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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 (95% CI 139%, 206%). Accordingly, mean residence
comparison of two nifedipine sustained-release products time and half-value duration values were smaller for the
marketed in Europe. Maximum plasma concentration test product than the reference product. Under fed
(Cmax) and area under the plasma-concentration curve conditions, a pronounced food effect could be observed
(AUC) values were derived after administration of single for the test product resulting in a pronounced increase of
doses (60 mg) of test product and reference product, Cmax values. The affiliating point estimate was calculated
both approved for once-a-day administration, to 24 as 340% with a 95% CI of 279%, 413%. However no
healthy male volunteers either after an overnight fast or remarkable influence of food intake was observed for the
immediately after a high-fat American breakfast. The reference product.
study was performed with a randomised, non-blinded, Conclusion: Under fasting conditions the modi-
four-period crossover design. Within- and between- fied-release characteristics of the test product are less
product comparisons were determined for fed versus pronounced than the reference product. No relevant
fasted administration considering bioavailability and impact of food intake could be observed for the refer-
tolerability of all treatments. Furthermore, in vitro dis- ence product when switching from fasted to fed state,
solution characteristics of both products were evaluated. whereas a significant loss of modified-release characteri-
Methods: Plasma samples were assayed using a liquid stics could be detected for the test product under fed
chromatography-mass spectrometry method, and re- conditions resulting in much higher maximum concen-
sulting pharmacokinetic parameters were determined trations. Such a phenomenon has been described in
model independently according to international re- literature as ‘‘dose-dumping effect’’.
quirements and the current European guidelines.
Results: Under fasted conditions the comparison of test Keywords Food interaction Æ Nifedipine Æ High-fat
and reference products showed a similar extent of bio- breakfast
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% Introduction

B.S. Schug (&) Æ M. Wonnemann Æ D. Wolf Æ H.H. Blume


Modified-release dosage forms are developed in order to
SocraTec R&D GmbH, reduce dosing frequency, to attain better therapeutic
Feldbergstrasse 59, compliance or to decrease maximum plasma concen-
61440 Oberursel, Germany trations in case of concentration-related side effects. For
E-mail: barbara.schug@socratec-pharma.de nifedipine modified-release dosage forms for twice-daily
Phone: +49-6171-585711
Fax: +49-6171-585725 administration were developed several years ago, fol-
lowed by Adalat OROS as once-daily dosage form [1].
E. Brendel
Bayer AG, Institute of Clinical Pharmacology,
The release characteristics of this osmotically driven
Aprather Weg, 42096 Wuppertal, Germany Gastrointestinal Therapeutic System (GITS) follow a
zero-order kinetic for almost the complete release time
M. Wargenau
M.A.R.C.O., Institute for Biomedical Statistics, of approximately 24 h [2]. The general robustness of the
Markenstrasse 5–13, 40227 Düsseldorf, Germany modified-release characteristics of this dosage form
A. Dingler against concomitant food intake could be demonstrated
Bayer AG, Department of Quality Control Development, in vivo for other drug compounds such as methylphen-
51368 Leverkusen, Germany idate, pseudoephedrine and brompheniramine [3, 4].
120

Meanwhile, several generic formulations intended for in order to achieve sink conditions. Furthermore, complete pro-
once-daily administration have entered the European tection from daylight was observed during the entire investigation.
market. Following the regulatory requirements in
Europe, such generic products are expected to exhibit Clinical study
comparable in vivo performance as the innovator
The study was performed following a randomised, non-blinded,
product after single oral dosing under fasted and fed four-way crossover design in 24 healthy, male subjects with wash-
conditions as well as after multiple dosing [5, 6, 7]. out periods of at least 1 week between the treatment periods. Each
The generic nifedipine products from the European volunteer received single oral doses of the test product or of the
market intended for once-daily administration comprise reference product containing 60 mg nifedipine each, both admin-
istered either after an overnight fast or immediately after a high-fat
a variety of galenic principles: e.g. monolithic tablets breakfast. Within pre-examination the general health status of the
with an erosive modified-release matrix on polymer basis subjects was determined by anamnesis and physical examination
either with or without an acid-resistant coating. Earlier including blood pressure and pulse rate measurements, a 12-lead
investigations of such dosage forms revealed significant electrocardiogram (ECG), haematological and clinical chemical
problems in bioavailability especially when co-adminis- parameters as well as urinalysis. Inclusion and exclusion criteria
were chosen to preserve the safety of the volunteers and to optimise
tered with food, however type and extent of food- standardisation of absorption conditions. Alcohol and drug tests
sensitivity obviously depended on the underlying galenic were performed prior to dosing. The entire clinical study was
principle. In these cases in vitro dissolution profiles gave performed in accordance with International Conference of
indications for potential food interactions, as the dis- Harmonization-Good Clinical Practices requirements and the
current version of the Declaration of Helsinki. Prior to the start of
solution profiles were strongly pH dependent. the study approval was obtained from the responsible ethics com-
The test product, which is approved as a generic mittee according to German Drug Law (Ethics Committee of the
formulation for once-daily administration, represents a Medicinal Chamber of Thuringia, Jena, Germany).
completely different galenic principle consisting of a Only healthy male, Caucasian subjects who had given their
written consent were enrolled in the study. A total of 24 male,
capsule containing several mini-tablets. Such multiple- Caucasian subjects entered the study, none of them dropped out.
unit dosage forms generally are at a lower risk for food Thus, all subjects completed the four treatment periods of the study
interactions especially when their release characteristics and were used for pharmacokinetic and safety analysis. Mean age
are independent from pH. of these 24 subjects was 29 years (range 22–40 years), mean weight
It was the intention of this study to investigate the 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
in vitro dissolution behaviour and the in vivo perfor- (range 19.9–26.4 kg/m2).
mances of the test product and the GITS system of the Volunteers were hospitalised for 12 h prior to and until 48 h
reference product in a comparative evaluation. Special after dosing. Both products were given under standardised condi-
focus of the in vivo study was set on the impact of tions together with 150 ml non-carbonated water either after an
overnight fast of 12 h or immediately after finishing a high-fat
concomitant food intake on bioavailability. breakfast served after the 12 h fasting period. The high-fat break-
Primary objective of the in vivo study was the com- fast consisted of 180 ml apple juice, 240 ml full-cream milk (3.5%
parison of the pharmacokinetic parameters maximum fat), two slices of wheat toast (25 g each), 20 g butter, one slice of
plasma concentration (Cmax) and area under the plasma- 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
concentration curve (AUC) of nifedipine after 60-mg administration, the subjects remained in supine position for an-
single doses of both products administered either after other 4 h. Subsequently, a standardised meal was served 4 h after
an overnight fast or immediately after a high-fat dosing to all volunteers followed by meals 7 h and 11 h after ad-
American breakfast. In addition, within-product com- ministration. Conditions were chosen in accordance with interna-
parisons of fed versus fasted states were performed for tional requirements for food-interaction studies [7]. Blood samples
for the determination of nifedipine pharmacokinetics were with-
Cmax and AUC. Furthermore, safety and tolerability of drawn over a total of 48 h after dosing (0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8,
both treatments were determined. 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
Methods were repeatedly determined during the hospitalisation phase.
Subjective well-being was surveyed by active requesting for adverse
In vitro dissolution events in a non-leading manner and by documentation of sponta-
neous reporting. Adverse events as provided by the volunteers were
The test product (Nifedicron, Production: Pharmatec Internation- classified according to severity and potential relation towards the
al, Milano, Italy, Approval: Searle farmaceutici, Milano, Italy) and study drug. Any concomitant medication within the course of the
the reference product (Adalat OROS, Bayer AG, Leverkusen, study was documented. Blood (4 ml) was taken for each phar-
Germany) were investigated with identical dissolution conditions in macokinetic sample and 15 ml for each determination of labora-
order to allow comparability. As the osmotically driven reference tory values, resulting in a total amount of 482 ml blood withdrawn
product was robust under all the conditions tested during the from each volunteer.
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 Bioanalytical method
standardised compendial paddle apparatus with a rotation speed of
50 rpm (n=6 for each value) using different buffer systems: 0.1 N Plasma samples were assayed for unchanged nifedipine using a
HCl (pH 1), acetate buffer pH 4.5, phosphate buffer pH 6.8 and selective liquid chromatography (LC)-mass spectrometry (MS)/MS
phosphate buffer pH 8.0. All investigations were performed in method validated according to international requirements [8]. The
900 ml buffer media containing 1% sodium dodecyl sulfate (SDS) limit of quantification (LOQ) was 0.1 lg/l. Quality control (QC)