Importance of chronopharmacokinetics in design and evaluation of transdermal drug delivery systems.

Circadian and meal effects on nicotine kinetics determine in part blood nicotine concentrations and in doing so may influence cigarette smoking behavior throughout the day. We have shown previously that nicotine clearance varies by approximately 17% (from peak to through) due to diurnal factors throughout the day and that meals increase nicotine clearance by about 42%. Until now pharmacokinetic analyses of nicotine absorption from patches have assumed a constant clearance of nicotine over 24 hr. Using 11 individual kinetic estimates from a previous study, we analyzed plasma nicotine concentrations vs. time data of two nicotine patch studies, and conducted a set of simulations to determine the extent to which time-varying kinetics would influence the design of transdermal drug delivery systems, intented to maintain a constant plasma nicotine concentration over 24 hr. Not incorporating time-varying kinetics leads to biased estimates of the delivery rate of the nicotine patches, and increases the variability in the delivery rates estimates. The hypothetical transdermal drug delivery systems designed assuming constant nicotine clearance results in a systematical underdosing during the first 12 hr after beginning therapy. The transdermal drug delivery systems obtained assuming the correct time-varying clearance shows three components: 1) an early high delivery rate, followed by 2) a rather constant, but slightly decreasing at night, release rate and 3) transient increases in delivery rate for 2 hr after each meal. The effect of circadian variations in clearance could be compensated for in patch design by decreasing the delivery rate during the night. Transient variations in clearance due to meals would require the corresponding use of rapid drug delivery dosage forms. The methods we devise to predict optimal dosing regimens in presence of chronopharmacokinetics might be useful for other medications in which blood levels need to be precisely controlled.