A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine.
OBJECTIVE
To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients.


METHODS
In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon(®) SR) in tablet matrix (0-5 % w/w) and coating (0-12 mg/cm(2)).


RESULTS
PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC0-2h, relative to AUC0-2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm(2), respectively. Corresponding AUC0-last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %).


CONCLUSIONS
Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm(2).
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. b.jacobs@nki.nl.|Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. b.jacobs@nki.nl.
Bart A W
BA
Jacobs
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Jelte
J
Meulenaar
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Hilde
H
Rosing
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Dick
D
Pluim
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Matthijs M
MM
Tibben
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Niels
N
de Vries
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Bastiaan
B
Nuijen
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Alwin D R
AD
Huitema
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Division of Pharmaco-epidemiology and Clinical Pharmacology, Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
Jos H
JH
Beijnen
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Division of Pharmaco-epidemiology and Clinical Pharmacology, Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
Jan H M
JH
Schellens
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Serena
S
Marchetti
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000069287:Capecitabine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D065546:Drug Liberation; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D015507:Drugs, Investigational; D000069287:Capecitabine
Cancer; Capecitabine; Extended release; Pharmacokinetics; Phase 0