Effect on endometrial histology and pharmacokinetics of different dose regimens of progesterone vaginal pessaries, in comparison with progesterone vaginal gel and placebo.

STUDY QUESTION: Which progesterone vaginal pessary dose regimen induces adequate secretory transformation of the endometrium, in comparison with progesterone vaginal gel and placebo? SUMMARY ANSWER: The best secretory transformation of the endometrium was observed during treatment with 400 mg progesterone vaginal pessaries, administered twice daily. WHAT IS KNOWN ALREADY: Vaginally administered progesterone is widely used for luteal phase support (LPS) in assisted reproductive techniques (ART). Although several vaginal formulations using various doses are available, little is known on the impact of formulation and doses at the endometrial level. STUDY DESIGN, SIZE, DURATION: The study had a randomised, observer-blind design and comprised two parts. The participants used study medication during two or three treatment periods, separated by washout periods. Subjects in Part 1 (n = 61 treated) received 200 mg progesterone vaginal pessaries twice daily (bid), 400 mg pessaries bid and the comparator 90 mg progesterone vaginal gel once daily (od) in a 3-way crossover design. Subjects in Part 2 (n = 64 treated) received 100 mg pessaries bid in one period and 400 mg pessaries od in the other period in a 2-way crossover design. A subgroup of these subjects (n = 22 treated) received placebo vaginal pessaries bid in a third period in a non-randomised manner. The study was performed from May 2012 until April 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed at a clinical research centre in healthy female volunteers of reproductive age. The subjects used 2 mg estradiol bid for 24 days in each treatment cycle. Progesterone or placebo was administered vaginally from Day 15 onwards during 10 days. In each treatment period, an endometrial biopsy for histological evaluation was performed on Day 23 and pharmacokinetic parameters were determined after the first progesterone dose on Day 15 and after the last dose on Day 24. MAIN RESULTS AND THE ROLE OF CHANCE: Frequencies of (early and late) secretory transformation of the endometrium, i.e. adequate responses, during treatment with 200 mg and 400 mg vaginal pessaries bid were comparable with those during 90 mg vaginal gel treatment (90-94%), whereas lower secretory transformation rates were observed during treatment with 100 mg bid and 400 mg od (64-75%). At the time of the endometrial biopsy in the cycle the late secretory state of the endometrium, which is characteristic of adequate luteal support, was observed more often with 400 mg pessaries bid (90%) than with vaginal gel (82%) and with lower pessary doses (64-78%). Pharmacokinetic parameters after repeated dosing of vaginal pessaries showed a dose-dependent, but not dose-proportional, increase of plasma progesterone levels. The lowest incidence of bleeding and spotting was reported during treatment with 400 mg pessaries bid. LIMITATIONS REASONS FOR CAUTION: The primary outcome parameter, rate of secretory transformation of the endometrium, is a surrogate for endometrial receptivity and for the actual clinical efficacy. WIDER IMPLICATIONS OF THE FINDINGS: Delivery of progestesterone through 400 mg pessaries bid is an effective alternative method for luteal support in ART. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and L.D. Collins. I.D. and C.K. are directors of Dinox, a contract research organisation. I.K. is Managing Director of Pharmaplex and M.W. is Managing Director of M.A.R.C.O., service organisations involved in organisation/supervision and evaluation/reporting of clinical trials. All received funding for the conduct of the study from Actavis. S.H. and Th.M. are employees of Actavis. TRIAL REGISTRATION NUMBER: EudraCT number 2012-001726-95.

Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations.

PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

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".

Dose finding strategies involving interim analyses and unbalanced treatment allocation.

Dose finding studies usually require the application of multiple test procedures (MTP). A variety of procedures is available for data analyses. Focusing on testing only subset hypotheses of interest requires only limited alpha-adjustment. Specific strategies based on MTP, in particular closed test procedures, which also consider dropping dose groups and unequal group sizes, lead to substantial reduction in total sample size. Of course, strategies discussed here can be extended to comparisons of more than five groups, and they may be generalized to cover equivalence tests, too. For example, one may want to demonstrate therapeutical equivalence of two dose regimens like b.i.d. and o.d. administrations of the drug.

Evaluation of the bioequivalence of tablet and capsule formulations of granisetron in patients undergoing cytotoxic chemotherapy for malignant disease.

Granisetron is a novel, highly specific 5-hydroxytryptamine receptor antagonist given prophylactically to patients undergoing chemotherapy. An open, randomized, crossover trial was performed with 37 patients (24 females and 13 males) undergoing cytotoxic chemotherapy for malignant disease to compare an oral tablet (1-mg tablet given twice daily) with a clinical-trial capsule (1-mg capsule given twice daily). Complete pharmacokinetic data were determined for 24 patients (14 females and 10 males). The concentration of granisetron in plasma was measured by HPLC; the limit of quantitation was 0.2 ng/mL. The bioavailability evaluation was based mainly on the area under the curve (AUC) (mean values: 52.1 ng.h/mL for the capsule and 54.2 ng.h/mL for the tablet) and the maximum concentration (Cmax) (mean values: 7.42 ng/mL for the capsule and 8.18 ng/mL for the tablet) measured at the steady state after 7 days of continuous therapy. Wide interpatient variability in plasma granisetron levels after oral administration was observed. The 90% standard confidence interval for the geometric mean ratio overlapped the critical range, 0.8-1.25. Point estimates for AUC and Cmax based on two one-sided t tests and log-transformed data showed that the upper limit of the confidence interval was not within 20% of the mean for the capsule; the corresponding power analysis values for AUC and Cmax were 0.89 and 0.81, respectively. Despite bioequivalence not being proven, any differences that exist between the two formulations are likely to be small. There was no difference in efficacy or safety between the two formulations assessed.

Effect of food on the pharmacokinetics of the active metabolite of the prodrug repirinast.

The effect of food on the pharmacokinetics of the active metabolite of the new antiasthmatic drug repirinast was investigated in two different studies after oral administration of 300 mg of repirinast. In each study, 12 healthy volunteers received the repirinast dose under fasting or fed conditions in a crossover manner. In one study, a high-fat meal (American breakfast) was used and in another study, a low-fat, high-carbohydrate meal (continental breakfast) was used. Concentrations of the active metabolite in plasma and urine were determined by reversed-phase high-performance liquid chromatography with UV detection. After administration of repirinast with a low-fat and a high-fat meal, the relative bioavailability of the active metabolite increased by factors of 1.9 and 2.4, respectively, as expressed by area under the curve of concentration versus time from 0 to 12 h. The amount excreted into urine doubled after drug administration with both types of food and accounted for approximately 8% of the dose under fasting conditions and approximately 16% of the dose under fed conditions. Maximum concentrations in plasma were different between the two studies: mean maximum concentrations in plasma increased by factors of 1.7 and 3.2 after administration of drug with a low-fat (drug intake immediately after breakfast) and a high-fat breakfast (drug intake just before breakfast), respectively, compared with fasting conditions.

Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure.

Nitrendipine solution 5 mg.ml-1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (> or = 110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance < 5 ml.min-1) and 10 were at the predialysis stage (endogenous creatinine clearance 5-20 ml.min-1). The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy. After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Planning of drug interaction studies involving digoxin treatment: a statistical view.

The most valuable information we obtained from literature research was, that digoxin serum concentrations are generally of primary interest rather than area under curve or maximum concentration. Steady-state plasma levels appeared as a generally accepted endpoint to judge pharmacokinetic interaction. However, time-points for measurements were chosen differently and varied widely. Often, digoxin clearance was also considered. Despite the large amount of data, publications, opinions and single conclusions, no general statement could be made either about what is considered a relevant interaction or what is judged as "no interaction".

Pharmacokinetics of the active metabolite of the prodrug repirinast in healthy Caucasian volunteers after a single oral dose.

The pharmacokinetics of BAY w 8199, the active metabolite of the prodrug repirinast (BAY u 2372), has been investigated after oral administration of 150, 300 and 450 mg repirinast to twelve healthy male Caucasians. Plasma BAY w 8199 concentrations were very variable between subjects. The mean peak level (geom.mean; 1s-range) was 0.14 (0.08-0.25), 0.19 (0.13-0.29) and 0.24 (0.14-0.42) mg/l after the 150, 300 and 450 mg doses, respectively. Peak levels were reached 0.5-2.5 h after drug intake. Terminal half-lives were calculated as 5.9 h (150 mg), 8.0 h (300 mg) and 9.8 h (450 mg). The dose proportionality of the plasma profiles of BAY w 8199 and of its excretion in urine was demonstrated by testing several parameters. About 7.4% of each dose (calculated as BAY w 8199) was excreted in urine over 36 h. The renal clearance of about 27 l/h suggests that BAY w8199 is excreted by tubular secretion in addition to glomerular filtration.

Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone.

OBJECTIVE: Acarbose inhibits alpha-glucosidases of the small intestine and thus delays glucose release from complex carbohydrates. Therefore, its efficacy and acceptability as a first-line drug in non-insulin-dependent diabetes mellitus (NIDDM) insufficiently treated with diet alone was tested in a randomized double-blind placebo-controlled study. RESEARCH DESIGN AND METHODS: Ninety-four NIDDM subjects, aged 43-70 yr with average body mass index of 28 kg/m2 and undergoing a pretreatment period of at least 3 mo with diet alone, were treated with 100 mg acarbose three times daily or placebo for 24 wk. The patients were recruited after a 4-wk screening period of dietary reinforcement. The inclusion limits for patients termed diet not satisfactory were fasting blood glucose (FBG) greater than or equal to 7.8 mM and/or postprandial blood glucose (BG) greater than or equal to 10 mM. RESULTS: FBG was lowered in the acarbose group from 9.8 to 8.4 mM and in the placebo group from 10.2 to 9.6 mM after 24 wk (P = 0.007 vs. placebo). The most impressive therapeutic effect was a highly significant reduction of postprandial hyperglycemia for at least 5 h after the test meal (1-h postprandial BG with acarbose 10.4 mM and placebo 13.5 mM at 24 wk, P less than 0.001) accompanied by a significant decrease in HbA1 (acarbose 8.65%, placebo 9.32%, P = 0.003). Whereas C-peptide and fasting serum insulin were not significantly affected by acarbose, postprandial insulin increment was approximately 30% lower after 24 wk compared with placebo. Furthermore, acarbose significantly reduced 1-h postprandial triglyceride levels. After an initial phase of greater than 4 wk (when 76.6% in the acarbose group vs. 28% on placebo complained about flatulence, P less than 0.001), the drug was well accepted. At the end of the study, only 32% showed mild or moderate gastrointestinal sensations. CONCLUSIONS: Extrapolation shows that acarbose is an efficient and acceptable drug for the treatment of NIDDM with poor metabolic control by diet alone. It has beneficial effects on postprandial hyperinsulinemia and postprandial hypertriglyceridemia.

Effect of rioprostil, an oral prostaglandin E1 (PGE1) analogue, on lower esophageal sphincter pressure and on the motility of the distal esophagus in healthy volunteers.

The influence of rioprostil on the resting pressure of the lower esophageal sphincter (LESP) and on the bolus-stimulated contraction wave amplitude of primary peristalsis was investigated in 9 healthy male volunteers receiving placebo or 300 and 600 micrograms of rioprostil orally in a randomised, double-blind, threefold cross over study. Manometry was performed using the low-compliance pneumohydraulic infusion system. Rioprostil in a dose of 600 micrograms slightly increased LESP and contraction wave amplitudes measured 5 cm and 10 cm above LES. The duration of the peristaltic contractions was not altered. We conclude that rioprostil in doses which inhibit effectively gastric acid and pepsin secretion and heal peptic ulcers has no inhibitory effects on esophageal motility. Thus rioprostil may be a candidate to treat reflux esophagitis and studies are warranted to establish its efficacy.

[Follow-up of hip endoprostheses following completion of true stress conditions over a 10-year period]. / Verlaufsbeobachtung von Hüftendoprothesen nach Abschluss realer Belastungsbedingungen von 10 Jahren.

Results of a long term followup with total hip-replacement of the Endo-Klinik are presented. The analysed data-material exhibits a relative homogeneity because of a large series of one system of prostheses and homogeneous technique in surgery. Thus, analytic statistical methods (life-tables and regression models) could be used. In this way, prognostic factors on the durability of total hip replacement could be determined. These are essentially: long practical experience of the surgeon with one matured prosthesis-system, type of hip-joint disease, and the age of the patient. It is assumed, that in well organized special centres for joint replacement the failure rate could be reduced generally.

Multiparametric tumor marker (CA 19-9, CEA, AFP, POA) analyses of pancreatic juices and sera in pancreatic diseases.

With respect to their diagnostic utility CA 19-9, CEA, AFP and POA were determined in pancreatic secretions and serum of patients suffering from pancreatic cancer (n = 76/55) or chronic pancreatitis (n = 79/45) and of controls (n = 81/42), respectively. While the determination of AFP and POA both in pancreatic secretions and serum does not permit a differential diagnosis, serum CEA (greater than 10 ng/ml) and CA 19-9 (greater than 50 U/ml) levels were indicative of pancreatic cancer in 30% and 83%, respectively, with a rate of false positive results of 5% and 8.5% confined to the chronic pancreatitis patients. A combination of tumor marker analyses, that is, serum CA 19-9 (greater than 50 U/ml) and pancreatic secretion CEA (greater than 70 ng/ml), proved to be positive in 92.9% of tumor patients with a maximum of 10.5% false positives. Likewise, values of serum CA 19-9 (greater than 50 U/ml) and serum CEA (greater than 10 ng/ml) were found in 85.8% of the pancreatic cancer patients with only 8.8% false positives, which were confined to the chronic pancreatitis patients. These results indicate the superiority of multiparametric tumor marker analyses for the diagnosis of pancreatic cancer, especially when including new monoclonal antibody defined tumor markers.