Order in patch absorption rates?
Panos Macheras[1]; Flavia de Toni Uchoa[2]; John C Lukas[2]
[1] Department of Pharmacy, National and Kapodistrian University of Athens Pharma; Current Address: Informatics Unit of Research & Innovation Center ATHENA (Athens, Greece); [2] Drug Modeling & Consulting, Dynakin SL (Derio, Spain)
Objectives: Transdermal delivery systems (“patch”) achieve steady “infusion-like” delivery avoiding sharp peaks & first pass metabolism, eliminating multiple dosing, increasing bioavailability and improving compliance. Absorption rates of patches are reported as zero-order, possibly not to their true complexity. The single dose PK for four compounds were extracted from the public domain and their absorption rates qualified vs. the zero-order assumption.
Methods: Patch PK in human from Rivastigmine[1], Nicotine[2], Estradiol[3] and Rotigotine[4] were extracted covering most patch types. The Wagner-Nelson method was used to obtain partial areas up to all profile times with lamda-extension to AUC[0-inf] and for Kel. The slope of the “log-amount vs. time” plot was used for evaluating actual absorption rates. This is assumed to be linear if absorption is first order (“ka”), i.e. passive. Visual estimation of levels of linearity in the calculated slopes was used to evaluate first to zero-order or mixture of rates transitions in the patch absorption PK.
Results: 17 profiles across multiplicities by dose and patient type of the 4 drugs were extracted. The listed zero-order rates were for Rivastigmine (e.g. 9 mg dose; 4.6 mg/day); Nicotine (40 mg; 27 mg/day); Rotigotine (4.5 mg; 2 mg/day). However, the absorption rates, independent of flip-flop kinetics and patch types, were complex for all drugs analyzed. Absorption appeared as zero order in the first quarter of total application time but became more complex in later times. Dose-dependencies existed for amount and rate partitioning.
Conclusions: Actual patch absorption rates appear to be far from single order and may have complex dependencies with patch formulation types, dose and patch size. There are limitations in this analysis in the small number of single dose profiles tested. Although in multiple applications, the absorption rate is not essential in determining exposure, in flip-flop kinetics this rule fails. The impact of gaining such knowledge as early as possible in drug development, for formulation design, bioequivalence and forward modeling and simulation in development is evident.
References:
[1] Lefevre G, Buche M, Sedek G et al, Similar Rivastigmine Pharmacokinetics and Pharmacodynamics in Japanese and White Healthy Participants Following the Application of Novel Rivastigmine Patch. J Clin Pharmacol, 2009; 49: 430-443
[2] Lewis A et al, Pharmacokinetic Evaluation of a Developed Nicotine Transdermal System, Indian J Pharm Sci, 2007; 69: 309-312.
[3] http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203752lbl.pdf
[4] Cawello W, Arhweiler S, Sulowicz W et al, Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. Br J Clin Pharmacol, 2011; 73: 46-54.