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document
Pharmacokinetic-pharmacodynamic modelling of the antihistaminic ( H1 ) effect of bilastine . OBJECTIVE To model the pharmacokinetic and pharmacodynamic relationship of bilastine , a new histamine H ( 1 ) receptor antagonist , from single- and multiple-dose studies in healthy adult subjects . METHODS The pharmacokinetic model was developed from different single-dose and multiple-dose studies . In the single-dose studies , a total of 183 subjects received oral doses of bilastine 2.5 , 5 , 10 , 20 , 50 , 100 , 120 , 160 , 200 and 220 mg . In the multiple-dose studies , 127 healthy subjects received bilastine 10 , 20 , 40 , 50 , 80 , 100 , 140 or 200 mg/day as multiple doses during a 4- , 7- or 14-day period . The pharmacokinetic profile of bilastine was investigated using a simultaneous analysis of all concentration-time data by means of nonlinear mixed-effects modelling population pharmacokinetic software NONMEM version 6.1 . Plasma concentrations were modelled according to a two-compartment open model with first-order absorption and elimination . For the pharmacodynamic analysis , the inhibitory effect of bilastine ( inhibition of histamine-induced wheal and flare ) was assessed on a preselected time schedule , and the predicted typical pharmacokinetic profile ( based on the pharmacokinetic model previously developed ) was used . An indirect response model was developed to describe the pharmacodynamic relationships between flare or wheal areas and bilastine plasma concentrations . Finally , once values of the concentration that produced 50 % inhibition ( IC ( 50 ) ) had been estimated for wheal and flare effects , simulations were carried out to predict plasma concentrations for the doses of bilastine 5 , 10 and 20 mg at steady state ( 72-96 hours ) . RESULTS A non-compartmental analysis resulted in linear kinetics of bilastine in the dose range studied . Bilastine was characterized by two-compartmental kinetics with a rapid-absorption phase ( first-order absorption rate constant = 1.50 h ( -1 ) ) , plasma peak concentrations were observed at 1 hour following administration and the maximal response was observed at approximately 4 hours or later . Concerning the selected pharmacodynamic model to fit the data ( type I indirect response model ) , this selection is attributable to the presence of inhibitory bilastine plasma concentrations that decrease the input response function , i.e . the production of the skin reaction . This model resulted in the best fit of wheal and flare data . The estimates ( with relative standard errors expressed in percentages in parentheses ) of the apparent zero-order rate constant for flare or wheal spontaneous appearance ( k ( in ) ) , the first-order rate constant for flare or wheal disappearance ( k ( out ) ) and bilastine IC ( 50 ) values were 0.44 ng/mL/h ( 14.60 % ) , 1.09 h ( -1 ) ( 15.14 % ) and 5.15 ng/mL ( 16.16 % ) , respectively , for wheal inhibition , and 11.10 ng/mL/h ( 8.48 % ) , 1.03 h ( -1 ) ( 8.35 % ) and 1.25 ng/mL ( 14.56 % ) , respectively , for flare inhibition . The simulation results revealed that bilastine plasma concentrations do not remain over the IC ( 50 ) value throughout the inter-dose period for doses of 5 and 10 mg . However , with a dose of 20 mg of bilastine administered every 24 hours , plasma concentrations remained over the IC ( 50 ) value during the considered period for the flare effect , and up to 20 hours for the wheal effect . CONCLUSION Pharmacokinetic and pharmacodynamic relationships of bilastine were reliably described with the use of an indirect response pharmacodynamic model ; this led to an accurate prediction of the pharmacodynamic activity of bilastine .
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Intervention_Pharmacological
bilastine
41762
Intervention_Pharmacological
bilastine
41763
Intervention_Pharmacological
bilastine
41764
Intervention_Pharmacological
bilastine
41765
Intervention_Pharmacological
bilastine
41766
Intervention_Pharmacological
bilastine
41767
Intervention_Pharmacological
bilastine
41768
Intervention_Pharmacological
bilastine
41769
Intervention_Pharmacological
bilastine
41770
Outcome_Other
Pharmacokinetic-pharmacodynamic modelling
41771
Outcome_Physical
pharmacokinetic
41772
Outcome_Physical
pharmacodynamic
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Outcome_Mental
pharmacokinetic profile
41774
Outcome_Other
concentration-time data
41775
Outcome_Physical
Plasma concentrations
41776
Outcome_Other
typical pharmacokinetic profile
41777
Outcome_Other
pharmacodynamic relationships
41778
Outcome_Physical
bilastine plasma concentrations
41779
Outcome_Other
concentration that produced 50 % inhibition ( IC ( 50 ) )
41780
Outcome_Physical
plasma concentrations
41781
Outcome_Physical
plasma peak concentrations
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Outcome_Other
maximal response
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Outcome_Other
input response function
41784
Outcome_Physical
apparent zero-order rate constant for flare
41785
Outcome_Physical
wheal spontaneous appearance
41786
Outcome_Physical
first-order rate constant for flare
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Outcome_Physical
wheal disappearance
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Outcome_Physical
bilastine IC
41789
Outcome_Physical
bilastine plasma concentrations
41790
Outcome_Other
plasma concentrations
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Participant_Condition
healthy
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Participant_Age
adult
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Participant_Sample-size
183
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Participant_Sample-size
127
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Participant_Condition
healthy