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This single-dose study assessed bilastine pharmacokinetics and safety in patients with varying renal impairment. A 20mg bilastine dose showed increased Cmax and AUC with worsening renal function, doubling in severely impaired patients compared to healthy controls. This increase stemmed from reduced plasma and renal clearance mirroring decreased GFR. However, protein binding remained constant, irrespective of renal function or bilastine concentration. Even with higher exposure in renal impairment groups, it remained below levels seen as safe in studies using higher bilastine dosages. The rapid urinary excretion prevented accumulation, even in severe renal insufficiency. The observed exposure in severely impaired patients stayed within safety margins established in previous studies, suggesting a dose adjustment is unnecessary. Bilastine was well-tolerated at the 20mg dose, with only mild adverse events reported.

4 Discussion
In this open-label, single-centre, single-dose, parallel-group, non-randomized study, the pharmacokinetics and safety of bilastine were evaluated in subjects with various degrees of renal insufficiency. A single oral dose of 20 mg of bilastine was given to each subject.
As bilastine is renally excreted, renal insufficiency was expected to lead to a greater exposure to the drug. This was borne out by the progressive increase in mean Cmax and AUC with increasing renal insufficiency, such that both parameters in group 4 (severe renal insufficiency) were approximately double their value in group 1 (healthy).
There were no substantial differences in median max or in the mean terminal rate constants for bilastine.
The increase in exposure was due to the reduction of both plasma and renal clearances, which paralleled the decrease of GFR across the groups. The constancy of the (CLp/F)/CLp ratio across the groups, and the reduction in CLe from mild to severe renal insufficiency, consistent with the parallel reduction in the GFR, suggest that renal excretion is the main elimination route for bilastine, with no alternative elimination routes (hepatic, biliary, or oth-ers) being used even in severe renal insufficiency.
The relationship between CLp/F and GFR (linear and crossing the origin when correlated) suggests that glomerular filtration is the main renal excretion mechanism.
The measurement of the protein-bound fraction of bi-lastine has shown that the amount of unbound bilastine is
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K. C. Lasseter et al.
not affected by progressive renal insufficiency, showing that protein binding of bilastine was independent of concentration [25]. It is important to point out that the degree of renal impairment is not affecting plasma protein bind-ing: a change in plasma protein binding can be the consequence of higher drug concentration but also due to the disease itself which can produce several molecules/agents that can act to displace bound drugs. It has been confirmed that this is not the case for bilastine as there is a constant plasma protein binding; therefore, even in severely renally impaired subjects [25], with higher bilastine concentrations and high levels of urea and other substances, known dis-placers of drugs bound to albumin. As the percentage of plasma protein binding is constant among the different groups, independent of the disease status and bilastine concentration, the results from the total plasma concentrations obtained in this pharmacokinetic study can be more or less directly linked with efficacy and safety in order to conclude a dose adjustment is not needed.
The higher exposure observed in the renal impaired groups was below that seen in healthy subjects given bi-lastine 50 and 100 mg orally as a single dose or as a multiple 14-day dose administration, which appeared to be safe and well-tolerated [7].
The rapid urinary excretion of bilastine suggests daily doses would not lead to accumulation even in subjects with severe renal insufficiency, since the amount in the plasma after 24 h was less than 5 % of the max in all the groups.
Moreover overall exposure (AUC.) in severely impaired subjects was within safety margins that corresponded to the mean estimated exposure and 95 % CI of a single 80 mg oral dose of bilastine (AUC, of 4,225.6 ng•h/mL, 95 % CI 3,174.7-6278.4) [6]. This was the dose at which the incidence of central nervous system events indicative of sedation (somnolence) showed a statistically significant difference versus placebo in a previous phase I study in healthy volunteers [13]. This indicates that even patients with severe renal impairment receiving 20 mg of bilastine once a day are unlikely to attain a blastine exposure exceeding the estimated safety margin.
Bilastine given as a 20 mg oral dose was well-tolerated.
The reported AEs were all mild. Clinical laboratory values were generally within reference ranges for all parameters in this study. Vital signs, ECGs, and physical measurements did not indicate any significant safety concerns.