Eur J Clin Pharmacol (2002) 58: 119–125
DOI 10.1007/s00228-002-0444-7
PHARMACOKINETICS AND DISPOSITION
B.S. Schug Æ E. Brendel Æ M. Wonnemann Æ D. Wolf
M. Wargenau Æ A. Dingler Æ H.H. Blume
Dosage form-related food interaction observed in a marketed
once-daily nifedipine formulation after a high-fat American breakfast
Received: 12 October 2001 / Accepted in revised form: 12 February 2002 / Published online: 17 April 2002
Ó Springer-Verlag 2002
Abstract Objective: Objective of the study was the
comparison of two nifedipine sustained-release products
marketed in Europe. Maximum plasma concentration
(Cmax) and area under the plasma-concentration curve
(AUC) values were derived after administration of single
doses (60 mg) of test product and reference product,
both approved for once-a-day administration, to 24
healthy male volunteers either after an overnight fast or
immediately after a high-fat American breakfast. The
study was performed with a randomised, non-blinded,
four-period crossover design. Within- and between-
product comparisons were determined for fed versus
fasted administration considering bioavailability and
tolerability of all treatments. Furthermore, in vitro dis-
solution characteristics of both products were evaluated.
Methods: Plasma samples were assayed using a liquid
chromatography-mass spectrometry method, and re-
sulting pharmacokinetic parameters were determined
model independently according to international re-
quirements and the current European guidelines.
Results: Under fasted conditions the comparison of test
and reference products showed a similar extent of bio-
availability with a mean ratio of AUC(0–1) of 99% [95%
confidence interval (CI) 86%, 114%], but significantly
higher Cmax values resulting in a mean ratio of 169%
B.S. Schug (&) Æ M. Wonnemann Æ D. Wolf Æ H.H. Blume
SocraTec R&D GmbH,
Feldbergstrasse 59,
61440 Oberursel, Germany
E-mail: barbara.schug@socratec-pharma.de
Phone: +49-6171-585711
Fax: +49-6171-585725
E. Brendel
Bayer AG, Institute of Clinical Pharmacology,
Aprather Weg, 42096 Wuppertal, Germany
M. Wargenau
M.A.R.C.O., Institute for Biomedical Statistics,
Markenstrasse 5–13, 40227 Düsseldorf, Germany
A. Dingler
Bayer AG, Department of Quality Control Development,
51368 Leverkusen, Germany
(95% CI 139%, 206%). Accordingly, mean residence
time and half-value duration values were smaller for the
test product than the reference product. Under fed
conditions, a pronounced food effect could be observed
for the test product resulting in a pronounced increase of
Cmax values. The affiliating point estimate was calculated
as 340% with a 95% CI of 279%, 413%. However no
remarkable influence of food intake was observed for the
reference product.
Conclusion: Under fasting conditions the modi-
fied-release characteristics of the test product are less
pronounced than the reference product. No relevant
impact of food intake could be observed for the refer-
ence product when switching from fasted to fed state,
whereas a significant loss of modified-release characteri-
stics could be detected for the test product under fed
conditions resulting in much higher maximum concen-
trations. Such a phenomenon has been described in
literature as ‘‘dose-dumping effect’’.
Keywords Food interaction Æ Nifedipine Æ High-fat
breakfast
Introduction
Modified-release dosage forms are developed in order to
reduce dosing frequency, to attain better therapeutic
compliance or to decrease maximum plasma concen-
trations in case of concentration-related side effects. For
nifedipine modified-release dosage forms for twice-daily
administration were developed several years ago, fol-
lowed by Adalat OROS as once-daily dosage form [1].
The release characteristics of this osmotically driven
Gastrointestinal Therapeutic System (GITS) follow a
zero-order kinetic for almost the complete release time
of approximately 24 h [2]. The general robustness of the
modified-release characteristics of this dosage form
against concomitant food intake could be demonstrated
in vivo for other drug compounds such as methylphen-
idate, pseudoephedrine and brompheniramine [3, 4].
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Meanwhile, several generic formulations intended for
once-daily administration have entered the European
market. Following the regulatory requirements in
Europe, such generic products are expected to exhibit
comparable in vivo performance as the innovator
product after single oral dosing under fasted and fed
conditions as well as after multiple dosing [5, 6, 7].
The generic nifedipine products from the European
market intended for once-daily administration comprise
a variety of galenic principles: e.g. monolithic tablets
with an erosive modified-release matrix on polymer basis
either with or without an acid-resistant coating. Earlier
investigations of such dosage forms revealed significant
problems in bioavailability especially when co-adminis-
tered with food, however type and extent of food-
sensitivity obviously depended on the underlying galenic
principle. In these cases in vitro dissolution profiles gave
indications for potential food interactions, as the dis-
solution profiles were strongly pH dependent.
The test product, which is approved as a generic
formulation for once-daily administration, represents a
completely different galenic principle consisting of a
capsule containing several mini-tablets. Such multiple-
unit dosage forms generally are at a lower risk for food
interactions especially when their release characteristics
are independent from pH.
It was the intention of this study to investigate the
in vitro dissolution behaviour and the in vivo perfor-
mances of the test product and the GITS system of the
reference product in a comparative evaluation. Special
focus of the in vivo study was set on the impact of
concomitant food intake on bioavailability.
Primary objective of the in vivo study was the com-
parison of the pharmacokinetic parameters maximum
plasma concentration (Cmax) and area under the plasma-
concentration curve (AUC) of nifedipine after 60-mg
single doses of both products administered either after
an overnight fast or immediately after a high-fat
American breakfast. In addition, within-product com-
parisons of fed versus fasted states were performed for
Cmax and AUC. Furthermore, safety and tolerability of
both treatments were determined.
Methods
In vitro dissolution
The test product (Nifedicron, Production: Pharmatec Internation-
al, Milano, Italy, Approval: Searle farmaceutici, Milano, Italy) and
the reference product (Adalat OROS, Bayer AG, Leverkusen,
Germany) were investigated with identical dissolution conditions in
order to allow comparability. As the osmotically driven reference
product was robust under all the conditions tested during the
method-development phase, the in vitro dissolution method was
optimised by focusing on the capsule/mini-tablet formulation.
After method optimisation dissolution was performed using a
standardised compendial paddle apparatus with a rotation speed of
50 rpm (n=6 for each value) using different buffer systems: 0.1 N
HCl (pH 1), acetate buffer pH 4.5, phosphate buffer pH 6.8 and
phosphate buffer pH 8.0. All investigations were performed in
900 ml buffer media containing 1% sodium dodecyl sulfate (SDS)
in order to achieve sink conditions. Furthermore, complete pro-
tection from daylight was observed during the entire investigation.
Clinical study
The study was performed following a randomised, non-blinded,
four-way crossover design in 24 healthy, male subjects with wash-
out periods of at least 1 week between the treatment periods. Each
volunteer received single oral doses of the test product or of the
reference product containing 60 mg nifedipine each, both admin-
istered either after an overnight fast or immediately after a high-fat
breakfast. Within pre-examination the general health status of the
subjects was determined by anamnesis and physical examination
including blood pressure and pulse rate measurements, a 12-lead
electrocardiogram (ECG), haematological and clinical chemical
parameters as well as urinalysis. Inclusion and exclusion criteria
were chosen to preserve the safety of the volunteers and to optimise
standardisation of absorption conditions. Alcohol and drug tests
were performed prior to dosing. The entire clinical study was
performed in accordance with International Conference of
Harmonization-Good Clinical Practices requirements and the
current version of the Declaration of Helsinki. Prior to the start of
the study approval was obtained from the responsible ethics com-
mittee according to German Drug Law (Ethics Committee of the
Medicinal Chamber of Thuringia, Jena, Germany).
Only healthy male, Caucasian subjects who had given their
written consent were enrolled in the study. A total of 24 male,
Caucasian subjects entered the study, none of them dropped out.
Thus, all subjects completed the four treatment periods of the study
and were used for pharmacokinetic and safety analysis. Mean age
of these 24 subjects was 29 years (range 22–40 years), mean weight
73.8 kg (range 62–89 kg) and mean height 179.9 cm (range 168–
196 cm). Average body mass index was calculated as 22.8 kg/m2
(range 19.9–26.4 kg/m2).
Volunteers were hospitalised for 12 h prior to and until 48 h
after dosing. Both products were given under standardised condi-
tions together with 150 ml non-carbonated water either after an
overnight fast of 12 h or immediately after finishing a high-fat
breakfast served after the 12 h fasting period. The high-fat break-
fast consisted of 180 ml apple juice, 240 ml full-cream milk (3.5%
fat), two slices of wheat toast (25 g each), 20 g butter, one slice of
Gouda cheese (45% fat in dry mass, 30 g), one slice of bacon
(35 g), 120 g potatoes, one fried egg and 10 g fat for roasting. After
administration, the subjects remained in supine position for an-
other 4 h. Subsequently, a standardised meal was served 4 h after
dosing to all volunteers followed by meals 7 h and 11 h after ad-
ministration. Conditions were chosen in accordance with interna-
tional requirements for food-interaction studies [7]. Blood samples
for the determination of nifedipine pharmacokinetics were with-
drawn over a total of 48 h after dosing (0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,
10, 12, 15, 24, 30, 36 and 48 h post-administration). Plasma
was prepared under protection from daylight due to the photo-
instability of nifedipine, deep frozen and stored below –20°C.
For safety reasons vital signs, ECGs and laboratory parameters
were repeatedly determined during the hospitalisation phase.
Subjective well-being was surveyed by active requesting for adverse
events in a non-leading manner and by documentation of sponta-
neous reporting. Adverse events as provided by the volunteers were
classified according to severity and potential relation towards the
study drug. Any concomitant medication within the course of the
study was documented. Blood (4 ml) was taken for each phar-
macokinetic sample and 15 ml for each determination of labora-
tory values, resulting in a total amount of 482 ml blood withdrawn
from each volunteer.
Bioanalytical method
Plasma samples were assayed for unchanged nifedipine using a
selective liquid chromatography (LC)-mass spectrometry (MS)/MS
method validated according to international requirements [8]. The
limit of quantification (LOQ) was 0.1 lg/l. Quality control (QC)