Integrated pharmacokinetic and metabolic modeling of selegiline and metabolites after transdermal administration

Abstract

Selegiline (SEL) is a selective, irreversible inhibitor of MAO‐B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L‐DOPA. Selegiline hydrochloride (HCl) undergoes significant first‐pass metabolism following oral administration. Transdermal delivery avoids the first‐pass effect and provides greater and more prolonged levels of unchanged SEL and reduced levels of metabolites (N‐desmethylselegiline (DES), L‐amphetamine (AMP), and L‐methamphetamine (MET)) compared to the oral regimen. An integrated pharmacokinetic–metabolic model which predicts plasma concentrations of SEL and metabolites following a single 24 h application of a selegiline transdermal system (STS) is proposed. The model is based on the metabolic conversion of SEL to DES and MET and subsequently to AMP. The input function is described by a zero‐order constant for the delivery of SEL from the STS system based on in vitro studies of penetration of SEL across human skin. The elimination–non‐metabolic constants for each analyte account for the urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which six healthy male volunteers were administered single 24 h applications of a 1·8 mg cm2, 10 cm2 STS were used to examine this model. The coefficient of determination was 0·98 and model selection criterion was 3·4 for mean data fits, supporting the goodness of fit of the model. The pharmacokinetic parameters obtained by non‐compartmental analysis were comparable to those predicted by a compartmental model. The model also predicted urinary recoveries for AMP and MET and negligible recovery for SEL and DES consistent with recent studies with the STS in which urine was collected. The metabolic conversion constant from SEL to DES was significantly lower than the conversion constant from SEL to MET, indicating that metabolism of SEL is primarily driven towards MET following transdermal administration. The metabolic conversion from MET to AMP was less than the conversion from DES to AMP. This simultaneous prediction of the SEL and metabolites is essential as the metabolic ratios have been linked to the neuroprotective effects of SEL. These findings support the proposed regional delivery advantage attributed to the transdermal route compared to the conventional therapy with the oral tablet. Future model applications may also help identify significant covariates (i.e. age, gender, and disease state) in upcoming clinical trials. © 1997 John Wiley & Sons, Ltd.

Pharmacokinetics and Absolute Bioavailability of Selegiline Following Treatment of Healthy Subjects With the Selegiline Transdermal System (6 mg/24 h): A Comparison With Oral Selegiline Capsules

“…These results are consistent with the work of others who have reported a significant first‐pass effect with orally administered selegiline 22 , 23 , 26 . Furthermore, our results are qualitatively similar to the early PK data in healthy elderly male and female subjects reported by Barrett et al 23 and in young healthy male subjects reported by Rohatagi et al, 30 both obtained with a prototype selegiline transdermal patch.…”

Physiologically Based Pharmacokinetic Modeling of Transdermal Selegiline and Its Metabolites for the Evaluation of Disposition Differences between Healthy and Special Populations

“…The difference in C max (pg/mL) and AUC 0-24 (h × pg/mL) values is more than 2-fold between clinical studies. Similarly, the inter-study variability was observed in another single transdermal PK study at 18.3 mg/10 cm 2 in healthy males [ 9 , 10 ]. The overall bias (AFE) and precision (AAFE) for C max of SEL (AFE: 0.87; AAFE: 1.33), MAP (AFE: 0.8; AAFE: 1.4), DMS (AFE: 0.89; AAFE: 1.36), and AMP (AFE: 1.22; AAFE: 1.29), and AUC 0-t of SEL (AFE: 1.02; AAFE: 1.44), MAP (AFE: 0.89; AAFE: 1.32), DMS (AFE: 1.15; AAFE: 1.38), and AMP (AFE: 1.20; AAFE: 1.29) were within 0.5–1.5-fold error [ 63 ].…”

“…The PBPK model was further verified by simulating the single and multiple dermal doses reported in the literature [ 9 , 10 , 11 ]. Single dose PK profiles in adult healthy males (18.3 mg/10 cm 2 for 24 h) presented in Figure 4 a show that the model adequately predicted the individual observed pharmacokinetic profiles.…”

“…Single dose PK profiles in adult healthy males (18.3 mg/10 cm 2 for 24 h) presented in Figure 4 a show that the model adequately predicted the individual observed pharmacokinetic profiles. The mean ± SD predicted to observed ratios were within the acceptable limits of the prediction window except for AUC 0-t DMS, which was due to a high variability in the observed AUC 0-t (68% CV) [ 10 ]. The single dose PK profiles in healthy elderly male and female subjects at 18.3 mg/10 cm 2 presented in Figure 4 c, show that model adequately predicted the observed pharmacokinetic profiles of SEL and its metabolites.…”

“…Only one clinical PK study for intravenous infusion dose was available in the literature [ 3 ]. Transdermal PK studies after single and multiple dosage regimens were reported in both healthy adult and geriatric populations [ 3 , 9 , 10 , 11 ]. Two studies reported in elderly male and female subjects by Barret et al, one that used a dose of 9.15 mg/10 cm 2 and another that used dose proportionality (0.5, 1, and 1.5 mg/cm 2 ) in elderly males; females were not considered for the model verification.…”