Bioavailability investigation of two different oral formulations of doxepin.

Two different oral doxepin (CAS 1668-195) formulations (Doxepin-ratiopharm 25 mg film-coated tablets as test preparation and 25 mg dragées of the reference preparation) were investigated in 30 healthy male and female volunteers in order to prove bioequivalence between these preparations. A single 75 mg oral dose (3 units of test or reference preparation) was given according to a randomised two-way cross-over design in the fasted state. Blood samples for determination of plasma concentration of doxepin and its metabolite N-desmethyldoxepin were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of three weeks separated both treatment periods. Doxepin and N-desmethyldoxepin plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 193,463 pgh/ml (test preparation) and 197,988 pg h/ml (reference preparation) for doxepin as well as values of 313,298 pg h/ml (test preparation) and 306,663 pgh/ml (reference preparation) for N-desmethyldoxepin for the parameter AUC0-infinity demonstrate a nearly identical extent of drug absorption. Maximum concentrations (Cmax) for doxepin/N-desmethyldoxepin of 15,960.06/6,883.69 pg/ml and 18,614.73/6,846.62 pg/ml were achieved for test and reference preparation. Time to reach doxepin maximum plasma concentration (tmax) was 1.98 h for both preparations and for N-desmethyldoxepin tmax was 4.52 h (test preparation) and 4.15 h (reference preparation). Cmax and AUC0-infinity values were tested for statistically significant differences by means of the Two One-Sided T-Tests procedure following ln-transformation of data. Bioequivalence was assumed if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for ln-transformed AUC0-infinity and 70%-143% for ln-transformed Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.

Bioavailability investigation of two different oral formulations of Tetrazepam.

Two different oral tetrazepam (CAS 10379-14-3) formulations (Tetrazepam-ratiopharm film-coated tablets as test preparation and tablets of a reference preparation marketed in France) were investigated in 20 healthy volunteers in order to prove bioequivalence between these preparations. A single 50 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of tetrazepam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A washout period of 14 days separated both treatment periods. Tetrazepam plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 3873.08 ngh/ml (test preparation) and 3930.69 ngh/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 482.08 ng/ml and 465.14 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 1.39 hours for both preparations. Cmax and AUC0-infinity-values were tested parametrically by an analysis of variance (ANOVA). Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for AUC0-infinity and 70%-143% for Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.

Bioavailability investigation of two different oral formulations of methylprednisolone.

Two different oral methylprednisolone (CAS 83-43-2) formulations (Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of a reference preparation (R)) were investigated in 16 healthy volunteers in order to prove bioequivalence between these preparations. A single 8 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of methylprednisolone plasma concentrations were collected at pre-defined time points up to 16 h following drug administration. A washout period of 3 days separated both treatment periods. Methylprednisolone plasma concentrations were determined by means of a validated HPLC method. Values of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity-values were tested parametrically by the two one-sided t-test procedure. Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the results obtained in this study, bioequivalence between Methylprednisolone ratiopharm and the reference preparation was demonstrated.

Bioavailability investigation of a new tilidine/naloxone liquid formulation compared to a reference formulation.

An oral solution available as ethanol-free droplets of the fixed drug combination tilidine-HCl 50 mg/naloxone-HCl 4 mg (CAS 27107-79-5 and CAS 465-65-6, respectively; Tilidin-ratiopharm plus Tropfen) was investigated in 12 healthy volunteers together with an ethanol-containing reference preparation for comparable bioavailability. The study was conducted in an open, randomized, two-way cross-over design applying single doses of 20 droplets (equivalent to 50 mg tilidine-HCl/4 mg naloxone-HCl) of either formulation in the fasting state. The drug plasma profiles were monitored for a period of 48 h by means of LC-MS/MS for tilidine and its active metabolite nortilidine, whereas GC-MS was employed in order to determine naloxone and its phase I metabolite, 6-beta-naloxole. Maximum concentrations (Cmax) achieved were 22.28 ng/ml (tilidine) and 92.78 ng/ml (nortilidine) for the test preparation. Corresponding values for the reference preparation were 24.95 ng/ml (tilidine) and 100.73 ng/ml (nortilidine). The extent of drug absorption (AUC0-infinity) amounted to 38.83 ng h/ml and 467.63 ng h/ml for the prodrug tilidine and the metabolite nortilidine of the test preparation and corresponded well to 43.81 ng h/ml and 493.85 ng h/ml of the reference. Regarding the rate of drug absorption, essentially identical tmax and Rabs values for both tilidine and nortilidine of either preparation in addition pointed to well comparable liquid formulations and equipotent analgesia may be inferred from opioid pharmakokinetic profiles. Pharmacokinetics of the opioid antagonist naloxone and 6-beta-naloxole were also determined and resulted in well coinciding profiles for both preparations. Thus despite the fact that only minimum oral naloxone bioavailabilities were observed, plasma level monitoring of naloxone and 6-beta-naloxole allowed for demonstration of systemic exposure of opioid antagonistic compounds throughout a period of 2-3 h after oral drug administration. Due to the limited number of subjects involved, the primary aim of the study did not consist in demonstration of drug bioequivalence. Rather a comparable bioavailability between preparations was assumed if AUC and Cmax point estimators of 90% confidence intervals would be contained within a 0.80-1.20 range. The study outcome revealed that all four investigated analytes met this requirement, whilst nortilidine pharmacokinetic parameters even fulfilled commonly accepted bioequivalence criteria, i.e. inclusion of 90% confidence intervals of AUC- and Cmax-ratios within acceptance limits of 80% and 125%. Increased data variation observed with bioavailability parameters of tilidine, naloxone and 6-beta-naloxole prevented their bioequivalence demonstration based on only 12 study participants. In conclusion, single doses of two different tilidine/naloxone 50 mg/4 mg liquid formulations revealed well comparable bioavailability for all 4 analytes investigated. Both treatments were fairly well tolerated. Most frequently reported adverse events were dizziness, headache and nausea, which all recovered without sequelae and necessity of concomitant treatment.

Bioequivalence evaluation of two flutamide preparations in healthy female subjects.

In the present study two different preparations containing 250 mg flutamide (3'-trifluoromethyl-4'-nitro-2-methyl-propionylanilide, CAS 13311-84-7) were compared in 20 female subjects. The trial was performed in a randomized two-way cross-over design. Each subject received one tablet with 250 mg flutamide in each period. The two treatment periods were separated by a wash-out phase of 7 days. Blood samples were obtained just before dosing and 18 times during the subsequent 36 h. The plasma concentrations of flutamide, 2-hydroxyflutamide and trifluoromethylnitroaniline were determined by HPLC with UV-detection. Due to the low plasma levels of the parent drug flutamide, the data of the pharmacologically active metabolite 2-hydroxyflutamide (CAS 52806-53-8) were used for bioequivalence assessment. The following mean values were obtained after administration of the test and reference preparation respectively: Flutamide: AUC0-36 = 95.82 ng.h/ml vs 93.33 ng.h/ml, Cmax = 44.78 ng/ml vs 38.73 ng/ml, tmax = 1.71 h vs 1.66 h, 2-hydroxyflutamide: AUC0-infinity = 6090.73 ng.h/ml vs 6068.83 ng. h/ml, Cmax = 772.74 ng/ml vs 779.84 ng/ml, tmax = 2.21 h vs 2.17 h, t1/2 = 8.21 h vs 8.32 h, trifluoromethylnitroaniline: AUC0-infinity = 1771.87 ng.h/ml vs 1701.44 ng.h/ml, Cmax = 173.36 ng/ml vs 171.32 ng/ml, tmax = 2.74 h vs 2.63 h, t1/2 = 10.75 h vs 9.83 h. The two preparations proved to be bioequivalent.

Comparative steady state study with 2 fenofibrate 250 mg slow release capsules. An example of bioequivalence assessment with a highly variable drug.

Twenty healthy male volunteers were treated with 2 different oral preparations of fenofibrate according to a randomized 2-way crossover design. The test preparation was Fenofibrate 250 mg retard capsules, batch No. YXF 001, provided by MTT Medical and Technological Transfer GmbH, Unterhaching, Germany. The reference preparation was Lipanthyl 250 mg retard capsules, batch No. R9110071, manufactured by Fournier Pharma, Sulzbach, Germany. On 12 consecutive days divided in 2 periods the volunteers received 6 doses of the test and reference formulation, respectively. The daily dose of 1 capsule contained 250 mg of fenofibrate and was administered together with a standardized high calory breakfast. Blood samples were taken immediately prior to each administration and at 14 points after the last administration of each period. The concentration of the pharmacologically active compound, fenofibric acid, was determined by means of HPLC with UV detection. The calibration curve was linear in the range 0.1-20.0 micrograms/ml (r = 0.99997). A lower limit of quantification of 0.1 microgram/ml was established. The following mean values were obtained after administration of the test preparation: AUC tau 184.68 microgramsh/ml; Cmax 13.11 micrograms/ml; PTF: 125.0%. After administration of the reference formulation the following values were observed: AUC tau 175.91 microgramsh/ml, Cmax 12.27 micrograms/ml, PTF: 120.0%. AUC tau, Cmax and PTF were tested for bioequivalence parametrically after logarithmic transformation. The preparations were found to be bioequivalent.

Bioequivalence evaluation of two different oral formulations of loperamide (Diarex Lactab vs Imodium capsules).

Twenty-four healthy male volunteers were treated with two different oral formulations of loperamide according to a randomized two-way cross-over design. The test preparation was Diarex Lactab (Mepha), the reference preparation Imodium 2 mg capsules. Divided in two periods the volunteers received single 8 x 2 mg (= 16mg) doses of the test and reference formulation, respectively. Blood samples were taken immediately prior to each administration and at 14 points within 60 h after the dose. A wash-out period of 1 week was interpaused between successive drug doses. The plasma concentration of the pharmacologically active compound, loperamide, was determined by HPLC with electrochemical detection. The calibration function was linear in the range 0-10.0 ng/ml. A lower limit of quantification of 0.2 ng/ml was established. The pharmacokinetic parameters Cmax and tmax were obtained directly from plasma data. The elimination constant was estimated by log-linear regression of the measured concentrations in the terminal phase. AUC was calculated by the trapezoidal rule and extrapolated to infinity. The following mean values were obtained after intake of 16 mg loperamide as film coated tablets: AUC0 infinity 62.04 ngh/ml, Cmax 3.35 ng/ml, tmax 4.08 h, t1/2 19.66 h and after administration of the capsules: AUC0 infinity 66.56 ngh/ml, Cmax 3.98 ng/ml, tmax 4.38 h, t1/2 18.43 h. The pharmacokinetic parameters AUC0 infinity and Cmax were tested for bioequivalence parametrically (two one-sided t-tests) after logarithmic transformation of data. Differences of tmax were evaluated non-parametrically. The preparations were found to be bioequivalent and, therefore, interchangeable.