International Journal of Pharmaceutics 376 (2009) 7–12 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib? C.G. Wilson a,∗ , B. O’Mahony a , S.M. Connolly a , M.V. Cantarini b , M.R. Farmer b , P.A. Dickinson b , R.P. Smith b , H.C. Swaisland b a Bio-Images Research Ltd., Glasgow G4 0SF, Scotland, UK b AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK article info Article history: Received 9 February 2009 Received in revised form 2 April 2009 Accepted 3 April 2009 Available online 14 April 2009 Keywords: Gefitinib Iressa ® Gastrointestinal transit Gamma scintigraphy abstract The selective EGFR tyrosine kinase inhibitor, gefitinib has been shown to be active against certain human carcinomas. It had been noted that a proportion of volunteers consistently had lower gefitinib expo- sure following oral administration. The shape of the elimination profile in this subset was also different, showing a monophasic elimination pattern rather than the biphasic pattern observed in the majority of subjects. A gamma scintigraphic study was conducted to examine the relationship of gastrointestinal transit and drug absorption in a cohort of rapid clearance subjects (n = 5) and normal profile volunteers (n = 7). The fasted volunteer panel received a 250 mg gefitinib tablet labelled with [ 111 In]–DTPA together with 240 mL [ 99m Tc]-labelled water. The rapid clearance cohorts were shown to have a faster mean gastric emptying T90 (37 min vs 74 min) and shorter small intestinal transit time (156 min vs 204 min), result- ing in an earlier colonic arrival time (181 min vs 244 min). Mean plasma C max was lower (99.2 ng/mL vs 116ng/mL) and AUC almost half in the rapid clearance group (2162 ± 81 ngh/mL vs 4996 ± 64 ngh/mL). These data suggest that gastrointestinal transit parameters play a role in the differences in the rapid clearance profile group, also contributing to the biphasic to monophasic switch. However, historical data show, at the recommended dose of 250 mg/day steady-state plasma concentrations adequate for clinical benefit are achieved in patients with non-small cell lung cancer. Crown Copyright © 2009 Published by Elsevier B.V. All rights reserved. 1. Introduction For poorly water-soluble or poorly absorbed drugs, the contact time with the small intestine is a critical determinant of absorp- tion. Early models of the relationship between gastrointestinal (GI) transit and absorption constructed by Ho et al. (1983) attempted to encapsulate this concept in a model of ‘intestinal reserve length’ derived from an observation of Hoffman et al. (1983) that drugs should be formulated to achieve 95% absorption in a small intesti- nal length of 180–350cm. The approach taken was simplistic as it assumed drug absorption to be a simple first order process and transit to be fairly constant and was based on the earlier idea of ‘intestinal reserve length’ proposed by Borgstrom et al. (1957), who observed that the majority of the nutrients delivered in a liquid meal are absorbed in the first 100 cm of gut. Dressman (1989) sug- gested that a better way of describing the impact of small intestinal transit time on drug absorption was to calculate the mean resi- dence time which allowed for supply, uptake and removal of the drug. Later modeling approaches utilised data derived from gamma ∗ Corresponding author. Tel.: +44 141 5528791; fax: +44 141 5527752. E-mail address: c.g.wilson@bio-images.co.uk (C.G. Wilson). scintigraphy, the formulation being radiolabelled by incorporation of indium-111 or technetium-99m. Using this data, the plasma concentration–time profile can be related to gastric emptying, small intestinal transit time and colonic residence (Wilson et al., 2001). Gefitinib (Iressa ® , AstraZeneca) is a potent inhibitor of epider- mal growth factor receptor (EGFR) tyrosine kinase. It is a lipophilic dibasic compound (Table 1) that is administered as the free base in Iressa ® tablets. The compound exhibits pH-dependent solubility which is higher at low pH, representative of the gastric environ- ment, but drops significantly as the pH increases towards pH 5. Gefitinib has increased solubility in biorelevant media and aspi- rates of human gastric fluid and intestinal fluid as shown in Table 2; however, the solubility is still likely (or believed) to be low in the intestine. Gefitinib demonstrates high permeability across CACO- 2 monolayers and has an absolute bioavailability in humans of 60%, suggesting high or even complete absorption (Swaisland et al., 2005). As defined by the Biopharmaceutical Classification System (Amidon et al., 1995), gefitinib is a Class 2 compound. Previous healthy volunteer studies with gefitinib have shown the pharmacokinetics to be highly variable (Swaisland et al., 2005). Among the subjects studied there was subgroup (ca. 18% of healthy subjects) that displayed a pharmacokinetic profile following sin- gle oral doses of gefitinib that is different to the profile seen in 0378-5173/$ – see front matter. Crown Copyright © 2009 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.04.008