Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib?

C. G. Wilson, B. O'Mahony, S. M. Connolly, M. V. Cantarini, M.R. Farmer, P.A. Dickinson, R. P. Smith, H.C. Swaisland

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 exposure 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 [111In]–DTPA together with 240 mL [99mTc]-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), resulting in an earlier colonic arrival time (181 min vs 244 min). Mean plasma Cmax was lower (99.2 ng/mL vs 116 ng/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.
LanguageEnglish
Pages7-12
Number of pages6
JournalInternational Journal of Pharmaceutics
Volume376
Issue number1-2
Early online date14 Apr 2009
DOIs
Publication statusPublished - 6 Jul 2009

Fingerprint

Gastrointestinal Transit
Pharmacokinetics
Volunteers
Gastrointestinal Agents
Pentetic Acid
Gastric Emptying
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Tablets
Area Under Curve
Oral Administration
Healthy Volunteers
Carcinoma
Water
gefitinib

Keywords

  • gefitinib
  • Iressa®
  • gastrointestinal transit
  • gamma scintigraphy

Cite this

Wilson, C. G., O'Mahony, B., Connolly, S. M., Cantarini, M. V., Farmer, M. R., Dickinson, P. A., ... Swaisland, H. C. (2009). Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib? International Journal of Pharmaceutics, 376(1-2), 7-12. https://doi.org/10.1016/j.ijpharm.2009.04.008
Wilson, C. G. ; O'Mahony, B. ; Connolly, S. M. ; Cantarini, M. V. ; Farmer, M.R. ; Dickinson, P.A. ; Smith, R. P. ; Swaisland, H.C. / Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib?. In: International Journal of Pharmaceutics. 2009 ; Vol. 376, No. 1-2. pp. 7-12.
@article{00b2a1d71ef3499eab211a5cb46ee9fc,
title = "Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib?",
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 exposure 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 [111In]–DTPA together with 240 mL [99mTc]-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), resulting in an earlier colonic arrival time (181 min vs 244 min). Mean plasma Cmax was lower (99.2 ng/mL vs 116 ng/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.",
keywords = "gefitinib, Iressa{\circledR}, gastrointestinal transit, gamma scintigraphy",
author = "Wilson, {C. G.} and B. O'Mahony and Connolly, {S. M.} and Cantarini, {M. V.} and M.R. Farmer and P.A. Dickinson and Smith, {R. P.} and H.C. Swaisland",
year = "2009",
month = "7",
day = "6",
doi = "10.1016/j.ijpharm.2009.04.008",
language = "English",
volume = "376",
pages = "7--12",
journal = "International Journal of Pharmaceutics",
issn = "0378-5173",
number = "1-2",

}

Wilson, CG, O'Mahony, B, Connolly, SM, Cantarini, MV, Farmer, MR, Dickinson, PA, Smith, RP & Swaisland, HC 2009, 'Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib?' International Journal of Pharmaceutics, vol. 376, no. 1-2, pp. 7-12. https://doi.org/10.1016/j.ijpharm.2009.04.008

Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib? / Wilson, C. G.; O'Mahony, B.; Connolly, S. M.; Cantarini, M. V. ; Farmer, M.R.; Dickinson, P.A.; Smith, R. P.; Swaisland, H.C.

In: International Journal of Pharmaceutics, Vol. 376, No. 1-2, 06.07.2009, p. 7-12.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib?

AU - Wilson, C. G.

AU - O'Mahony, B.

AU - Connolly, S. M.

AU - Cantarini, M. V.

AU - Farmer, M.R.

AU - Dickinson, P.A.

AU - Smith, R. P.

AU - Swaisland, H.C.

PY - 2009/7/6

Y1 - 2009/7/6

N2 - 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 exposure 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 [111In]–DTPA together with 240 mL [99mTc]-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), resulting in an earlier colonic arrival time (181 min vs 244 min). Mean plasma Cmax was lower (99.2 ng/mL vs 116 ng/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.

AB - 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 exposure 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 [111In]–DTPA together with 240 mL [99mTc]-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), resulting in an earlier colonic arrival time (181 min vs 244 min). Mean plasma Cmax was lower (99.2 ng/mL vs 116 ng/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.

KW - gefitinib

KW - Iressa®

KW - gastrointestinal transit

KW - gamma scintigraphy

U2 - 10.1016/j.ijpharm.2009.04.008

DO - 10.1016/j.ijpharm.2009.04.008

M3 - Article

VL - 376

SP - 7

EP - 12

JO - International Journal of Pharmaceutics

T2 - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1-2

ER -