Comparison of two marketed nifedipine modified-release formulations: An exploratory clinical food interaction study (original) (raw)
Related papers
European Journal of Clinical Pharmacology, 2002
Objective: Objective of the study was the comparison of two nifedipine sustained-release products marketed in Europe. Maximum plasma concentration (C max) 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 betweenproduct comparisons were determined for fed versus fasted administration considering bioavailability and tolerability of all treatments. Furthermore, in vitro dissolution characteristics of both products were evaluated. Methods: Plasma samples were assayed using a liquid chromatography-mass spectrometry method, and resulting pharmacokinetic parameters were determined model independently according to international requirements and the current European guidelines. Results: Under fasted conditions the comparison of test and reference products showed a similar extent of bioavailability with a mean ratio of AUC (0-1) of 99% [95% confidence interval (CI) 86%, 114%], but significantly higher C max values resulting in a mean ratio of 169% (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 C max 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 modified-release characteristics of the test product are less pronounced than the reference product. No relevant impact of food intake could be observed for the reference product when switching from fasted to fed state, whereas a significant loss of modified-release characteristics could be detected for the test product under fed conditions resulting in much higher maximum concentrations. Such a phenomenon has been described in literature as ''dose-dumping effect''.
Journal of Bioequivalence & Bioavailability, 2021
Purpose: The nifedipine immediate-release formulation has been associated with reflex sympathetic nervous system activation leading to several adverse effects such as flushing, tachycardia, worsening myocardial ischemia, and cerebrovascular ischemia. Development of a modified-release formulation represents a challenge, particularly the development of a once-daily formulation. Therefore, these studies evaluated the pharmacokinetic profile of a new 30-mg Extended-Release Nifedipine Tablets in Mexican population. The formulation [ANHITEN-A ® ] was manufactured by Ultra Laboratorios S.A. de C.V. [Jalisco, Mexico] with number of batch 9JN134A and expiration date September 2021. Methods: They were a single-center, single-dose, open-label, one-way trial. Study A was evaluated at a fasted state [at least 10 hours] and Study B was evaluated at a fed state [30 minutes before dosing]. The studies population were 14 [per study] healthy male and female adult [aged 18-55 year] Mexican volunteers. These trials comprised one day treatment period and a 7-day wash-out period before final evaluation. Serial blood samples were collected before and after dosing and evaluated by UPLC-MS/MS. The bioavailability of the 30-mg Extended-Release Nifedipine Tablets was assessed Non-Compartmental Pharmacokinetic analysis and in accordance with local law regulation. Tolerability and safety were evaluated throughout the research. Findings: The non-compartmental model [NCA] pharmacokinetic parameters obtained are mean [SD] C max 43.95 [16.082] ng/mL and 100.71 [42.441] ng/mL, t max 7.2 [3.326] h and 4.7 [2.343] h, AUC 0-∞ 739.100 [224.436] ng h/ mL and 676.605 [355.791] ng h/mL, t 1/2 8.1 h [2.081] and 5.6 [2.174] h, V d /F 526.46 [238.67] L and 434.35 [218.15] L and CL/F 44.49 [15.98] L/h and 56.97 [32.03] L/h for fasted [trial A] and fed [trial B] state, respectively. C max and t ½ values showed statistically significant differences [p<0.05] between studies, with the higher C max values for the fed state [trial B] and higher t ½ values for the fasted state [trial A], data correlated with dose-dumping effect. Only two Adverse Events [AEs] were reported in trial A, headache, in trial B, two AEs of headache were reported. Implications: The pharmacokinetic modifications observed in trial B [compared to trial A] may be therapeutically relevant; plasma concentrations at 24 hours in studies A and B show that dosing after food intake decreases the maintained time of the Minimum Effective plasma Concentration with a duration of 24 hours in trial A and 12 hours in trial B. Variations in plasmatic concentrations associated with the dosage condition; higher C max values for the fed state [trial B] and higher t½ values for the fasted state [trial A], did not impact the presence of adverse events, that was similar between studies.
European Journal of Drug Metabolism and Pharmacokinetics, 1997
The pharmacokinetic parameters (AVC, Cmax, Tmax. and t1/2) of nifedipine following single oral administration of a 10 mg capsule of test product were compared to those of the same amount of a reference product. The two products in capsule form were administered according to a randomized two-way crossover design in 22 healthy male volunteers. Nifedipine plasma concentrations were determined using a rapid, sensitive and precise high performance liquid chromatography (HPLC) method with ultraviolet (UV) detection at 235 nm. The parametric 90% confidence intervals of the mean value of the ratio [Myogard® (test product) /Adalat® (reference product)] for pharmacokinetic parameters were 0.90-1.08,0.80-1.07, and 0.93-1.12 for AUCo--, C max and lIn, respectively. In each case, values were within the acceptable bioequivalence range of 0.8-1.25. Distribution free point estimate for the difference in expected medians of Tmax of the two products (Myogard®-Adalat®) was 0.00 h with a 90% confidence interval of 0.00-0.13 which is greater than the accepted bioequivalence of ± 0.12. The kinetic parameters were comparable to those reported for nifedipine, and no statistically significant differences were found in any of them when comparing the two products by analysis of variance (ANOVA) on log-transformed data. Thus, the two products could be considered bioequivalent regarding absorption rate (C max and Tmax), extent of absorption (Cmax and AUC) and elimination (lIn) Please send reprint requests to :
Acta Pharmaceutica, 2015
With the increased reliance on in vitro dissolution testing as an indicator of in vivo drug behavior and the trend towards the in silico modeling of dosage form performance, the need for bioperformance dissolution methodology development has been enhanced. Determination of the in vivo drug delivery profile is essential for the bioperformance dissolution test development and in vitro/in vivo correlation modeling, as well as the understanding of absorption mechanisms. The aim of this study was to compare different methods in terms of their usefulness and applicability in deciphering in vivo delivery of nifedipine administered in modified release dosage forms. A detailed survey of publications on nifedipine pharmacokinetics was done and used to identify the magnitude of food effect. In vitro dissolution testing was performed under various experimental conditions. Obtained results indicate the potential for using the developed in silico model coupled with discriminative in vitro dissolution data for identification of the in vivo drug product behavior.
Clinical Drug Investigation, 2005
To investigate the relative bioavailability and bioequivalence, in fasting and fed conditions, of repeated doses of two omeprazole enteric-coated formulations in healthy volunteers. Open label, single-centre study consisting of two consecutive randomised, two-way crossover trials (a fasting trial and a fed trial). Each trial consisted of two 7-day treatment periods in which subjects received one daily dose of the test (Ompranyt((R))) or reference (Mopral((R))) formulations. At day 7 and day 14 (fasting trial), products were administered in fasting conditions and blood samples were taken for omeprazole plasma assay over 12 hours. At day 21 and day 28 (fed trial), products were administered after a standard high-calorie and high-fat meal and 12-hour blood samples taken. Omeprazole plasma concentrations were quantified by a validated method using a reverse-phase high performance liquid chromatography with UV detection (HPLC-UV). Twenty-four subjects were enrolled and 23 completed the study. Under fasting conditions, the mean +/- SD maximum omeprazole plasma concentration (C(max)) was 797 +/- 471 mug/L for Ompranyt((R)) and 747 +/- 313 mug/L for Mopral((R)) with a point estimate (PE) of 1.01 and a 90% confidence interval (CI) of 0.88, 1.16. The mean +/- SD area under the plasma concentration curve from administration to last observed concentration (AUC(0-12)) was 1932 +/- 1611 mug . h/L and 1765 +/- 1327 mug . h/L for Ompranyt((R)) and Mopral((R)), respectively (PE = 1.09; 90% CI 0.95, 1.25). In the presence of food, the C(max) was 331 +/- 227 mug/L and 275 +/- 162 mug/L (PE = 1.21; 90% CI 0.92, 1.59) and AUC(0-12) was 1250 +/- 966 mug . h/L and 1087 +/- 861 mug . h/L (PE = 1.16; 90% CI 0.92, 1.47) for Ompranyt((R)) and Mopral((R)), respectively. Bioequivalence of the formulations in the fasting condition was demonstrated both for AUC(0-12) and for C(max) because the 90% CI lay within the acceptance range of 0.80-1.25. In contrast with the fasting condition, there were significant reductions in rate (C(max)) and extent (AUC(0-12)) of systemic exposure when test and reference formulations were administered with food. The food effect was more marked with Mopral((R)) than with Ompranyt((R)), and the bioequivalence criterion was not fulfilled because the 90% CI fell out of the acceptance range of 0.80, 1.25, for both C(max) and AUC(0-12). The two formulations were similarly well tolerated. Bioequivalence of Ompranyt((R)) (test formulation) and Mopral((R)) (reference) formulations was demonstrated after repeated dosing in the fasting condition. Following a high-calorie and high-fat meal, there was a significant reduction in rate and extent of systemic exposure for both products, with Ompranyt((R)) being less affected than Mopral((R)) by the presence of food.
European Journal of Pharmaceutical Sciences, 2006
Artificial digestive system Acetaminophen Food impact Immediate release tablets Level A in vitro/in vivo correlation Abbreviations: ADS, artificial digestive system BCS, biopharmaceutical classification system FASSIF, fasted state simulated intestinal fluid FD, fraction of dose FESSIF, fed state simulated intestinal fluid GI, gastro-intestinal IR, immediate release IVIVC, in vitro/in vivo correlation kcal, kilocalory a b s t r a c t The first purpose of this study was to simulate the impact of food intake on drug release and absorption in vivo using a novel in vitro system which mimics the gastro-intestinal (GI) tract in man. The drug studied was acetaminophen in the form of immediate release (IR) tablets. The second purpose was to establish a level A in vitro/in vivo correlation that could predict the bioavailability of a drug instead of using difficult, time-consuming and expensive in vivo bioequivalence studies. The artificial digestive system was used to estimate the availability of acetaminophen IR tablets for absorption in fasted and fed states. The same study was performed in vivo under similar conditions. A comparison study was carried out between the classical and the novel methods to estimate the efficacy of the new in vitro system to simulate the influence of food on drug release and absorption in vivo. A level A in vitro/in vivo correlation was established with a correlation coefficient of 0.9128 and 0.9984 in the fasted and fed states, respectively. Compared to USP II method, the novel in vitro model demonstrated a high level of efficacy in mimicking the behaviour of acetaminophen IR tablets in vivo in fasted and fed states.
Antimicrobial Agents and Chemotherapy, 2013
PA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios of C max and AUC 0–∞ revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The median T max in the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the median T max was 4 h for the 50- and 200-mg doses and 6.5 h for the 1,0...
Molecular Pharmaceutics, 2004
The purpose of this study is to test the hypothesis that rapidly dissolving immediaterelease (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of C max and AUC inf were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of C max and AUC inf were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for C max and AUC inf were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.