ABSTRACT
The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and <30 mL/min). Cmax was not statistically different between the groups, while AUC and T1/2el increased, and CL/F decreased, with increasing severity of CKD. Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.
Subject(s)
Baclofen/pharmacokinetics , GABA-B Receptor Agonists/pharmacokinetics , Muscle Relaxants, Central/pharmacokinetics , Renal Insufficiency, Chronic/metabolism , Adult , Aged , Aged, 80 and over , Baclofen/administration & dosage , Baclofen/adverse effects , Baclofen/blood , Creatinine/metabolism , Female , GABA-B Receptor Agonists/administration & dosage , GABA-B Receptor Agonists/adverse effects , GABA-B Receptor Agonists/blood , Glomerular Filtration Rate , Humans , Male , Middle Aged , Muscle Relaxants, Central/administration & dosage , Muscle Relaxants, Central/adverse effects , Muscle Relaxants, Central/bloodABSTRACT
BACKGROUND: Rosuvastatin, a synthetic lipid-lowering agent acts selectively by competitive inhibition of 3-hydroxy- 3-methylglutaryl-coenzyme A. It is indicated as an adjunct to diet in patients with hypercholesterolemia and mixed dyslipidemia. OBJECTIVE: The purpose of this study was to demonstrate bioequivalence between a generic rosuvastatin 40 mg tablet (Zentiva, Prague, Czech Republic) and a reference product (Crestor, AstraZeneca, Luton, UK), under fasting conditions as required by the European Medicinal Agency. METHODS: A single-oral 40 mg-dose, randomized, open-label, 2-way crossover design study was conducted in 42 healthy volunteers under fasting conditions. Rosuvastatin was administered following an overnight-fast in two occasions with a 14-day washout period in-between. Blood samples were collected in EDTA-K2 tubes prior to dosing and over a 96-hour period. Rosuvastatin was measured in plasma using an automated LC-MS/MS assay (range 81.02 - 40,512.00 pg/ml). Pharmacokinetics were performed using non-compartmental analyses approach to evaluate AUC(last), AUC∞ and C(max). ANOVA was performed on the ln-transformed data and the 90% Confidence Interval (CI) was determined. Bioequivalence will be concluded if the 90% CI falls within 80.00 - 125.00% for AUC(last) and C(max). Safety and tolerability were also evaluated. RESULTS: 39 volunteers completed the study and were considered for the pharmacokinetic and statistical analyses. Descriptive safety data analyses were performed on all subjects. All pharmacokinetic parameters met the acceptance criteria as the 90% CI were within 80.00 - 125.00%. Both formulations were well tolerated and no serious adverse events were reported. CONCLUSION: This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 40 mg oral dose under fasting conditions.
