Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects.

WHAT IS KNOWN AND OBJECTIVE: Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. METHODS: A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18-45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h ) and the maximal serum concentration (Cmax ) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax , AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8-1·25). RESULTS AND DISCUSSION: Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8-1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. WHAT IS NEW AND CONCLUSION: These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs.

Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: a Spanish group for research on sarcomas (GEIS) study.

BACKGROUND: This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma. METHODS: Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m(2) respectively). A 3 + 3 dose escalation design with cohorts of 3-6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted. RESULTS: Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m(2) and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m(2). Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro. CONCLUSIONS: RD was sorafenib 400 mg bid plus ifosfamide 6 g/m(2), allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing.

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors.

PURPOSE: Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin. METHODS: Patients with advanced solid tumors were treated with 75 mg/m(2) cisplatin on day 1 and 1,250 mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400 mg twice daily was started and continued throughout the complete treatment cycles without interruption. RESULTS: Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug-drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC(0-72) and C (max) of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C (max) of gemcitabine by 12 and 21%. CONCLUSIONS: Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400 mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.

Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors.

BACKGROUND: Blocking both receptor and ligand of the vascular endothelial growth factor (receptor) VEGF(R) pathway might be feasible and increase antitumor activity. This phase I study investigated telatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, combined with bevacizumab, in adults with solid tumors. PATIENTS AND METHODS: Twenty-six patients were treated in successive cohorts with telatinib (twice-daily continuously, 450-900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed. RESULTS: Most frequent adverse events were pain, nausea, voice changes and fatigue. Five dose-limiting toxicities (DLTs) occurred: hypertension (cohort I and II), bowel perforation, lipase increase and atrial flutter (cohort III). Cumulative toxicity resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. Twelve patients had stable disease (clinical benefit 46%). EPC and SDF-1α levels increased during monotherapy telatinib. CONCLUSIONS: Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.

Differences in bioavailability between 60 mg of nifedipine osmotic push-pull systems after fasted and fed administration.

OBJECTIVES: This study was designed to evaluate and compare the bioavailability of two osmotically active formulations of 60 mg nifedipine, Gen-Nifedipine extended release Test tablets (Genpharm ULC, Etobicoke, ON, Canada) and Adalat XL Reference tablets (Bayer Healthcare AG, Leverkusen, Germany) after single dose fasted and fed administration. MATERIALS AND METHODS: The study was performed following a 4-period crossover design with both investigational products obtained from marketed batches. The complete pharmacokinetic evaluation was carried out in 26 healthy male subjects with a median age of 29.5 years (range 18 - 44 years), mean weight of 79.7 kg (range 66.0 - 97.5 kg), and a mean body mass index (BMI) of 24.1 kg/m(2) (range 22.1 - 26.9 kg/m(2)). Tablets were administered with tap water either under fasting conditions or immediately following a high-fat, high-calorie breakfast. Blood samples were taken predose and at pre-defined time points until 48 h post dosing. Samples were protected from light during handling and frozen until analysis. A validated LC-MS/MS method was used for the quantification of nifedipine in plasma samples. All kinetic parameters were determined model-independently for each treatment directly from measured concentrations. Monitoring of subject safety was accomplished by routine monitoring of blood pressure, heart rate and probing for adverse events. RESULTS: In-vitro dissolution curves show later onset and considerably lower quantity of nifedipine release from Test compared to Reference tablets. Under fasting conditions total and maximum exposure, represented by geometric mean AUC(0-tlast)- and C(max)-values, respectively were 466.7 h*ng/ml (AUC(0-tlast)) and 21.9 ng/ml (C(max)) for Test and 507.8 h*ng/ml (AUC(0-tlast)) and 22.0 ng/ml (C(max)) for Reference tablets. However, the Test product exhibited a notably longer lag-time and less rapid onset of absorption than the Reference tablets. Moreover, the plateau phase is maintained for about 14 hours on Test but for almost 20 hours on Reference. Point estimates (PE) and associated 90% confidence intervals (CI) were determined as 91.8% and 79.9 - 105.5% for AUC(0-tlast), as well as 99.8% and 88.6 - 112.4% for C(max). Larger differences were found for AUC(0-9h) (PE: 54.8%; CI: 45.8 - 65.5%) determined as parameter for early exposure. Under fed conditions, although the mean plasma concentration time curves look similar in shape, concentrations of Test compared to Reference tablets are considerably lower at all time points until 36 hours after dosing. Again the lag time in onset of drug absorption is notably longer for the Test product. Both, total and maximum exposure, represented by geometric mean values for AUC(0-tlast) and C(max), were considerably lower (differences also statistically significant) after administration of Test with 481.8 h*ng/ml for AUC(0-tlast) and 25.3 ng/ml for C(max) in comparison to Reference tablets with 595.9 h*ng/ml for AUC(0-tlast) and 31.9 ng/ml for C(max). Test/Reference point estimates (PE) and associated 90% confidence intervals (CI) were determined as 80.7% and 73.7 - 88.5% for AUC(0-tlast), as well as 79.6% and 70.3 - 90.0% for C(max). Differences were also even more expressed for AUC(0-9h) (PE: 54.9%; CI: 47.4 - 63.5%) determined as parameter for early exposure. CONCLUSION: The results indicate that although both products are osmotic release systems they are not bioequivalent according to the accepted standards. This difference between both osmotic delivery systems might be substantiated by the fact that the core of the Test product is designed as a monolayer system (containing both, the active ingredient and the osmotic component) while Reference tablets consist of two separate layers. The observed pharmacokinetic differences may have an impact on blood pressure control in patients and thus, should be kept in mind when switching during treatment.

Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial.

Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m(2) IV for up to six 3-week cycles. Sorafenib 400mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C(max) (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.

Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib.

PURPOSE: This single-centre, open-label, phase I dose-escalation study was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafenib, a multi-kinase inhibitor, combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. PATIENTS AND METHODS: In an initial dose-escalation phase, patients received irinotecan 125 mg/m(2) and sorafenib 100, 200 and 400 mg twice daily (bid) (cohorts 1-3). In an extended phase, colorectal cancer (CRC) patients received fixed-dose irinotecan 140 mg and sorafenib 400 mg bid (cohort 4). RESULTS: Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Frequent drug-related adverse events were gastrointestinal symptoms, dermatological reactions and constitutional symptoms. The maximum tolerated dose was not reached. Generally, concomitant administration of irinotecan had no impact on the PK of sorafenib. Sorafenib 100 or 200 mg bid had no impact on the PK of irinotecan or its metabolite SN38. In contrast, sorafenib 400 mg bid significantly increased irinotecan and SN38 exposures; however, this was not associated with increased toxicities. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1-3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a K(i) value of 2.7 micromol/l. CONCLUSION: Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m(2) or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended.

Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.

BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union.

The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.

Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours.

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast.

AIMS: The aim of this study was to investigate the effect of concomitant food intake on the bioavailability of two nifedipine containing modified release dosage forms for once daily administration. The clinical study was performed to investigate the in vivo relevance of pH-dependent differences in the in vitro release properties of the two dosage forms. METHODS: This was a randomized, open, 4-way crossover study in 24 healthy, male subjects. Following an overnight fast of 12 h single doses of Adalat OROS or Slofedipine XL were administered either in the fasted state or immediately after a high fat American breakfast. Nifedipine plasma concentrations in samples obtained until 48 h after drug administration were determined using a validated LC-MS/MS method. Calculation of pharmacokinetic parameters was conducted model-independently. The two dosage forms as well as the two administration conditions were compared by calculating point estimates and 90% confidence intervals for the relevant pharmacokinetic parameters. In vitro dissolution tests were performed using a paddle apparatus 3 acc. USP, a pharmacopoeial dissolution system consisting of reciprocating cylinders in flat-bottomed glass vessels, with various buffer systems covering the entire physiological pH-range of the gastrointestinal tract. RESULTS: After fasted administration the extent of bioavailability of nifedipine as characterized by AUC(0,infinity) was slightly lower for Slofedipine XL compared with Adalat OROS with a point estimate of 82.3% primarily resulting from pronounced differences in nifedipine concentrations during the first 15 h after administration. Accordingly, maximum plasma concentrations were lower after administration of Slofedipine XL compared with Adalat OROS (point estimate: 84.3%). Under fed conditions the differences in bioavailability between the two products as characterized by the pharmacokinetic parameters AUC(0,tn) and Cmax were greater than after fasting conditions with point estimates of 69.6% and 81.0%, respectively. However, most striking was a pronounced delay in nifedipine absorption observed under fed conditions after administration of Slofedipine XL which resulted in lag-times of more than 15 h in 15 out of 24 subjects. Owing to this lag-time under fed conditions the relative bioavailability of nifedipine from Slofedipine XL compared with Adalat OROS was only 28% over the intended dosing interval of 24 h. CONCLUSIONS: In this study a dosage form-dependent food interaction was observed which, under fed conditions, resulted in pronounced differences in the relative bioavailability of nifedipine between Slofedipine XL and Adalat OROS over the intended dosing interval of 24 h. The delay in nifedipine absorption when Slofedipine XL is administered after a high-fat breakfast may be explained by the formulation properties. Slofedipine XL is an erosive tablet with an acid resistant coating whereas Adalat OROS is designed with an osmotic push-pull system. Under fed conditions drug from the single unit enteric coated dosage form exhibits a delayed absorption probably due to an extensively prolonged gastric residence time which does not allow drug release, on the other hand the osmotically driven push-pull system is not sensitive to concomitant food intake. The observed phenomenon might be of therapeutic relevance. For example a change from taking Slofedipine XL in the fed to the fasted state might result in increased systemic concentrations of nifedipine.

Dosage form-related food interaction observed in a marketed once-daily nifedipine formulation after a high-fat American breakfast.

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 between-product 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-)(infinity)()) 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".

Lack of drug-drug interaction between cerivastatin and nifedipine.

Cerivastatin is a novel, potent HMG-CoA reductase inhibitor. It is primarily cleared via demethylation and hydroxylation with involvement of cytochrome P450 (CYP) 3A4 and subsequent biliary and renal excretion of the metabolites. Both cerivastatin and the dihydropyridine calcium antagonist nifedipine, which is primarily metabolized by CYP 3A4, are used concomitantly in the prevention and therapy of coronary heart disease. To study the drug-drug interaction potential, the mutual effects of cerivastatin and nifedipine were investigated in a controlled, randomized, non-blind 3-way crossover study in healthy male subjects. Single oral doses of 0.3 mg cerivastatin or of 60 mg nifedipine were administered either alone or concomitantly under fasting conditions. The mean AUC- and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.04 (0.98 - 1.10) and 1.00 (0.93 - 1.07) for cerivastatin, and 0.98 (0.73 - 1.32) and 0.95 (0.80 - 1. 13) for nifedipine, respectively. Our results indicate that no mutual drug-drug interaction between cerivastatin and nifedipine occurs.

Determination of nifedipine in human plasma by flow-injection tandem mass spectrometry.

For use in clinical studies, a fast and sensitive assay method was developed for the determination of nifedipine in human plasma samples. The assay method is based on tandem mass spectrometry detection (HPLC-MS-MS). The effect of flow injection as well as HPLC separation on the results of the nifedipine determination were evaluated. The limit of quantification is 0.5 ng/ml and the accuracy (as determined by spiking recovery) was found to be good.

Pharmacokinetics of miglitol. Absorption, distribution, metabolism, and excretion following administration to rats, dogs, and man.

The absorption, distribution, metabolism, and excretion of miglitol ((2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinet riol, CAS 72432-03-2, BAY m 1099) have been studied following single and repeated administration of non-labelled and radiolabelled (3H, 14C) drug to rats, dogs, and human volunteers via different routes of administration (intravenous, oral, intraduodenal) and at various doses (0.3-450 mg/kg). After intravenous administration, miglitol is excreted rapidly and completely via the renal route. No indication was found for a metabolization of radiolabelled miglitol. The (renal) clearance of miglitol is in the range of the glomerular filtration rate. Miglitol is rapidly eliminated from plasma with apparent elimination half-lives of 0.4-1.8 h. Miglitol is virtually not bound to plasma proteins. After oral administration miglitol is rapidly and at low doses also completely absorbed. At higher doses (> or = 5 mg/kg in rats and dogs, > 50 mg in humans) a saturation of absorption becomes evident. Miglitol is distributed predominantly in the extracellular space. The volumes of distribution are low (0.3-0.8 l/ kg). In rats high concentrations were initially found in the kidneys, the blood and some well-perfused tissues. The permeation across the blood/brain barrier is very low. Elimination from organs and tissues occurs rapidly resulting in very low residual radioactivity in the body 2 days after dosing (< 0.9% of the dose). At this very low concentration level a terminal elimination phase of radioactivity characterized by half-lives of 50-110 h was observed giving rise to a slight tendency for accumulation (accumulation factors < 6) following repeated administration to rats. In pregnant rats [14C]miglitol crossed the placental barrier slowly and to a limited extent. In lactating rats miglitol was found in milk in concentrations similar to those in the maternal plasma.

Investigation of nifedipine absorption in different regions of the human gastrointestinal (GI) tract after simultaneous administration of 13C- and 12C-nifedipine.

OBJECTIVE: To evaluate the absorption of nifedipine in man from four different sites of the gastrointestinal tract. METHODS: On separate occasions, nifedipine solution was administered locally to the stomach, the small intestine and two sites in the colon in 4 healthy male volunteers (age 29-34 y weight 73-82 kg, non-smokers) using a remote controlled drug delivery device (HF-capsule). In order to assess absolute and relative bioavailabilities, an intravenous infusion was given on a separate occasion and all treatments were accompanied by a simultaneous oral dose of a stable-isotope labelled nifedipine solution. This allowed to minimise the influence of intra-individual variability. Plasma samples were collected up to 24 h post dose and faeces for 72 h. A new method of analysis of nifedipine in plasma and faeces using gas chromatography with mass-selective detection (GCMS) was employed. RESULTS: Dissolved nifedipine was found to enter the systemic circulation completely along the intestine, being absorbed from jejunum to colon. Absorption was less rapid from the colon than from the upper part of the gut, but this was not associated with a decrease in absorption and/or bioavailability: Absolute bioavailability, calculated from the normalised AUC values, ranged from 42 to 56%, and bioavailability relative to oral solution was 100 to 126% (medians of the application sites). CONCLUSION: The absence of an absorption window in the intestinal tract suggests that nifedipine is well suited for use in controlled-release formulations.