Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling.

AIM: To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. METHODS: Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients. RESULTS: The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C(max), and T(max)) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles. CONCLUSION: The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.

Simultaneous determination of amlodipine and bisoprolol in rat plasma by a liquid chromatography/tandem mass spectrometry method and its application in pharmacokinetic study.

A sensitive, specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantitative determination of amlodipine and bisoprolol, using clenbuterol as the internal standard (IS). The analytes and IS were isolated from 100µL plasma samples by a simple liquid-liquid extraction (LLE). Reverse-phase high performance liquid chromatography (RP-HPLC) separation was accomplished on a Diamonsil C(18) column (50mm×4.6mm, 5µm) with a mobile phase composed of methanol-water-formic acid (75:25:0.01, v/v/v) at a flow rate of 0.3mL/min. The method had a chromatographic total run time of 3min. Multiple reacting monitoring (MRM) transitions of m/z [M+H](+) 409.1→237.9 (amlodipine), m/z [M+H](+) 326.2→116.0 (bisoprolol) and m/z [M+H](+) 277.0→203.0 (clenbuterol, IS) were used to quantify amlodipine, bisoprolol and IS, respectively. The method was sensitive with a lower limit of quantitation (LLOQ) of 0.2ng/mL for both amlodipine and bisoprolol, and the linear range was 0.2-50ng/mL for both amlodipine and bisoprolol (r(2)>0.9961). All the validation data, such as accuracy, precision and inter-day repeatability, were within the required limits. The method was successfully applied to pharmacokinetic studies of amlodipine and bisoprolol in Sprague-Dawley (SD) rats.

[Assessment of therapeutic equivalence of original bisoprolol and its generics in patients with ischemic heart disease with concomitant chronic obstructive pulmonary disease].

Therapeutic equivalence of original bisoprolol (Concor) and its two generics (Biprol and Biol) was studied in 102 patients with ischemic heart disease (IHD) combined with chronic obstructive pulmonary disease (COPD). Concor, Biprol and Biol were given for 12 weeks to 36, 36, and 30 patients, respectively. Methods comprised test with endothelium dependent vasodilation, 24-hour ECG monitoring, pulmonary ventilation tests, and measurement of blood concentrations of nitrous oxide metabolites. Hypotensive and antiischemic effects were similar in all groups. However significant improvement of endothelial function occurred only among Concor treated patients. No negative changes of parameters of pulmonary ventilation took place after 4 weeks of therapy but after 12 weeks their significant lowering was observed among Biprol treated patients. We conclude that in this study on patients with IHD and COPD original bisoprolol demonstrated higher clinical efficacy and better tolerability than its generics.

[Bisoprolol: opportunities in the treatment of hypertension].

Bisoprolol (bisoprolol fumarate) - -cardioselective blocker, does not possess intrinsic sympathomimetic and membrane stabilizing activity. The main indications for bisoprolol are arterial hypertension (AH) and heart failure. This article provides an overview of the literature on the potential uses of bisoprolol in the treatment of hypertension. The features of the pharmacokinetics of the drug. The data on the effectiveness of bisoprolol in hypertension and tolerability in patients with concomitant disorders: diabetes, chronic obstructive pulmonary disease, peripheral atherosclerosis. Proofs of the high efficiency of antianginal bisoprola and justified the use of the drug in patients with hypertension and coronary heart disease. The capabilities of bisoprolol in the perioperative correction of hypertension. The data and pharmacoeconomic properties of bisoprolol generic counterparts.

Bisoprolol: a review of its use in chronic heart failure.

Bisoprolol is a highly selective beta(1)-adrenoceptor antagonist. Administration of bisoprolol to patients with chronic heart failure is associated with increases in left ventricular function and reductions in heart rate; increases in heart rate variability are also seen. Two major randomised, double-blind, placebo-controlled, multicentre trials have examined the clinical efficacy of bisoprolol in combination with ACE inhibitors and diuretics in patients with stable chronic heart failure (New York Heart Association class III or IV): the Cardiac Insufficiency Bisoprolol Study (CIBIS; n = 641) and CIBIS II (n = 2 647). All-cause mortality (primary endpoint) was significantly lower in bisoprolol than in placebo recipients in CIBIS II (11.8 vs 17.3%) and was reduced by bisoprolol regardless of dosage. All-cause mortality was also lower in CIBIS (16.6 vs 20.9%) although the difference did not achieve statistical significance. In a meta-analysis of CIBIS and CIBIS II (n = 3 288), a relative reduction of 29% in the incidence of all-cause mortality was seen in bisoprolol versus placebo recipients; this analysis also demonstrated that bisoprolol reduces mortality in patients with chronic heart failure regardless of aetiology or severity. In CIBIS II, there were significantly fewer cardiovascular deaths, admissions to hospital for any reason, or cardiovascular deaths or cardiovascular hospitalisations (combined endpoint) in bisoprolol, compared with placebo, recipients (secondary endpoints). Compared with standard treatment alone, the addition of bisoprolol was a cost-effective option in chronic heart failure in UK, French, German and Swedish pharmacoeconomic studies. Bisoprolol is generally well tolerated in patients with chronic heart failure. In CIBIS II, adverse events occurring more commonly in bisoprolol than placebo recipients, regardless of causal relationship with the study medication, included dizziness, bradycardia, hypotension and fatigue. Bisoprolol recipients were less likely than placebo recipients to experience worsening of heart failure, dyspnoea or tachycardia. In both CIBIS and CIBIS II there was no significant difference between bisoprolol and placebo recipients in the incidence of permanent treatment withdrawal. In conclusion, adding the highly selective beta(1)-blocker bisoprolol to a treatment regimen comprising an ACE inhibitor and a diuretic significantly improves survival in patients with stable chronic heart failure and reduces the need for hospitalisation. The use of bisoprolol in this disorder is generally well tolerated and is cost effective. Thus, bisoprolol should be considered a standard treatment option when selecting a beta-blocker for use in combination with ACE inhibitors and diuretics in patients with stable, moderate to severe chronic heart failure.