20]. Therefore, the iothalamate method was used to obtain a highly accurate estimate of GFR because it is based on only passive glomerular filtration of an exogenous substance entirely
excreted through the kidnev
[21]. Categories of renal
insufficiency according to GFR values were based on the definition provided in the regulatory guidance in place at the time the study was conducted.
All participants and his/her partner were either infertile or willing to use an approved method of double-barrier contraception (hormonal plus barrier or barrier plus barrier) from the time of dose administration and for 1 month thereafter.
Healthy subjects with a similar distribution of age, bodyweight, and sex as the subjects with renal insufficiency (variability within 10 %) were enrolled in the study after completion of the three groups of renal insuf-ficiency. Healthy subjects were to be at least 18 years old with no evidence of significant organic or psychiatric ill-ness. On clinical examination their systolic and diastolic blood pressure, heart rate, temperature, electrocardiogram (ECG), hematology, and biochemistry parameters were to be all within the normal range.
Eligible renally impaired subjects were to be between 45 and 110 kg, aged 18-80 years, and with a stable
renal function for 3 months before inclusion in the study.
Renally impaired subjects with end-stage renal disease on hemodialysis or peritoneal dialysis, with bilirubin levels

1.5 mg/dL and/or increment of aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) levels two times higher than the maximum limit of normality, with a platelet count lower than 75,000/mm', or with serum potassium
higher than 6 mEq/L were excluded.
Subjects treated with P-gp/CYP inhibitors or inducers within 30 days were excluded. Ingestion of grapefruit juice, cranberry juice, apple juice, Seville orange juice, any well-known P-gp inhibitor in the previous 7 days, or Saint John's wort in the previous 15 days also excluded subjects from enrolment.
Screening evaluations were performed within 21 days prior to admission to the clinic. Blood and urine samples for the iothalamate GFR test were obtained at least 7 days prior to the anticipated clinic admission, and results were required to be obtained prior to the clinic visit. Subjects were accommodated in the clinic from the evening prior to dosing until released by the investigator subsequent to obtaining the 72-h blood sample and urine collection.
On the day of dosing, all subjects received a single oral
20-mg dose of bilastine with 200 mL of water by mouth following a fast of 8-10 h. Subjects continued fasting for 2 h after dosing and were provided with a standard diet at all other times.
Bilastine tablets were manufactured by FAES FARMA S.A., Leioa (Vizcaya), Spain, according to Good Manufacturing Practice guidelines and were supplied in blister strips containing 4 × 20 mg tablets of bilastine. The drug was securely stored during the study.
2.2 Pharmacokinetic Assessments
Blood samples were collected pre-dose and at 0.25, 0.50, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 8.0, 12, 24, 36, 48, and 72 h after bilastine administration. Approximately 7 mL of blood for each sample were collected into sodium heparin Vacu-tainer® tubes. Plasma was separated by centrifugation at 48 °C for 10 min at 1,500xg, and stored frozen within
1 h of collection.
Urine samples were collected at 0-12, 12-24, 24-48,
and 48-72 h after bilastine administration.
Urine wa
refrigerated during the collection intervals.
Total urine
volumes were measured for each time period and 25 mL. aliquots were stored at -20 °C.
Bilastine was extracted and quantified using a liquid chromatography with tandem mass spectrometer detection
(LC/MS/MS) system of analysis. The lower and upper limits of quantification were 0.20 and 402.40 ng/mL, respectively, for bilastine in human plasma and 5.00 and 5,000 ng/mL, respectively, for bilastine in human urine
[22]. Analysis was undertaken by Anapharm Inc., Québec City, QC, Canada.
The following pharmacokinetic parameters were derived for bilastine from individual plasma or urine concentrations: