Fosfomycin Pharmacokinetic Profile in Plasma and Urine and Quantitative Estimation in Prostate and Seminal Vesicles after One and Two Consecutive Doses of Oral Fosfomycin Trometamol in Healthy Male Volunteers.

The present Phase I study investigated, for the first time, fosfomycin pharmacokinetics in humans after two 3 g doses of fosfomycin trometamol administered 27 h apart, according to the dose regimen recommended for the prophylactic indication for transrectal prostate biopsy in adult men. Plasma, urine and seminal plasma concentrations were measured after one and two consecutive doses in 24 healthy men, representative of the target population of the prophylactic indication. Prostate and seminal vesicle concentrations were estimated based on seminal plasma concentrations using a one-step regression method. The exposure to fosfomycin was very similar in rate (Cmax, tmax) after one and two doses. The AUC showed a minimal increment. On average, the apparent volume of distribution was high (>100 L), and the mean clearance had an intermediate value. The total amount and dose fraction of fosfomycin excreted in urine showed a small increment after two doses. The renal clearance was about 5 L/h. The fosfomycin concentration in the prostate and seminal vesicles showed that the antibiotic increased on average after two consecutive doses. This result confirmed the ability of fosfomycin to distribute into the prostate and into seminal vesicles after one single dose and that a two consecutive dose regimen increases the antibiotic availability inside these peripheral tissues.

Randomized Pharmacokinetic Study of a Highly Purified Human Chorionic Gonadotropin and of a Recombinant Human Chorionic Gonadotropin Following Single Subcutaneous Administration in Healthy Women.

BACKGROUND AND OBJECTIVES: Exogenous human chorionic gonadotropin (hCG) acts on the final phase of the follicle maturation. Choriomon®, a highly purified hCG formulation, is approved in many European and extra-European countries for the induction of ovulation after stimulation of follicular development. The present study compares hCG bioavailability of Choriomon® (Test product) versus a recombinant hCG preparation (Ovitrelle®; Reference product). METHODS: In this randomized, two-way cross-over study, 26 healthy women received a single dose of Choriomon® (10,000 IU) and Ovitrelle® (250 µg; 6500 IU) by subcutaneous injection. hCG was determined in serum up to 192 h post-dose. Dose-normalized peak concentration (Cmax) and area under the concentration-time curve up to the time of the last quantifiable concentration (AUC0-t) and extrapolated to infinity (AUC0-∞) were calculated and compared between the two treatments. RESULTS: Serum hCG concentrations increased rapidly with a very similar pharmacokinetic curve for the two products. The test/reference geometric means ratio (GMR) for AUC0-t and AUC0-∞ corresponded to 121.31 and 119.81%, and the upper limits of the 90% confidence intervals (CIs) (130.21% and 128.51%, for AUC0-t and AUC0-∞, respectively) exceeded the 125% bioequivalence threshold. Cmax GMR was 146.89%, indicating a rate of hCG absorption approximately 50% greater for the test product (90% CI 132.30-163.10). Half-life (t1/2) was very similar (36.77 ± 5.11 h and 38.63 ± 6.08 h), whereas time to achieve Cmax (tmax) significantly differed, with median values of 16 h and 24 h for Choriomon® and Ovitrelle®, respectively, (p = 0.0023). CONCLUSIONS: The differences between Choriomon® and Ovitrelle® pharmacokinetic parameters can be ascribed to the different raw source of the products and are reflected in the approved dose regimens of the two hCG formulations. The observed lack of bioequivalence between the two compounds at the given doses is not clinically relevant, as results from Phase III studies indicated similar clinical efficacy and safety. The safety data are in line with the known safety profile of the two products. GOV REGISTRATION NO: NCT03735030.

Comparative Bioavailability Study of a New Vitamin D3 Orodispersible Film Versus a Marketed Oral Solution in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: An orally disintegrating film (ODF) formulation of vitamin D3 that dissolves rapidly in the mouth without drinking or chewing may be a worthwhile alternative to currently available drug products for therapeutic vitamin D supplementation. This study aimed to compare the bioavailability of a single dose of a vitamin D3 25000 I.U. ODF with those of a marketed oral vitamin D3 preparation in healthy subjects. METHODS: This Phase 1, randomised, parallel-group, open-label study compared the pharmacokinetics of calcifediol [25(OH)D3], the precursor of bioactive vitamin D3, after a single dose of a new vitamin D3 25,000 I.U. ODF with those of a Reference formulation (vitamin D3 25000 I.U./2.5 mL oral solution) in healthy adult subjects using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary objective was bioavailability under fed conditions, defined as maximum plasma concentration (Cmax) of 25(OH)D3 and area under the concentration-time curve from time zero to time t, the last quantifiable concentration (AUC0-t). The pharmacokinetics of 25(OH)D3 were also evaluated following the ODF administration under fasting conditions. Subjects were randomised to receive a single dose of the vitamin D3 25000 I.U. ODF or the Reference oral solution under fed conditions or the vitamin D3 ODF under fasting conditions. RESULTS: Forty-eight healthy subjects were randomised and completed the study. Overall, the pharmacokinetic profile was very similar across the three treatment groups, and bioavailability did not significantly differ among treatments. Under fed conditions, mean 25(OH)D3 plasma values for Cmax were 6.68 ± 2.03 versus 6.61 ± 2.62 ng/mL for the Test versus Reference formulations. Corresponding values for AUC0-t were 2364.80 ± 1336.97 versus 2150.52 ± 1622.76 ng/mL × h. Mean Cmax was slightly lower (6.68 ± 2.03 vs 7.23 ± 1.48 ng/mL) and the time to reach peak concentration was delayed (144 h [36-312] versus 42 h (2-480]) with the ODF under fed versus fasting conditions (p = 0.0371). The point estimates and 90 % CIs of the Testfed/Referencefed ratios of the geometric means showed that the bioavailability of exogenous 25(OH)D3 was, both in rate and extent of absorption, slightly higher with the vitamin D3 ODF than the vitamin D3 oral solution under the administration conditions recommended for the vitamin D3 oral solution. Palatability and ease of use of the ODF were satisfactory. CONCLUSION: The new ODF 25000 I.U. formulation provided a valuable alternative to the marketed oral solution for therapeutic vitamin D supplementation, with a bioavailability that was slightly higher than that of the vitamin D3 oral solution administered under the same conditions. TRIAL REGISTRATION: The study was retrospectively registered with the ISRCTN Registry (Registry code: ISRCTN13208948) on 27 November 2020.

Pharmacokinetics and Safety of Rifamycin SV after Single and Multiple Doses of MMX® Modified Release Tablets in Healthy Male and Female Volunteers.

The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV's pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0-24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18.

Pharmacokinetics and Safety of Single and Multiple Doses of Oral N-Acetylcysteine in Healthy Chinese and Caucasian Volunteers: An Open-Label, Phase I Clinical Study.

INTRODUCTION: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals. METHODS: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3 days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study. RESULTS: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8 years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0 h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean ± standard deviation 1.5 ± 0.4) and Caucasian (1.4 ± 0.2) participants. The half-life was 15.4 h in Chinese and 18.7 h in Caucasian participants, and the fraction of NAC excreted in urine in the 36 h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants. CONCLUSIONS: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile.

Effect of 3 Single Doses of Trazodone on QTc Interval in Healthy Subjects.

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60- and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60- and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure.

Pharmacokinetics and Safety of a Diclofenac Sodium 75 mg/1 mL Solution (Akis®/Dicloin®) Administered as a Single Intravenous Bolus Injection in Healthy Men and Women.

BACKGROUND: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-ß-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration. OBJECTIVES: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products. METHODS: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation. RESULTS: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus. CONCLUSIONS: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.

Survival of L. casei DG® (Lactobacillus paracasei CNCMI1572) in the gastrointestinal tract of a healthy paediatric population.

PURPOSE: Ability to survive the digestive process is a major factor in determining the effectiveness of a probiotic. In this study, the ability of the probiotic L. casei DG® (Lactobacillus paracasei CNCMI1572) to survive gastrointestinal transit in healthy children was investigated for the first time. METHODS: Twenty children aged 3-12 years received L. casei DG® as drinkable solution of 1 × 109 colony forming units (CFU), once daily for 7 consecutive days. Recovery in faecal samples was evaluated at baseline and at different time-points during and after administration. Defecation frequency, faeces consistency, digestive function and product safety were also assessed. RESULTS: Nineteen (95%) of the 20 enrolled children presented viable L. casei DG® cells in their faeces at least once during the study, with a maximum count (mean 4.3 log10 CFU/g ± 2.3) reached between day 4 and 6 from the beginning of consumption. Notably, for 11 (57.9%) of the 19 children with viable cells, L. casei DG® survived in faecal samples up to 3 days after treatment end. Defecation frequency, faeces consistency and digestive function did not change considerably during or after study treatment. Safety of the study product was very good. CONCLUSIONS: This study showed for the first time that L. casei DG® survives the gastrointestinal transit when ingested by children with a paediatric probiotic drinkable solution containing 1 × 109 CFU, and persists in the gut up to 3 days after the end of product intake, demonstrating resistance to gastric juices, hydrolytic enzymes and bile acids.

Pharmacokinetics of a Novel Sildenafil Orodispersible Film Administered by the Supralingual and the Sublingual Route to Healthy Men.

BACKGROUND: Sildenafil was the first selective drug available on the market as oral therapy for erectile dysfunction (ED). A novel sildenafil orodispersible film (ODF) for ED treatment, containing sildenafil citrate, has recently been marketed. OBJECTIVES: Study objective was to investigate sildenafil bioavailability of the novel ODF formulation after sublingual and supralingual administration. METHODS: In this randomised, two-way cross-over study, 12 healthy male volunteers received a single 50 mg sildenafil dose by the sublingual and supralingual administration routes. Plasma sildenafil was determined up to 12 h post-dose. Peak concentration (Cmax) and area under concentration-time curve (AUC0-t) were calculated and compared between the two administration routes by analysis of variance (ANOVA). RESULTS: Sublingual and supralingual administration can be claimed equivalent regarding the extent of sildenafil exposure since AUC0-t 90 % CIs corresponded to 94.90-110.58% and were within the pre-specified acceptance range. Cmax 90% CIs (79.92-125.57%) were only slightly outside the 80.00-125.00% limits, due to the small sample size, while the time to achieve Cmax did not differ between treatments (p = 0.9277). Rate of exposure of the two administration routes was therefore similar. Reported treatment-related adverse events were mild to moderate headache (33.3% of subjects) and vomiting (8.3%). CONCLUSIONS: In healthy men, sublingual and supralingual administration of sildenafil ODF resulted in a remarkably similar pharmacokinetic profile and confirmed the safety of both study treatments. The recently marketed sildenafil ODF, administered by both investigated routes, can provide a valuable alternative to the marketed solid oral forms (tablets) in ED treatment.

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers.

A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra®) after single-dose administration to 53 healthy male volunteers (aged 18-51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; Cmax) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC0-t) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration-time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film formulation can be used interchangeably with the conventional film-coated formulation.

Pharmacokinetics and Pharmacodynamics of Follicle-Stimulating Hormone in Healthy Women Receiving Single and Multiple Doses of Highly Purified Human Menotrophin and Urofollitrophin.

BACKGROUND AND OBJECTIVE: Highly purified human menotrophin and urofollitrophin preparations obtained from human urine via a novel patented purification method have been tested over a timeframe of 14 years in the studies presented in this article. The objective of the studies was to investigate the pharmacokinetics and the pharmacodynamics of follicle-stimulating hormone (FSH) after single subcutaneous and intramuscular doses and multiple subcutaneous doses of the tested preparations in healthy fertile pituitary-suppressed women. DESIGNS: We performed five open, randomised, crossover, single-dose bioequivalence and/or bioavailability studies and one open, multiple-dose, pharmacokinetics and pharmacodynamics study. STUDY SUBJECTS AND TREATMENTS: The six studies included 121 healthy fertile women taking their usual combined oral contraceptives for 3 months before the study: Study 1: 300 international units (IU) of highly purified menotrophin as single subcutaneous and intramuscular doses. Study 2: 300 IU of highly purified menotrophin (test formulation vs. comparator) as single subcutaneous doses. Study 3: 300 IU of highly purified urofollitrophin (hp-FSH) (test formulation vs. comparator) as single subcutaneous doses. Study 4: 300 IU (2 × 150 IU vs. 4 × 75 IU) of hp-FSH as single subcutaneous doses. Study 5: 225 and 445 IU of hp-FSH as single subcutaneous doses. Study 6: daily 225 IU of hp-FSH as subcutaneous doses for 5 consecutive days. MAIN OUTCOME MEASURES: The main outcome measures were the FSH pharmacokinetic parameters, estradiol concentrations, and the number and size of the follicles. RESULTS: FSH after single subcutaneous and intramuscular injections of menotrophin or urofollitrophin attained a systemic peak (maximum) concentration (C max) that was on average consistent throughout the first four studies and ranged from 4.98 to 7.50 IU/L. The area under the plasma concentration-time curve (AUC) from administration to the last observed concentration time t (AUCt) ranged from 409.71 to 486.16 IU/L·h and the elimination half-life (t ½) ranged from 39.02 to 53.63 h. After multiple doses of urofollitrophin (225 IU) for 5 days, FSH attained a mean C max of 14.93 ± 2.92 IU/L and had an AUC during the time interval τ between two consecutive doses at steady state (AUCτ) of 322.59 ± 57.92 IU/L·h, which was similar to the mean AUCt after a single subcutaneous dose of 225 IU of urofollitrophin in study 5 (306.82 ± 68.37 IU/L·h). CONCLUSIONS: In our studies, the intramuscular and subcutaneous routes of menotrophin were equivalent; both menotrophin and urofollitrophin were bioequivalent to their marketed reference; FSH kinetic parameters following injection of urofollitrophin were dose proportional and independent from the administered concentration; and multiple doses of FSH increased estradiol levels and enhanced growth of follicles with a good dose-response correlation. Local tolerability was excellent throughout the six studies.

Effects of a novel finasteride 0.25% topical solution on scalp and serum dihydrotestosterone in healthy men with androgenetic alopecia.

OBJECTIVE: The effects on scalp and serum dihydrotestosterone (DHT) of different doses of a novel topical solution of 0.25% finasteride (P-3074), a type 2 5α-reductase, were investigated in men with androgenetic alopecia. METHODS: Two randomized, parallel-group studies were conducted. Study I: 18 men received 1 mL (2.275 mg) P-3074, applied to the scalp once a day (o.d.) or twice a day (b.i.d), or 1 mg oral tablet o.d. for 1 week. Study II: 32 men received P-3074 at the dose of 100 (0.2275 mg), 200 (0.455 mg), 300 (0.6285 mg), or 400 (0.91 mg) µL or the vehicle o.d. for 1 week. Scalp and serum DHT and serum testosterone were evaluated at baseline and treatment end. RESULTS: Change from baseline in scalp DHT was -70% for P-3074 o.d. and approx. -50% for P-3074 b.i.d. and the tablet. Serum DHT decreased by 60 - 70%. The doses of 100 and 200 µL P-3074 resulted in a -47/-52% scalp DHT reduction, similar to the 300 and 400 µL doses (i.e., -37/-54%). A -5.6% inhibition was observed for the vehicle. Serum DHT was reduced by only -24/-26% with 100 and 200 µL P-3074 and by -44/-48% with 300 and 400 µL P-3074. No relevant changes occurred for serum testosterone. CONCLUSIONS: The novel finasteride 0.25% solution applied o.d. at the doses of 100 and 200 µL results in an appropriate inhibition of scalp DHT potentially minimizing the untoward sexual side-effects linked to a systemic DHT reduction.

Recombinant filgrastim (BK0023) pharmacodynamics and pharmacokinetics after single and multiple escalating doses in an equivalence study in healthy men.

BACKGROUND AND OBJECTIVES: The new filgrastim formulation, BK0023, whose synthesis method is patented, was tested in a phase I clinical study that was aimed at investigating the pharmacodynamic and pharmacokinetic equivalence and the safety of BK0023 in healthy male subjects. METHODS: Single and multiple escalating doses were administered to healthy male volunteers according to a double-blind, randomised, two-way crossover design. Thirty-two subjects received subcutaneous filgrastim 2.5 µg/kg/day for 7 consecutive days in each period, 36 subjects received 5 µg/kg/day for 7 days in each period, and 22 subjects received 10 µg/kg/day for 5 days. Absolute neutrophil count (ANC) and CD34+ cell count were measured in whole blood as primary and secondary pharmacodynamic parameters. Filgrastim concentrations were measured in serum to calculate the primary pharmacokinetic parameters. RESULTS: The maximum ANC and the area under the curve of the ANC after the first dose and to the end of treatment satisfied the equivalence criterion (95 % confidence intervals within 85-115 or 85-117 % in case of log-transformation). At all three dose regimens, BK0023 was also bioequivalent to the reference product in terms of pharmacokinetic profile of serum filgrastim. The frequency of the treatment-emergent adverse events did not differ significantly between treatments, with the most frequent untoward effects being back and bone pain. CONCLUSIONS: Equivalence could be established using both the baseline-adjusted values and the original unadjusted values. The tested formulation at all three dose regimens was also bioequivalent to the reference product in terms of pharmacokinetic profile.

A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers.

OBJECTIVE: Finasteride, a selective inhibitor of type 2 5-α reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT. METHODS: 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined. RESULTS: After multiple doses, mean (± SD) finasteride C(max) and AUC(0-t) corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT was reduced by ~ 68 - 75% with the topical solution and by ~ 62 - 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred. CONCLUSIONS: A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride ormulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).

Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results.

BACKGROUND: Prostate-specific antigen (PSA) is used as an outcome measure for relapsed disease in prostate cancer. Nonetheless, there are considerable concerns about its indiscriminate use as a surrogate endpoint for cell growth or survival. We hypothesized that treatment with a luteinizing hormone releasing hormone (LHRH) analog would decrease PSA levels even in the absence of malignant disease. METHODS: We determined testosterone and PSA levels in 30 healthy volunteers after a single intramuscular injection of a LHRH depot formulation. Testosterone and PSA levels were quantified by radioimmunoassay and electrochemi-luminescence immunoassay, respectively. RESULTS: After an initial flare-up during the first 3 days testosterone decreased reaching castration levels in 18 of the 30 young men (60%). After the nadir on day 28, testosterone levels increased to normal again. Changes in PSA paralleled those of testosterone. Castration reduced PSA levels by 29% (95% CI 19%-39%) compared to baseline (p<0.0001). CONCLUSIONS: LHRH superagonists decrease PSA levels by testosterone deprivation. Conferring these findings to tumor patients, decreases in PSA after treatment with LHRH analogs might not only reflect disease regression but also a direct testosterone mediated effect on PSA. Thus, PSA levels should be cautiously interpreted when patients receive hormonal therapy.

Pharmacodynamics and pharmacokinetics of a novel, low-dose, soft-gel capsule of acetylsalicylic acid in comparison with an oral solution after single-dose administration to healthy volunteers: a phase I, two-way crossover study.

BACKGROUND: Low-dose acetylsalicylic acid (ASA; aspirin) is well-established as a platelet anti-aggregating agent for the secondary prevention of cardiovascular events. OBJECTIVES: The objective of this study was to investigate the non-inferiority of a novel ASA 75 mg soft-gel capsule formulation compared with a marketed powder for oral solution in terms of reduction in serum thromboxane B2 (TXB2), a surrogate for platelet aggregation. Pharmacokinetics and tolerability of the products were also investigated. METHODS: In this randomised, two-way crossover study, 46 male and female healthy subjects received a single dose of the investigational products in two periods separated by a 14-day washout. Serum TXB2 and plasma ASA were determined up to 24 h post-dose. Maximum percentage of TXB2 inhibition (I max) and area under the inhibition-time curve (AUICt) were calculated. Non-inferiority was assumed if the lower limits of the 95 % confidence intervals (CIs) for the two pharmacodynamic parameters were above 85 %. RESULTS: The 95 % CI lower limits were 95.35 % for I max and 86.12 % for AUICt, i.e. within the pre-specified delta. Time to achieve I max did not differ between treatments (p = 0.88). The two formulations were bioequivalent as regards the extent of ASA exposure (area under the plasma concentration-time curve from zero to time t [AUCt] 90 % CIs 96.67-113.37); a delayed ASA absorption (later time to reach maximum plasma concentration [t max], lower maximum plasma concentration [C max]) was observed for the test product. No treatment-related adverse events were reported. CONCLUSIONS: In healthy subjects, the 75 mg soft-gel capsules were not inferior to the oral solution in terms of serum TXB2 inhibition, indicating that the novel formulation could be an effective alternative in the secondary prevention of cardiovascular events.

Bioequivalence study of a novel orodispersible tablet of meloxicam in a porous matrix after single-dose administration in healthy volunteers.

BACKGROUND: Meloxicam is a non-steroidal anti-inflammatory drug, indicated for osteoarthritis exacerbations, rheumatoid arthritis and ankylosing spondylitis symptomatic treatment. OBJECTIVE: To compare the bioavailability of a 15 mg meloxicam orodispersible tablet (ODT) and a reference 15 mg tablet in healthy volunteers. METHODS: Two randomized, crossover, bioequivalence studies were conducted. In both studies, 28 volunteers were randomly assigned to receive test ODT and reference tablet formulations in single dose under fasting conditions in two study periods, with a 7-day (Study I) or 14-day (Study II) wash-out between administrations. Blood samples were collected at pre-specified times. Pharmacokinetic parameters were obtained by noncompartmental analysis. Bioequivalence was assumed if the 90% confidence interval of the test/reference ratio of the least-squares means for Cmax, AUC0-t and AUC0-∞were within the 80.00 -125.00% range, according to the current guidelines. RESULTS: All 28 subjects in Study I and 26 subjects in study II completed the study and were included in the analysis. The 90% confidence intervals of the geometric means ratios for the logtransformed Cmax, AUC0-t and AUC0-∞were 87 - 96%, 88 - 96% and 87 - 96% in Study I, and 99 - 105%, 98 - 104% and 108 - 120% in Study II. Test product was characterized by a slightly earlier tmax than the reference, i.e., 4.9 ± 1.1 vs. 5.8 ± 2.6 hours in Study I (p = 1.000) and 3.8 ± 2.0 vs. 4.8 ±1.6 hours in Study II (p = 0.0054). The two drugs were well tolerated. CONCLUSIONS: Test and reference formulations met the regulatory criteria for bioequivalence in the fasting healthy volunteers enrolled.

Pharmacokinetic and tolerability of i.m. disodium clodronate 200 mg/lidocaine 1%, given twice monthly, in comparison with i.m. disodium clodronate 100 mg/lidocaine 1%, given weekly, in healthy postmenopausal female patients.

BACKGROUND: Clodronate is a bisphosphonate effective in the prevention and treatment of osteoporosis in postmenopausal women. Non-adherence to bisphosphonates, however, is a major issue in clinical practice. Simplifying dose regimens may increase compliance. OBJECTIVES: To assess bioequivalence between an intramuscular (i.m.) clodronate 200 mg/lidocaine 1% twice-a-month formulation and a clodronate 100 mg/lidocaine 1% weekly formulation in 32 postmenopausal women. METHODS: In this double-blind, randomized, two-way crossover study, test and reference formulations were administered in single dose, with a 2-week wash-out between administrations. The primary endpoint was clodronic acid cumulative excretion in the first 24 hours after injection (Xu0-24h). Cumulative excretion in the 72 hours post-dose (Xu0-72h) and maximum excretion rate (Ratemax) were also evaluated. Bioequivalence was assumed if the 90% confidence intervals (CIs) of the geometric means ratios of the dose-normalized parameters were within the 80.00 - 125.00% range. Local tolerability was evaluated. RESULTS: Mean Xu0-24h values were 114.03 ±23.13 mg and 55.22 ±9.73 mg for clodronate 200 mg and 100 mg. The 90% CIs for dose-normalized Xu0-24h, Xu0-72h and Ratemax ere 95 -110%, 94 -107% and 95 - 113%. Local tolerability of both treatments was good. The differences in pain intensity between formulations were not sigificantly different at most assessment times. Headache was the only treatment-related adverse event. CONCLUSIONS: Bioequivalence of the two formulations was confirmed in terms of dose-normalized rate and amount of clodronic acid excretion. This result, together with the favorable tolerability of the novel 200 mg formulation, suggests the possibility of reducing the number of i.m. administrations from once-a-week to twice-a-month.

Pressor response to oral tyramine and monoamine oxidase inhibition during treatment with ralfinamide (NW-1029).

Ralfinamide, an original Na(+) channel blocker developed for the treatment of chronic pain, inhibits monoamineoxidase-B with no apparent effect on monoamineoxidase-A. To evaluate the pressor response to oral tyramine under fasting conditions during treatment with ralfinamide in healthy normotensive subjects. Ten women and 10 men aged 52.9 ± 5.5, sensitive to the oral tyramine pressor effect in the dose range 200-400 mg, received ralfinamide 320 mg daily during 7 days of confinement. Starting on day 5, ascending doses of tyramine 50, 100 and 200 mg were daily administered to subjects, who had responded to 200 mg at screening, and 100, 200 and 400 mg to the 400 mg responders. Vital parameters were monitored. The systolic blood pressure peak (ΔSBP), the time to achieve the peak (Δt) and the area under the pressure curve (over baseline) were calculated. ΔSBP ≥ 30 mmHg were measured for one subject with tyramine 200 mg and for 11 subjects with 400 mg, whilst ΔSBP was <30 mmHg for eight subjects at all the tested doses. ΔSBP, Δt and AUC after co-treatment with ralfinamide and tyramine were not significantly different from those measured after tyramine alone. Ralfinamide did not potentiate the pressor response to single oral doses of tyramine from 50 to 400 mg. These preliminary results give an evidence for the specificity of ralfinamide for MAO-B in comparison with MAO-A, analogously to the observations previously done for safinamide. Dietary tyramine restrictions may not be necessary in neuropathic pain patients receiving ralfinamide as a therapy.

Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route.

A novel aqueous progesterone formulation was developed. Study I: Three-way cross-over, open-label study in 24 post-menopausal women. Comparison of the pharmacokinetic profiles of a single 100 mg dose of test product administered by subcutaneous (s.c.) and intramuscular (i.m.) injection and an i.m. reference oily product. Study II: Three-way cross-over open-label study of 25, 50 and 100 mg s.c. single doses of the aqueous formulation in 12 post-menopausal women. Study III: Parallel-group, observer-blinded study in 25 fertile women administered multiple s.c. 25 and 50 mg doses of the aqueous formulation once daily for 11 days. Baseline-corrected pharmacokinetic parameters were evaluated. Aqueous formulation (100 mg) was promptly absorbed, achieving progesterone peak serum levels at an earlier time than the reference (1 h vs. 7 h; p < 0.0001). Test and reference were bioequivalent in the extent of exposure: confidence intervals for AUC(0-t) geometric means ratios were within the pre-specified 80-125% limits. Pharmacokinetics was linear over the range of doses studied. Steady state was reached within 4 days of multiple dose treatment. All treatments were well tolerated. Considering the advantages given by the possibility of self-medication, the s.c. aqueous formulation could offer a convenient alternative for patients on assisted reproductive technology treatments.