Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration.

OBJECTIVE: To compare the steady-state pharmacokinetics and pharmacodynamics following multiple subcutaneous administration of a new erythropoiesis stimulating agent (HX575, Binocrit, Sandoz GmbH, Holzkirchen, Germany) with that of epoetin beta (NeoRecormon, Roche Ltd., Welwyn Garden City, UK). METHODS: An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or epoetin beta three-times-weekly for 4 weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratios of hematological characteristics were used as surrogate parameters for efficacy evaluation. RESULTS: The pharmacokinetic profiles after multiple doses were similar for both treatments. HX575 was bioequivalent to epoetin beta with respect to the rate and extent of exposure of exogenous epoetin, as indicated by the ratios (90% confidence intervals) of AUC(tau) (96.1 (86.4 - 106.9)) and C(max,ss) (98.5 (85.2 - 113.9)). The hematological profiles of both treatments were similar as determined from the population mean curves and the AUEC(Hb) ratio (90% confidence interval] (99.2 (97.7 - 100.7)), the primary endpoint of this study. Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected at any time. CONCLUSIONS: HX575 and epoetin beta were bioequivalent with respect to their steady-state pharmacokinetic profile and pharmacodynamic action. These results support the conclusion that HX575 and epoetin beta will be equally efficacious and may be interchangeable as therapy.

Bioavailability and pharmacokinetic profile of dihydroergotoxine from a tablet and from an oral solution formulation.

Dihydroergotoxine mesylate (DHETM, CAS 8067-24-1), the combination of the mesylates of four dihydrogenated ergot alkaloid derivatives (dihydroergocornine, dihydroergocristine, alpha-dihydroergocryptine and beta-dihydroergocryptine), is used mainly for age-related cognitive impairment. The bioavailability of DHETM was investigated in a cross-over study on 20 male healthy volunteers to whom two single doses of 9 mg DHETM were administered either in tablets (Orphol spezial) or in oral solution (Orphol forte). DHETM was assayed in serum with a double radioimmunoassay method displaying a satisfactory cross-reactivity with the principal components of DHETM. After administration of tablets the peak of DHETM was (mean +/- SE) 124 +/- 16 pg/ml, the tmax 1.15 +/- 0.21 h, the AUC 790 +/- 93 pg/ml x h and the terminal elimination half-life 7.54 +/- 1.23 h. After oral solution the peak of DHETM was 176 +/- 16 pg/ml, the tmax 0.50 +/- 0.04 h, the AUC 779 +/- 94 pg/ml x h and the terminal elimination half-life 6.13 +/- 0.76 h. The bioavailability of DHETM from tablets vs. that from oral solution differed only by a retard related to the dissolution time of DHETM from the tablets, but not for other pharmacokinetic parameters. The relatively high two single doses of 9 mg DHETM administered to the 20 subjects were well tolerated, causing only known and expected adverse reactions to DHETM (tiredness, headache and vertigo) that did not require discontinuation of the study.

Bioavailability of a new effervescent tablet of diclofenac.

OBJECTIVE: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). SUBJECTS AND METHOD: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-infinity and Cmax. RESULTS: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean +/- SD) for DIC-effervesc is 950+/-341 ng/ml (first Cmax) and for DIC-enteric 1364+/-335 ng/ml. The mean AUC0-infinity, (arithm. mean +/- SD) amounts to 1097+/-210 ng/ml x h for DIC-effervesc and 1262+/-220 ng/ml x h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 - 91.3%). DIC-effervesc was well tolerated. CONCLUSION: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragee. A rapid onset of therapeutic effect is postulated in acute pain disorders.

Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate.

OBJECTIVE: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. SUBIECTS AND METHODS: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. RESULTS: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 microg/ml, 6.8 microg/ml and 12.8 microg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-infinity as well as Cmax related to each other approximately according to the expected ratios of 0.33:0.5:1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-infinity, Cmax) were included by the acceptance range of 80-125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. CONCLUSION: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.

Study on the interaction of the dopamine agonist alpha-dihydroergocryptine with the pharmacokinetics of digoxin.

AIM: The study was carried out to explore the potential for pharmacokinetic interaction of a single oral dose of alpha-dihydroergocryptine (CAS 14271-05-7, DHEC, Almirid) with digoxin. METHODS: The serum pharmacokinetics of digoxin were analysed after the administration of single oral doses of 0.5 mg digoxin administered either alone or concomitantly with 20 mg DHEC according to a randomised, non-blinded, two-period cross-over design, with study periods 2 weeks apart. Twelve healthy male subjects, 23 to 39 years of age were enrolled and were investigated in accordance with the protocol. Venous blood was sampled up to 48 h after dosing. Concentrations of digoxin in serum were determined by a competitive radioimmunoassay. RESULTS: The mean Cmax were 1.97 +/- 0.87 (after a median tmax of 1 h) and 2.05 +/- 0.95 ng/ml (after a median tmax of 0.83 h) after the administration of digoxin with (test) and without (reference) concomitant DHEC, respectively; the corresponding estimated treatment ratio for test: reference was 0.939, 95% CI: 0.781 to 1.129. The mean AUC(0-48) were 13.6 +/- 5.0 ng.h/ml and 13.3 +/- 4.7 ng.h/ml for the test and reference treatment, respectively; the corresponding estimated treatment ratio for test: reference was 1.011, 95% CI: 0.866 to 1.142. In addition, no clinically significant changes were observed by ECG monitoring. The tolerability of digoxin alone was good, significantly more adverse events occurred when co-administered with DHEC; these corresponded with the known adverse reaction profile and were of moderate intensity. No premature study termination was thus necessary. CONCLUSION: The present study did not demonstrate clinically relevant interaction of a single dose of DHEC on the pharmacokinetics of digoxin. On the basis of these observations there is no indication for an a priori adjustment of the dose of digoxin when concomitant treatment with DHEC is initiated.

Pharmacokinetic characteristics of a new multiple unit sustained release formulation of sodium valproate.

AIM: Two bioavailability studies were conducted in healthy male volunteers to determine the absorption characteristics of a new dosage form of sodium valproate consisting of sustained release pellets in a hard gelatine capsule. SUBJECTS, MATERIAL AND METHODS: To obtain first data on the in vivo behavior of the new multiple unit formulation a single dose pilot study in comparison with an oral solution was performed in 6 volunteers. Following the pilot study the pharmacokinetics were investigated versus a conventional enteric-coated tablet after multiple dosing in 18 volunteers. The volunteers were administered either a single or multiple dose of 300 mg sodium valproate. In both studies a wash-out period of at least 1 week elapsed between the periods. Valproic acid was determined from serum by gas chromatography at intervals suitable for obtaining concentration time curves for both regimens. RESULTS: The results of the pilot study showed that the valproate concentration in serum following administration of the new sustained release capsule increased smoothly and a longer lasting plateau was observed as compared with the solution. The average maximum serum valproate concentration of 12.5 microg/ml (sustained release capsule) and 24.3 microg/ml (solution) appeared at 9.3 h and 0.58 h after dosing. The extent of valproate absorption as reflected in the AUC data for each formulation was equivalent for the new sustained release capsule and reference formulation (AUC0-infinity: 369 +/- 88.9 and 339 +/- 76.2 microg/ml x h). Data obtained after multiple dose administration provided an indication of the consistency of valproate absorption from each dosage form. The time concentration profiles following twice daily administration of 300 mg sodium valproate in the multiple dose study showed that the extent parameters for absorption of valproate (AUC(8tau9tau) = 842 +/- 166 microg/ml x h) are equivalent with the enteric-coated preparation (AUC(8tau9tau) = 823 +/- 139 microg/ml x h). However, the fluctuation of the new sustained release formulation (PTF(8tau9tau) = 0.33 +/- 0.09) is about only one third of the fluctuation observed with the enteric-coated formulation (PTF(8tau9tau) = 0.88 +/- 0.22) when administered twice daily. CONCLUSION: These data indicate that the new sustained release capsule possesses desirable absorption characteristics in a form that allows twice daily or even once daily dosing and therefore improves patient compliance.

Pharmacokinetics of estradiol and of estrone during application of a new 7-day estradiol transdermal patch with active matrix.

The pharmacokinetic patterns of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) were investigated in 18 women in natural or surgical menopause during the application of a new estradiol transdermal patch with active matrix and without absorption enhancers designed for epicutaneous applications of 7 days (hereinafter called "patch 7D"). The study was made with randomized and balanced sequences of applications in cross-over of either patch 7D or of an authorized estradiol transdermal patch with a nominal release rate of 50 micrograms/day estradiol designed for a twice-a-week epicutaneous application (hereinafter called "patch 50"). The sequences consisted of applications for 3 weeks either of 3 patches 7D or of 6 patches 50. The patches were applied on the skin of the hips or upper buttocks. The serum samples were obtained during the 1st and during the last week of application of the patches. Estradiol (E2) was assayed in serum by a double-antibody RIA method selective for free estradiol. Estrone (E1) was assayed in serum using a 3H-estrone RIA method. The steady state with regard to E2 and E1 was achieved already during the application of the 2nd patch. Patch 7D provided within 6 h an increase of the E2 concentrations in serum from the basal postmenopausal level of less than 3 pg/ml to therapeutically effective concentrations. The Cmax of E2 of 45 pg/ml was reached on average after 25 h, the concentrations of E2 remaining at sustained and therapeutically effective levels during the whole application of patch 7D. At steady state, during the 3rd week of application, the Cav was on average 31 pg/ml. With a small delay, E1 also increased from the basal 15 pg/ml to a Cmax of 41 pg/ml after 44 h. At steady state, during the 3rd week of application, the Cav was on average 38 pg/ml. Patch 7D provided a similar bioavailability as patch 50 with regard to the rate and the extent of absorption of E2, as shown by the AUCs during the 7-day applications of one patch 7D compared to those during the 7-day applications of 2 patches 50. The release of E2 from patch 7D is therefore similar to that of patch 50, i.e. on an average of 50 micrograms/day over a 7-day period of application. The E2/E1 ratio increased from the postmenopausal values lower than 0.2 found before the application of patch 7D to average values of 0.67, i.e., to values that are normally found during the fertile life of the woman. The improvement of the E2/E1 ratio occurred already in the first 6-12 h of application of patch 7D. The E2/E1 ratio returned rapidly to the initial low postmenopausal levels after removal of the patch. Patch 7D was well tolerated by the skin, probably because it does not contain absorption enhancers. It provoked, however, some systemic adverse reactions typical of E2 overdosing. In the therapeutic practice these adverse reactions can easily be avoided using patches 7D of lower strength. No drop-out due to systemic or local intolerance occurred. The adhesion of patch 7D on the skin was good. During the application of a total of 54 patches, only in one occasion one patch became partially detached (about 40% of the total area) from the 3rd to the 7th day during the first 7-day period of application.

Bioavailability and pharmacokinetic characteristics of two monofluorophosphate preparations with calcium supplement.

Two studies on the rate and extent of bioavailability of fluoride from a single dose of oral preparations of sodium monofluorophosphate (Na2FPO3) combined with calcium supplement were conducted according to a cross-over design on 18 (Study 1) and 20 (Study 2) male healthy volunteers, respectively. Evaluated were: a) tablets containing 76 mg Na2FPO3 (Ref1); b) chewable tablets containing 76 mg Na2FPO3 and 1250 mg calcium carbonate (Test 1); c) effervescent tablets containing 76 mg Na2FPO and 3240 mg calcium lactogluconate/carbonate (Ref 2); d) effervescent tablets containing 76 mg Na2FPO3 and 1250 mg calcium carbonate (Test 2). In all preparations Na2FPO3 was equivalent to 10 mg elemental F. The calcium supplement was equivalent to 500 mg elemental Ca. Fluoride was assayed in serum and in urine by a gas chromatographic method with a limit of quantitation of 10 ng/ml. Test 1 was found equivalent to Ref1 with regard to rate and extent of bioavailability of fluoride in serum. Test 2 (effervescent tablets resulting in an oral solution of Na2FPO3 and calcium salts) was found bioequivalent in rate and extent to Ref2 (effervescent tablets authorized for marketing with the same content in F and Ca equivalents as Test 2). The pharmacokinetics of fluoride from all investigated preparations was characterized by a short lag time, a rapid absorption, a Cmax of fluoride of 291-351 ng/ml (without significant differences between preparations) reached 30-75 min after administration, and a terminal t1/2 of 6-14 h. About 50% of the absorbed fluoride was eliminated with the urine (from 0 to infinity time). The kur.el was 0.06 h-1. The renal clearance 65 ml/min. The preparations were well tolerated by the subjects. In conclusion, Test1 and Test2 represent combinations of Na2FPO3 with calcium supplement which are well tolerated and provide a rapid, reliable and practically complete bioavailability of fluoride. They are therefore suitable for the bone-forming therapy of osteoporosis.

Influence of food on the pharmacokinetics of a new multiple unit sustained release sodium valproate formulation.

The influence of concomitant food intake on the pharmacokinetics of sodium valproate (CAS 1039-66-5) was studied in 16 healthy male volunteers. A single dose of a new sustained release formulation containing 300 mg sodium valproate (Orfiril long) was administered on two occasions either after a 12-h over-night fast or immediately after a standardised high energy high fat breakfast. A wash-out period of at least 1 week elapsed between the administrations. Valproate serum concentrations were measured by gas chromatography at intervals suitable for obtaining concentration-time curves for both regimens up to 72 h. The mean maximum serum concentration after fasting (17.0 micrograms/ml) was virtually the same as after a meal (16.8 micrograms/ml). Maximum concentrations were reached after 8 h for both nutritional states. The rate of elimination was not affected (terminal half-life approximately 15 h). The mean AUC0-infinity values were 468 micrograms/ml x h in fasting subjects and 458 micrograms/ml x h in postprandial subjects. The 90% confidence intervals for all pharmacokinetic target parameters were entirely confined in the bioequivalence range of 80 to 125%. The confidence intervals were even tighter, thus demonstrating homogeneity of drug release from the newly developed sodium valproate sustained release preparation. Bioequivalence with respect to extent and rate of absorption is therefore concluded for the comparison of fasting and non-fasting administration. The bioavailability of the sustained release sodium valproate preparation is not altered by the concomitant ingestion of food.

Pharmacokinetics of estradiol and of estrone during repeated transdermal or oral administration of estradiol.

The estradiol (CAS 50-28-2, E2) and estrone (CAS 53-16-7, E1) concentrations in blood were investigated during a 3-week twice weekly application of an E2 transdermal patch, or daily oral administration of E2 tablets. The transdermal patch (Dermestril 50, hereinafter called "Patch") contains 4 mg E2 and delivers daily 50 micrograms E2. The E2 tablets (hereinafter called "Tablet") contains 2 mg micronized E2. The study was performed on 32 healthy postmenopausal women randomly assigned to two parallel groups, each of 16 subjects, one treated with Patch and the other with Tablet. During the first transdermal Patch application, E2 reached effective concentrations of 30 pg/ml of more 12 h after application. During the following 5 applications the concentrations of E2 remained rather constant (fluctuation = 0.65). The study state was reached with the second Patch, with an average concentration (Cav) of 35 pg/ml. After removal of the last Patch, the E2 concentrations returned to the basal levels within 12 h. The E1 concentrations reached the maximum concentration (Cmax) of 48 pg/ml 41 h after the first Patch application and then remained rather constant (fluctuation = 0.28), with a Cav at steady state of 47 pg/ml. During the oral administration of the first Tablet, E2 reached the peak of 1084 pg/ml 49 min after administration and then decreased rapidly in the following 3 h. There was a progressive cumulation of E2 until steady state, which was reached after the 5th Tablets with a Cav of 418 pg/ml i.e. 12.0 times greater than during Patch, and very large pulses of E2 (fluctuation = 3.68). The E1 concentrations reached the peak of 334 pg/ml 4.28 h after the first administration. The steady was reached with the 14th daily administration. There were Large pulses of E1 (fluctuation = 1.15). The Cav was 441 pg/ml, i.e. 9.4 times greater than during Patch. In conclusion the twice weekly application of the transdermal Patch elicits rather constant and therapeutically effective blood concentrations of E2 and E1. In contrast, the daily oral administration of E2 Tablets elicits large pulses of E2 and E1, and exposes the subjects to high concentrations of E2 and of E1, which are 12.0 and 9.4 times greater, respectively, than those elicited by the Patch. Both treatments were fairly well tolerated, and no withdrawal of the medications during the study was necessary.

Bioavailability of estradiol from two transdermal patches.

The bioavailability of estradiol (CAS 50-28-2; E2) from a new "matrix type" estradiol transdermal patch (Dermestril; Test patch) was compared to that of the widely used "liquid-reservoir, membrane-controlled type" transdermal patch (Reference patch) in a two-way randomized cross-over study on 28 healthy postmenopausal women, during a single 4-day application of 2 patches (total content 8 mg E2, total nominal release rate 100 micrograms E2 in 24 h). Evaluated from the AUC0-96h, the extent of bioavailability was practically the same for the two patch types. Conversely the rate of bioavailability was significantly different, because from the Reference patch the release rate is fast in the first 24 h, leading to an E2 peak at 8 h and to a Cmax in average at 23 h. But after the 2nd day the release/absorption rate declines markedly, leading to E2 serum concentrations at the 3rd and 4th days possibly below the effective threshold. From the Test patch the release/absorption rate of E2 is more constant, leading to sustained E2 concentrations during the 4 days of application, with smaller fluctuations than during application of the Reference patch. In conclusion the Test patch can be considered practically bioequivalent to the Reference patch with regard to the extent of absorption, but not with regard to the rate of absorption, because the E2 concentrations in serum are more constant during the application of the Test transdermal patch than during the application of the Reference.

[Evaluation of the bioequivalence of two fast-releasing iron(II) sulfate formulations]. / Prüfung der Bioäquivalenz von zwei schnellfreisetzenden Eisen(II)-Sulfat-Formulierungen.

Bioequivalence of a new oral iron formulation (A: FE(II)SO4.H2O, capsule with 100 mg Fe++, Eryfer 100, CAS 7782-63-0) with the standard formulation (B: Fe(II)SO4.H2O, capsule with 50 mg Fe++, Eryfer) was demonstrated after administration of 100 mg Fe++ in a single-dose two-way cross-over design to 16 normal female volunteers. Iron concentrations were monitored from 24 h before (basal) to 24 h post application. The area under concentration difference curve AUC(diff) and the maximal concentration difference Cmax(diff) were calculated subtracting the basal from the time-corresponding postabsorptive concentrations. AUC(diff) (A: 170 nmol/ml. h, B: 168 nmol/ml.h) and Cmax(diff) (A: 23.3 nmol/ml, B: 21.8 nmol/ml) showed but minor differences between formulations. The AUC(diff) and Cmax ratio (A/B) and the corresponding 90% confidence intervals, 102% (74-129%) and 107% (91-123%), were included by the acceptance range of 70-130% as stated in the study protocol. Hence, both formulations were bioequivalent with respect to rate and extent. The ANOVA coefficient of variation of Cmax(diff) was considerably smaller than that of AUC(diff) (26% versus 44%). The characteristics based on the postabsorptive iron increase (post-absorptive concentrations minus concentration preceding immediately application) AUC(pad) (ratio 99% (83-114%) and Cmax(pad) (ratio 104% (95-112%) exhibited smaller ANOVA-CVs (25% and 14%, respectively) as compared with AUC(diff) and Cmax(diff). All these characteristics appeared to be rather normal than log-normal distributed. It was concluded that the study design was selective to demonstrate an adequate bioavailability of iron formulations.

[Comparison of the pharmacokinetics of a quick-release bezafibrate formulation with a sustained-release formulation. 1. Single-dose administration]. / Vergleich der Pharmakokinetik einer schnellfreisetzenden Bezafibrat-Formulierung mit einer Retard-Formulierung. 1. Mitteilung: Single-dose-Applikation.

Comparison of the Pharmacokinetic Profiles of a Quick and a Sustained Release Bezafibrate Formulation/1st Communication: Single-dose application The hypolipaemic agent bezafibrate (CAS 41859-67-0) is available as immediate and sustained release formulation. The pharmacokinetic profile of an immediate release 300 mg dragee (A) was compared in a two-way cross-over design to that of a 400 mg sustained release dragee (B). Neglecting the dose difference, the AUEC of A (28.8 micrograms/ml.h) was equal to that of B (27.6 micrograms/ml.h), whereas the bioavailability of A appeared to be higher than that of B when AUEC was corrected for dose (AUEC ratio = 137%). Regarding Cmax and tmax, both formulations exhibited the expected differences.

[Comparison of the pharmacokinetics of a quick-release bezafibrate formulation with a sustained-release formulation. 2. Multiple-dose administration and chronopharmacokinetics]. / Vergleich der Pharmakokinetik einer schnellfreisetzenden Bezafibrat-Formulierung mit einer Retard-Formulierung. 2. Mitteilung: Multiple-dose-Applikation und Chronopharmakokinetik.

The pharmacokinetic profile of a 300 mg immediate release formulation (A) was compared to a 400 mg sustained release formulation (B) of the lipid lowering drug bezafibrate (CAS 41859-67-0). Preparation A was applied twice a day whereas B was applied once a day in the evening. The means of Cmax (12.5 micrograms/ml) and AUC (66.8 micrograms/ml.h) for preparation A were considerably higher than for B (Cmax: 6.6 micrograms/ml, AUC: 39.8 micrograms/ml.h), whereas no differences were found regarding Tcav (A: 8.9 h, B: 8.3 h) and PTF (A: 4.6, B; 4.1). An AUC ratio for A/B of 119% (CI90%: 108-132%) was determined after dose correction. For A an AUC/AUEC ratio of 110% was found when comparing multiple versus single-dose application, whereas this ratio with 136% appeared to be considerably higher for B. Slight chronopharmacological effects were found for preparation A, which was applied twice a day in the evening and in the morning. During night-time the AUC was (insignificantly) 12% higher than during day-time, whereas the apparent elimination halflife time was 40% longer at night (p < 0.025), which corresponded to an extended tmax of median 3 h during night-time as compared to 1.75 h at day-time.