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9 december 2010, 15:08 • 3 minuten leestijd

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PRA Acquisition of Pharma Bio-Research May Lead to New Drug Development Labs in US

PRA International (Reston, VA, www.prainternational.com) has completed the acquisition of Pharma Bio-Research (Zuidlaren, The Netherlands), an early-phase clinical development and bioanalytical company.

PRA International (Reston, VA, www.prainternational.com ) has completed the acquisition of Pharma Bio-Research (Zuidlaren, The Netherlands), an early-phase clinical development and bioanalytical company. Plans for PRA International to acquire Pharma Bio-Research were originally announced on June 19. The acquisition, valued at 84.6 million Euros, provides PRA International with early-phase development and bioanalytical laboratory facilities in Europe. PRA also expects to draw on Pharma Bio-Research’s expertise to establish drug development laboratory facilities in the US for biotech and pharmaceutical clients.

PRA INTERNATIONAL ANNOUNCES DEFINITIVE AGREEMENT TO ACQUIRE PHARMA BIO-RESEARCH

PRA International, a leading global clinical research organization, today announced a definitive agreement to acquire Pharma Bio-Research (PBR), a private early- phase clinical development company based in Zuidlaren, The Netherlands. Yahoo News

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Pra health sciences acquires pharma bio-research bv, on june 19, 2006, pra health sciences acquired life science company pharma bio-research bv from hgcapital for 85m eur, acquisition highlights.

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Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator

Birte k skrumsager.

1 Clinical Pharmacology, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

Benedicte Kiehr

2 Pharmacokinetics, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

Poul Christian Pedersen

3 Biostatistics, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

Mireille Gerrits

4 Pharma Bio-Research International B.V., Zuidlaren, The Netherlands

Norma Watson

5 Inveresk Clinical Research Limited, Edinburgh, United Kingdom

Ketil Bjarnason

6 Clinical Development, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days.

The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing.

Levormeloxifene was tolerated well after single doses in the range of 2.5–320 mg and multiple once daily dosing in the range of 20–160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg levormeloxifene. Five weeks of treatment with 20–160 mg levormeloxifene and 8 weeks of treatment with 40 or 80 mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLaps™) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19–25% and 28–35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean t max : 2–3 h), a slow elimination (mean t 1/2 : 4.8–8.4 days) and dose linearity of C max and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (R A : 3–5).

Conclusions

Short-term administration of levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.

Introduction

Levormeloxifene (NNC 46–0020, (−)-3,4- trans -7-methoxy-2,2-dimethyl-3-phenyl-4-[4-[2-(pyrrolidin-1-yl)ethoxy] phenyl]chromane) is a selective oestrogen receptor modulator (SERM). It is the (−)-enantiomer of ormeloxifene which, under the name Centchroman, has been on the market in India as an oral contraceptive since the late 1980s and is presently under development in India for the treatment of advanced breast cancer [ 1 ].

Oestrogen replacement therapy (ERT) is effective in both preventing postmenopausal osteoporosis and reducing the risk of cardiovascular disease [ 2 , 3 ]. However, without the concomitant administration of progesterone supplements, ERT is associated with an increased stimulation of the endometrium causing hyperplasia and risk of cancer [ 4 – 6 ]. As an alternative to current ERT, levormeloxifene was being developed for the prevention and treatment of postmenopausal osteoporosis.

In an oestrogen-depleted rat model of human osteoporosis an oral dose of 0.5 mg kg −1 of levormeloxifene given three times weekly for 5 weeks was sufficient to maintain bone densities at the level of sham-operated animals [ 7 ] and the average steady state plasma concentration of levormeloxifene corresponding to an effective dose was approximately 20–25 ng ml −1 . The uteri from ovariectomized (OVX) animals treated with levormeloxifene showed no evidence of epithelial proliferation or glandular stimulation [ 8 – 10 ]. In addition, levormeloxifene was shown to reduce the serum cholesterol in OVX rats [ 11 ] and to prevent aortic cholesterol accumulation in the OVX rabbit model [ 9 ]. In summary, the preclinical data suggest that levormeloxifene has oestrogenic effects on the skeleton and the cardiovascular system without inducing endometrial hyperplasia.

The objectives of the first two human studies of levormeloxifene were to investigate the tolerability, safety and pharmacokinetics of levormeloxifene and to confirm in man the promising pharmacological profile observed in preclinical studies.

Prior to the study the clinical trial protocols and written informed consent forms were approved by independent ethics committees of Inveresk Research, Edinburgh, Phase I (Clinical Trials Unit) Limited, Plymouth, Drug Development (Scotland) Limited, Dundee, and Simbec Research Limited, Methyr Tydfil all in the United Kingdom (first human single dose trial) and in the Netherlands of the Stichting Beoordeling Ethiek Bio-Medisch Onderzoek (multiple dose trial). Before entering the trials, the nature of the studies was explained to each participant and written informed consent was obtained. The trials were conducted in accordance with the amended Helsinki Declaration of 1989 [ 12 ] and Good Clinical Practice (GCP) described by the Commission of the European Communities in 1990 [ 13 ].

All methodological details apply to both trials unless otherwise stated. The two trials were of a randomized, double-blind, placebo controlled, parallel group design. Levormeloxifene was administered orally as levormeloxifene fumarate. Doses were stated in mg of the base. In total, 104 healthy postmenopausal women aged 47–66 years, all having at least a 1 year history of physiological or surgical amenorrhoea and all not receiving hormone replacement treatment (HRT) for the last 3 months before drug administration, participated in the trials. The 17-β-oestradiol (E 2 ) plasma concentration was below 110 nmol ml −1 and the follicle stimulating hormone (FSH) measured in trial 2 only was above 40 IU l −1 . For all subjects body weights were within 20% of ideal weight (Metropolitan Life tables) and ranged from 42 to 90 kg. All subjects were healthy based on a pre-study physical examination, routine haematology and clinical chemistry, urinalysis, screening for drugs of abuse, tests of hepatitis B and C, and HIV and pregnancy test. The dose administration was managed by a nurse, the investigator or coinvestigators.

Trial 1, single dose study

Single ascending doses of 2.5, 10, 30, 80, 160 and 320 mg levormeloxifene were administered to six groups of eight subjects (six active, two placebo). Levormeloxifene was given as a solution of 1 mg ml −1 and the placebo as a solution of 40 mg l −1 quinine sulphate. Hydroxypropyl-β-cyclodextrin was added to both as a solubiliser. The subjects were fasted from 8 h before until 4 h after dose administration. The trial was conducted by Inveresk Clinical Research Limited, Edinburgh in cooperation with three other Clinical Research Organizations in the United Kingdom.

Trial 2, multiple dose study

The trial consisted of two parts: Part 1 with multiple dosing for 35 days, and Part 2 with multiple dosing for 56 days. The objectives of Part 1 were to assess the safety profile, tolerability and pharmacokinetics after ascending oral multiple dosing at three dose levels of levormeloxifene in three groups. The objectives of Part 2 were to gain additional safety information in a larger group of women for a longer period of dosing at two dose levels of levormeloxifene. A secondary objective of both parts of the trial was to investigate any effect of levormeloxifene on a metabolic marker of bone resorption, urinary collagen I C-terminal telopeptide fragments (CrossLaps™) corrected for creatinine excretion. In Part 1, three groups of eight subjects (six active, two placebo) received, respectively, ascending doses of 20, 80 and 160 mg levormeloxifene once daily for 35 days. Based on the results of Part 1, two groups of 16 subjects (12 active, four placebo) were dosed daily for 56 days with 40 and 80 mg levormeloxifene, respectively, in Part 2. The duration of the trial was 69 days for all subjects. The trial products were given as tablets in the morning after an overnight fast and fasting was continued until 0.5 h after dosing.

The trial products were tablets of 10 mg for a dose of 20 mg levormeloxifene, tablets of 40 mg at the other doses and corresponding placebo tablets of similar size and colour.

The trial was performed by Pharma Bio-Research, Zuidlaren, the Netherlands.

Safety assessment and pharmacodynamic evaluation

Vital signs [blood pressure (BP), heart rate (HR), body temperature], ECG (in trial 1 including continuous ECG monitoring 0–4 h after dosing), routine haematology and clinical chemistry, urinalysis, plasma concentrations of E 2 , follicle stimulating hormone (FSH), luteinizing hormone (LH, in trial 2 only) and adverse events were evaluated before and at regular intervals during the trials. In trial 2 the concentrations of a marker of metabolic bone turnover, [urinary collagen I C-terminal telopeptide corrected for creatinine (CrossLaps™, Osteometer Biotech, Herlev, Denmark)], was determined by Hôpital Edouard Herriot, Lyons, France before commencement of dosing, after the last dose and at the final visit. For subjects reporting bleeding, an ultrasonic measurement of the endometrium was performed, and for subjects with an endometrium above 8 mm, a biopsy for histopathological examination was removed to establish a precise diagnosis.

Pharmacokinetics

In trial 1, blood samples were collected before and at intervals up to 648 h (27 days) after dosing (18 samples in total). In trial 2, blood sampling was performed before the first dose and at intervals up to 24 h after the first dose and weekly thereafter (trough sampling) and again after the final dose at intervals up to 34 or 13 days after last dose. In total 31 and 25 samples were taken in Part 1 and Part 2, respectively. Plasma was separated by centrifugation and assayed for levormeloxifene and 7-desmethyllevormeloxifene, the main metabolite of levormeloxifene, by a validated reversed phase high pressure liquid chromatography assay using solid phase extraction [ 14 ]. The lower limits of quantification were 1.5 ng ml −1 and 2.5 ng ml −1 for levormeloxifene and 7-desmethyllevormeloxifene, respectively. Inter- and intra-assay coefficients of variation were < 8% for both compounds at all concentrations except at the limit of quantification where they were 15%. Inter- and intra-assay accuracy calculated as a percentage of the nominal value were between 90 and 114% for both compounds.

Pharmacokinetic data were analysed by noncompartmental techniques using the WinNonlin 1.1 software (Scientific Consulting Inc. Apex, NC, USA). For peak concentration in plasma, C max , and time to reach peak concentration, t max , observed values were taken. The apparent elimination rate constant, λ z , was estimated by log-linear regression analysis on the terminal phase of the plasma concentration vs time curve. The terminal phase was assessed subjectively over at least the final three sampling points with a measured concentration equal to or above the lower limit of quantification. The terminal half-life, t 1/2, was calculated as (ln2)/λ z . After single doses, the total area under the plasma concentration vs time curve (AUC) was determined by the linear trapezoidal rule from time zero to the last sampling point equal or above the lower limit of quantification, AUC(0, t ), plus the residual area as estimated by log-linear extrapolation to infinity. After multiple dosing, the area during one dosing interval (τ: 24 h) was calculated after the first dose, AUC(1, τ), and at steady state AUC ss (0, τ) using the linear trapezoidal rule. Trough plasma concentrations on the approach to and at steady state were determined at weekly intervals. The observed degree of accumulation as calculated by

on days 35 or 56 was compared with the anticipated accumulation deduced from the equation

Statistical analysis

The statistical evaluations were performed using the statistical package SAS (v 6.07 or SAS for Windows). The level of significance of all tests was 0.05.

For all endpoints, i.e. vital signs, ECG, FSH, LH, E 2 , haematology, clinical chemistry, urinary collagen I C-terminal telopeptide concentration (corrected for creatinine excretion and logarithmic transformed), changes from baseline to each time point separately were analysed using analysis of variance ( anova ) techniques including terms for dose group and dose level. In addition, a repeated measurement analysis of variance was performed at the given time points. The factors in this model included dose group, dose level, subject within dose level and dose group, time point, dose level × time point interaction and dose group × time point interaction. Furthermore, the overall percent reduction in urinary collagen I C-terminal telopeptide concentration for active treatment compared with placebo was calculated as 100(Y T – Y P )/(100 – Y P ), where Y T is percent reduction for active treatment and Y P is percent reduction for placebo, with 95% confidence intervals.

The statistical analysis of the pharmacokinetic results in both trials was performed using analysis of variance testing differences between dose levels. For the assessment of dose relationship, linear regression analysis was performed for ln-transformed values of dose adjusted C max , AUC (trial 1 only), C ss,min , AUC(1, τ) and AUC ss (0, τ) (trial 2 Part 1 only) on ln(dose). In trial 2 Part 2 with two dose levels only, dose linearity was not assessed.

Tolerability and adverse events

Forty-eight subjects were randomized and completed the single dose trial. Levormeloxifene was tolerated well after all single doses studied. There was one serious event with four separate symptoms. Five minutes after dosing (10 mg) the subject developed tachycardia (maximum 131 beats min −1 ), distal parasthesia, bodily discomfort and increased blood pressure (maximum 180/100 mmHg). All events resolved in 30–60 min, but as a similar pattern of events, of milder degree, continued to happen on a daily basis for approximately 1 h each morning, the investigator concluded that they were unlikely to be related to the trial medication. All other adverse events were generally mild to moderate in severity and resolved completely. No maximum tolerated dose was identified, and no differences between the adverse event profiles, in frequency or type of event, after levormeloxifene or placebo were observed. There was no evidence of an increase in the frequency of adverse events with increasing dose ( Table 1 ).

Number of subjects with adverse events (in > 10% of subjects) at ascending single doses of levormeloxifene or placebo.

In Part 1 of this trial, daily administration of the highest dose (160 mg levormeloxifene) resulted in significantly more adverse events per subject than after administration of 20 mg or 80 mg levormeloxifene. Consequently, lower daily doses of 40 mg and 80 mg levormeloxifene were selected for Part 2 of the study. The most frequent adverse events reported with daily dosing of levormeloxifene (20 mg to 160 mg) for up to 56 days were headache, abdominal pain, hot flushes and leukorrhea, the latter in five subjects after the highest dose ( Table 2 ). One severe adverse event, syncope, was reported after treatment with placebo but none after the drug. One subject developed a painful breast tumour, which was histopathologically benign and was withdrawn after 25 days of 80 mg levormeloxifene. The event was considered unrelated to the drug treatment. A second subject was withdrawn after 13 days of placebo treatment as a result of a depressive disorder which was present before the first drug administration.

Number of adverse events per subject during multiple dosing for 35 or 56 days for those events with a frequency ≥0.5 in one dose group.

In Part 1, 71 (50%) of a total of 142 events were reported during treatment with 160 mg levormeloxifene compared with 17%, 21%, and 12% during treatment with placebo, 20 mg levormeloxifene and 80 mg levormeloxifene, respectively. Most of the adverse events (83%) were mild. The most frequently reported drug-related adverse events after 160 mg levormeloxifene treatment were headache (four subjects), leukorrhea (five subjects), and abdominal pain (three subjects). In Part 2, most adverse events (92%) were mild, 57% were considered to be possibly or probably related to the trial product, and most of them occurred during active treatment (15%, 46% and 39% after placebo, 40 mg levormeloxifene and 80 mg levormeloxifene, respectively). Abdominal pain was the most frequently observed drug-related adverse event, reported by 46% of subjects taking levormeloxifene compared with 13% of the placebo group.

After withdrawal of levormeloxifene, five subjects reported haemorrhagic vaginal discharge (one subject in each of 20, 40 and 80 mg groups, and two subjects in the 160 mg group), starting 12–33 days after withdrawal of levormeloxifene (80–160 mg) and lasting from 3 h up to 2 weeks. An ultrasonic measurement of the endometrium found a thickened endometrial stripe (> 8 mm) in four of the five subjects (9–15 mm). Histopathological examinations of the endometrium showed a normal endometrium without hyperplasia or atypia.

Pharmacodynamics

Effect on metabolic bone marker, alkaline phosphatase and lipids.

The effect on urinary excretion of collagen I C-telopeptide, total alkaline phosphatase, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, and on the hormones FSH and LH after 35 or 56 days of treatment are given in Tables 3 and ​ and4. 4 . Treatment with levormeloxifene resulted in a statistically significant reduction in urinary collagen I C-terminal telopeptide excretion compared with placebo ( Table 3 ). After 35 days of dosing, there was no statistically significant difference in the reduction of collagen I C-terminal telopeptide concentrations between the three active groups and placebo. However, with more subjects per dose group and a treatment period of 56 days, the difference between active groups and placebo became statistically significant. The reduction in the concentration of this biochemical bone marker was 44% in the two active groups compared with 13% in placebo ( P = 0.015). The overall percent reduction in collagen I C-terminal telopeptide for active treatment compared to placebo were 44.4% [95% CI: 11.3, 65.1] in Part 1 and 35.5% [95% CI: 14.0, 51.6] in Part 2, calculated from the expression 100(Y T −Y P )/(100−Y P ), where Y T is percent reduction after active treatment and Y P is percent reduction after placebo. No dose-dependent decrease was observed over the dose range studied. The collagen I C-terminal telopeptide concentrations remained below baseline values after 14 or 35 days of withdrawal (data not shown).

Effect of levormeloxifene on collagen I C-telopeptide, total alkaline phosphatase, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, FSH, and LH after 35 or 56 days of treatment, expressed as % decrease from baseline (mean±s.e. mean).

Mean of baseline and mean of absolute change in collagen I C-telopeptide, total alkaline phosphatase, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, FSH, and LH after 35 or 56 days of treatment with levomeloxifene.

Following treatment with 160 mg levormeloxifene for 5 weeks, and with 40 mg or 80 mg levormeloxifene for 8 weeks, alkaline phosphatase was significantly reduced by approximately 24–27% as compared with placebo ( Table 3 ). The reductions in total cholesterol and LDL-cholesterol were approximately 19–25% and 28–35%, respectively, after active treatment compared with placebo ( Figure 1 and Table 3 ). There were no statistically significant effects on triglycerides or HDL-cholesterol.

Serum alkaline phosphatase, total cholesterol and LDL-cholesterol concentrations during 8 weeks of administration of levormeloxifene expressed as a percentage of baseline values (mean±s.e. mean). ▪ placebo, □ 40 mg, ^ 80 mg levormeloxifene.

Vital signs and ECG

No clinically significant alterations of supine and standing blood pressure, pulse or body temperature were found in either of the trials and no clinically relevant changes in the ECG or 4 h ECG monitoring were observed.

Haematology and clinical chemistry

No clinically significant `changes were detected in haematology or clinical chemistry measurements except the expected therapeutic effects on bone and lipid metabolism parameters as described earlier.

Following 5 and 8 weeks treatment with levormeloxifene, the concentrations of FSH and LH were significantly reduced by approximately 50% from mean concentrations of FSH of 59–85 IU l −1 and mean concentrations of LH of 24–39 IU l −1 ( P < 0.05) ( Tables 3 and ​ and4). 4 ). No effect on plasma oestradiol concentrations was observed (data not shown).

The pharmacokinetics of levormeloxifene are reported in Table 5 and the corresponding plasma concentrations are shown for the drug and its major metabolite in Figure 2 . Levormeloxifene was rapidly absorbed with peak plasma concentrations appearing 1–2 h after dosing in 28 of 35 subjects. The time to reach peak was independent of the dose ( P = 0.56). The elimination of levormeloxifene was slow with half-lives ranging from 87 to 250 h (3.6–10.4 days) with an overall harmonic mean of 6.4 days. Differences in mean λ z values between doses were statistically significant ( P = 0.02), the t 1/2 decreasing with increasing doses (8.4 and 6.0 days after lowest and highest dose, respectively). AUC showed dose proportionality, but C max increased nonproportionally ( Figure 4 , panel a and c). For the metabolite 7-desmethyllevormeloxifene t max was 4–6 h. The decline in plasma concentrations of the metabolite was parallel with that of the parent compound ( Figure 2 ) and consequently the range and mean values of the apparent half-life of elimination were very similar to the values for levormeloxifene (range of t 1/2 = 4.3–13.1 days, overall harmonic mean = 6.9 days). The 7-desmethyl-metabolite exhibited dose-proportional pharmacokinetics. The pharmacokinetic parameters for the metabolite are not shown.

Mean (s.d.) plasma concentration-time curves of levormeloxifene and its major metabolite after administration of ascending single oral doses (• 2.5 mg, ▪ 10 mg, ▴ 30 mg, ^ 80 mg, □ 160 mg, ▵ 320 mg, n = 6 subjects).

Dose normalized values of C max and AUC (trial 1) or AUC(1, τ) alternatively AUC ss (0, τ) (trial 2) as a function of dose. The lines were generated by linear regression.

Pharmacokinetic parameters for levormeloxifene after administration of single oral doses. Data are presented as mean (± s.d.). NA: insufficient data for estimation of AUC and t 1/2 ; Numbers in brackets represent the range. The final eight (or more) sampling points were used for the estimation of λ z .

Steady state concentrations of levormeloxifene and 7-desmethyllevormeloxifene were achieved approximately 28 days after commencement of daily dosing ( Figure 3 ). As in the single dose trial, the absorption of levormeloxifene was rapid (mean t max : 1.5–5.6 h) and the elimination slow ( Table 6 ). The individual half-life of elimination after multiple dosing ranged from 77 to 201 h (3.2–8.4 days) with overall harmonic mean of 5.2 days. The elimination half-life was not dose-dependent and mean values per dose group ranged from 4.8 to 5.9 days. Plasma concentrations of the metabolite peaked 12–24 h after dosing and the elimination rate from plasma was almost identical with that of the parent compound. For both compounds the relative fluctuations around the steady-state concentrations were small ( Figure 3 ), with a fluctuation index of no more than 0.9 for any subject. The AUC(1, τ), AUC ss (0, τ), C ss, min and C max values on days 1, 35 and 56, respectively, were proportional to the dose ( Figure 4 , panel b and d- C ss, min data not shown). Other pharmacokinetic parameters calculated in this trial were independent of the dose ( t max : Part 1: P = 0.69; Part 2: P = 0.94-λ z ; Part 1: P = 0.70; Part 2: P = 0.53). The actual accumulation in plasma concentrations over time was smaller than that predicted at all doses ( Table 6 ). The significance of this finding is somewhat unclear as the half-life of elimination at the 80 mg and 160 mg doses remained constant and independent of the dosing period.

Mean (s.d.) plasma concentration-time curves of levormeloxifene and its major metabolite after administration of ascending multiple oral doses for 35 days (Part 1, n = 6 subjects, •, ^ 20 mg, ▪, □ 80 mg, ▴, ▵ 160 mg) and 56 days (Part 2, n = 12 subjects, •, ^ 40 mg, ▪, □ 80 mg). Filled symbols: levormeloxifene; unfilled symbols: 7-desmethyllevormeloxifene.

Pharmacokinetic parameters for levormeloxifene after administration of multiple oral doses. Data are presented as mean (± s.d.). NA: insufficient data for estimation of t 1/2 ; Numbers in brackets represent the range. After 35 and 56 days of dosing at least the final nine and three (or more) sampling points were used for the estimation of λ z , respectively.

Levormeloxifene was administered to postmenopausal women as single doses of up to 320 mg and as multiple doses of up to 160 mg once daily for 35 or 56 days. The multiple dose study included investigation of the pharmacodynamic properties of levormeloxifene.

Levormeloxifene was tolerated well after all single and multiple doses and no maximum tolerated dose was achieved. In the single dose study there were no differences between the adverse event profiles after levormeloxifene and placebo, in frequency or type, even after the highest dose of 320 mg. However, after multiple dosing the highest dose group receiving 160 mg experienced almost double the number of adverse events compared with those receiving lower doses. The most frequent adverse event was headache. Subjects in the highest dose group reported this event approximately 2–3 times during the treatment period compared with a frequency of 0.4–0.7 in the other dose groups. Besides leukorrhea, adverse events were not dose related. Vaginal bleeding after withdrawal was observed in one or two subjects in all dose groups. The observed increased endometrial stripe determined by ultrasound is compatible with previous reports of increased volume of stroma in the endometrium of levormeloxifene treated rats accompanied by inactive endometrial epithelium and atrophic endometrial glands [ 7 – 10 ]. In subsequent clinical phase II studies in the daily dose range of 1.25–40 mg levormeloxifene, increase of the endometrial stripe was found at most dose levels. However no proliferative changes or hyperplasia were observed. After initiation of the clinical phase III studies, the clinical development of levormeloxifene was interrupted due to other adverse events, such as incontinence and uterine prolapse. Such events were not reported in the present studies of short duration.

Urinary collagen I-C-telopeptide is liberated from bone during bone resorption and correlates to bone resorptive activity [ 15 ]. In the present studies after 8 weeks of levormeloxifene treatment the urinary collagen I-C-telopeptide was reduced by 25–28% compared with placebo. A similar trend was also observed after 5 weeks of treatment at the lowest dose of 20 mg levormeloxifene, but the difference from placebo did not reach statistical significance. The effect of levormeloxifene on bone metabolism was also supported by a significant reduction after treatment for 5 and 8 weeks in the nonspecific marker of bone formation, total serum alkaline phosphatase, which is partly produced by osteoblasts but also is synthesised in liver, kidneys and gut [ 16 ]. However, the more specific assay [ 17 ] for the skeletal variant was not used. These observed effects of levormeloxifene are both considered indicative of a bone preserving action [ 16 ]. The effect of levormeloxifene on collagen I-C telopeptide is similar to those of other antiresorptive drugs like HRT [ 18 ], raloxifene [ 19 ], and alendronate [ 20 ]. For a direct comparison of efficacy between levormeloxifene and other antiresorptive treatment modalities, a longer term treatment with lower doses of levormeloxifene is required. Also the lowering effect on serum total cholesterol and LDL-cholesterol without affecting the concentrations of triglycerides and HDL-cholesterol exceeds what has been reported for HRT [ 21 ] or other SERMs [ 19 ], and is comparable with data on lipid lowering statins [ 22 ]. These changes in the lipid profile resulting from treatment with levormeloxifene may have a beneficial effect on the incidence of cardiovascular diseases [ 21 ].

The plasma concentrations of LH and FSH were reduced following multiple dosing with levormeloxifene. The effect was similar to that of oestrogens [ 23 ], and by thus this may be indicative of an oestrogen agonist-like action on the hypothalmo-pituitary axis.

Similar pharmacokinetic data were obtained in both trials. Plasma concentration curves indicated a rapid absorption of levormeloxifene with peak concentrations detectable within the first 4 h after dosing in almost all subjects. Levormeloxifene and its metabolite 7-desmethyllevormeloxifene, the latter with no in-vitro binding properties to the oestrogen receptor [S Bain, private communication] were eliminated slowly from the plasma. The half-life of levormeloxifene in the single dose trial decreased with increasing doses, but remained constant and independent of dose and treatment duration in the multiple dose study. The mean t 1/2 was highest at 8.4 and 6.9 days after the lowest single doses (10 and 30 mg, respectively), whereas for the remaining eight dose groups t 1/2 was in the narrow range of 4.8–6.0 days. With an increase in the elimination constant at higher doses in the single dose study, we would also expect to find a correspondingly lower exposure. However the statistical analysis did not indicate any deviation from dose proportionality of drug exposure in the single or multiple study up to 160 mg, as measured by AUC, AUC ss (0, τ), C ss,min and AUC(1, τ). On the other hand C max data showed a greater increase than expected at higher doses, however, suggesting a change in distribution with dose.

Steady state plasma concentrations of levormeloxifene were achieved approximately 4 weeks after commencement of daily dosing. The relative fluctuations of plasma concentrations around the plateau were small and C ss, max values in all subjects were no more than double the value of the corresponding trough concentration. Therefore, in future clinical trials, once daily dosing in contrast to once weekly dosing, should be considered more favourable from a safety point of view. The latter would give rise to pronounced fluctuations in plasma concentration at steady state with the risk causing adverse events immediately after dosing. Following 35 days of dosing with 20 mg of drug, the average steady state concentration of levormeloxifene in subjects dosed was 230 ng ml −1 . Using oestrogen-depleted OVX rats, a dose of 0.5 mg kg −1 of levormeloxifene given three times weekly p.o. for 5 weeks (11) corresponding to an average steady state plasma concentration ( C ss, av ) of levormeloxifene of approximately 20–25 ng ml −1 , was sufficient to maintain bone densities at the sham level. Assuming that the antiresorptive effect is correlated to steady-state concentrations of levormeloxifene and is species independent, an effective human daily dose should be about 2 mg, which is 10 times less than the lowest dose used in this multiple dose study.

In conclusion, the studies provide the first data on the short-term administration of levormeloxifene to postmenopausal women and suggest that the drug has oestrogen-like bone preserving and antiatherogenic effects.

A comparative study of the steady-state pharmacokinetics of immediate-release and controlled-release diltiazem tablets

Affiliation.

• 1 Pharma Bio-Research International BV, Zuidlaren, The Netherlands.
• PMID: 8070505
• DOI: 10.1007/BF00192556

We have studied the controlled-release properties and relative systemic availabilities of two dosages of the same controlled-release (CR) diltiazem tablet formulation by comparing them at steady state with those of an immediate-release formulation. We measured 24-hour plasma concentration profiles during 4-day treatments with diltiazem 90 mg CR tablet bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three-way crossover design. Twelve healthy men (38-52 y) participated. Trough plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the last morning dose on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), the time interval during which the plasma concentration exceeded 75% of Cmax (t75), the area under the plasma concentration-time curve (AUC72-96), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF). Steady state was achieved on day 3. The pharmacokinetics were comparable. For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC84-96 (night) was approximately 75% of AUC72-84 (daytime). The diltiazem plasma concentration increased slowly from about 6 h after the evening dose of both CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 mg were the plasma concentrations of diltiazem maintained above the minimum therapeutic plasma concentration of 50 micrograms.l-1 throughout the full 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

• Clinical Trial
• Comparative Study
• Randomized Controlled Trial
• Research Support, Non-U.S. Gov't
• Biological Availability
• Delayed-Action Preparations
• Diltiazem / administration & dosage*
• Diltiazem / blood
• Diltiazem / pharmacokinetics*
• Middle Aged

Restructuring events

European Restructuring Monitor (ERM)

The restructuring events database contains factsheets with data on large-scale restructuring events reported in the principal national media and company websites in each EU Member State. This database was created in 2002.

Pharma Bio Research PBR

Description.

Dutch pharmaceutical research company Pharma Bio Research (PBR) will cut 40 of its 315 full-time jobs in 2005. The job cuts will include forced redundancies. The company has reached an agreement with trade unions about a social plan. The company will close two of the six operating sites. Two research locations will remain active, one in Groningen and one in Zuidlaren. The research clinic in Assen will be closed.

• 1 December 2004: Dagblad van het Noorden

Eurofound (2004), Pharma Bio Research PBR, Internal restructuring in Netherlands, factsheet number 60821, European Restructuring Monitor. Dublin, https://restructuringeventsprod.azurewebsites.net/restructuring-events/detail/60821.

Eurofound publications on restructuring

Ethics in the digital workplace.

Digitisation and automation technologies, including artificial intelligence (AI), can affect working conditions in a variety of ways and their use in the workplace raises a host of new ethical concerns.

• Date 30 May 2022

Going digital: Restructuring trends in retail banking

The retail banking sector is fertile ground for studying the impacts of digitalisation on work and employment. Financial services are increasingly provided online, without the intermediary of customer-facing institutions.

• Date 26 Sep 2022

Recovery from COVID-19: The changing structure of employment in the EU

European labour markets have recovered strongly from COVID-19. By the end of 2021, little more than 18 months after the start of the pandemic, employment rates in the EU were almost at pre-crisis levels.

• Date 20 Oct 2022

The digital age: Implications of automation, digitisation and platforms for work and employment

Technological change is accelerating as the capacity of electronic devices to digitally store, process and communicate information expands.

• Date 15 Dec 2021

• © 2001

Muscarinic Receptors in Airways Diseases

• Johan Zaagsma 0 ,
• Herman Meurs 1 ,
• Ad F. Roffel 2

Dept. of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands

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Department of Research Management, Pharma Bio-Research Group B.V., Zuidlaren, The Netherlands

Part of the book series: Progress in Inflammation Research (PIR)

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Table of contents (10 chapters)

Front matter, cholinergic and noncholinergic parasympathetic control of airway smooth muscle.

• Bradley J. Undem, Allen C. Myers

Role of non-neuronal and neuronal acetylcholine in the airways

• Ignaz K. Wessler, Charles J. Kirkpatrick

Identification, localization and function of muscarinic receptor subtypes in the airways

• Ad F. Roffel, Herman Meurs, Johan Zaagsma

Functional roles of postjunctional muscarinic M2 receptors in airway smooth muscle

• Richard M. Eglen, Nikki Watson

Dysfunction of prejunctional muscarinic M2 receptors: role of environmental factors

• Darryl J. Adamko, Allison D. Fryer, David B. Jacoby

Muscarinic receptor-β-adrenoceptor cross-talk in airways smooth muscle

• Herman Meurs, Ad F. Roffel, Carolina R. S. Elzinga, Johan Zaagsma

Gene regulation of muscarinic receptor subtypes

• Peter J. Barnes

Muscarinic control of airway mucus secretion

• Duncan F. Rogers

The role of anticholinergics in asthma and COPD

• Kenneth R. Chapman

Novel perspectives in anticholinergic therapy

• Bernd Disse

Back Matter

• pathophysiology

Johan Zaagsma, Herman Meurs

Ad F. Roffel

Book Title : Muscarinic Receptors in Airways Diseases

Editors : Johan Zaagsma, Herman Meurs, Ad F. Roffel

Series Title : Progress in Inflammation Research

DOI : https://doi.org/10.1007/978-3-0348-8358-0

Publisher : Birkhäuser Basel

eBook Packages : Springer Book Archive

Copyright Information : Springer Basel AG 2001

Hardcover ISBN : 978-3-7643-5988-1 Published: 01 April 2001

Softcover ISBN : 978-3-0348-9532-3 Published: 23 October 2012

eBook ISBN : 978-3-0348-8358-0 Published: 08 March 2013

Series ISSN : 1422-7746

Series E-ISSN : 2296-4525

Edition Number : 1

Number of Pages : XI, 266

Topics : Pneumology/Respiratory System , Neurosciences

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Chinese Company Under Congressional Scrutiny Makes Key U.S. Drugs

Lawmakers raising national security concerns and seeking to disconnect a major Chinese firm from U.S. pharmaceutical interests have rattled the biotech industry. The firm is deeply involved in development and manufacturing of crucial therapies for cancer, cystic fibrosis, H.I.V. and other illnesses.

A WuXi Biologics facility in Wuxi, China. WuXi AppTec and an affiliated company, WuXi Biologics, have received millions of dollars in tax incentives to build sprawling research and manufacturing sites in Massachusetts and Delaware. Credit... Imaginechina Limited, via Alamy

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By Christina Jewett

• April 15, 2024

A Chinese company targeted by members of Congress over potential ties to the Chinese government makes blockbuster drugs for the American market that have been hailed as advances in the treatment of cancers, obesity and debilitating illnesses like cystic fibrosis.

WuXi AppTec is one of several companies that lawmakers have identified as potential threats to the security of individual Americans’ genetic information and U.S. intellectual property. A Senate committee approved a bill in March that aides say is intended to push U.S. companies away from doing business with them.

But lawmakers discussing the bill in the Senate and the House have said almost nothing in hearings about the vast scope of work that WuXi does for the U.S. biotech and pharmaceutical industries — and patients. A New York Times review of hundreds of pages of records worldwide shows that WuXi is heavily embedded in the U.S. medicine chest, making some or all of the main ingredients for multibillion-dollar therapies that are highly sought to treat cancers like some types of leukemia and lymphoma as well as obesity and H.I.V.

The Congressional spotlight on the company has rattled the pharmaceutical industry, which is already struggling with widespread drug shortages now at a 20-year high . Some biotech executives have pushed back, trying to impress on Congress that a sudden decoupling could take some drugs out of the pipeline for years.

WuXi AppTec and an affiliated company, WuXi Biologics grew rapidly, offering services to major U.S. drugmakers that were seeking to shed costs and had shifted most manufacturing overseas in the last several decades.

WuXi companies developed a reputation for low-cost and reliable work by thousands of chemists who could create new molecules and operate complex equipment to make them in bulk. By one estimate, WuXi has been involved in developing one-fourth of the drugs used in the United States. WuXi AppTec reported earning about $3.6 billion in revenue for its U.S. work.

“They have become a one-stop shop to a biotech,” said Kevin Lustig, founder of Scientist.com, a clearinghouse that matches drug companies seeking research help with contractors like WuXi.

WuXi AppTec and WuXi Biologics have also received millions of dollars in tax incentives to build sprawling research and manufacturing sites in Massachusetts and Delaware that local government officials have welcomed as job and revenue generators. One WuXi site in Philadelphia was working alongside a U.S. biotech firm to give patients a cutting-edge therapy that would turbocharge their immune cells to treat advanced skin cancers.

The tension has grown since February, when four lawmakers asked the Commerce, Defense and Treasury Departments to investigate WuXi AppTec and affiliated companies, calling WuXi a “giant that threatens U.S. intellectual property and national security.”

A House bill called the Biosecure Act linked the company to the People’s Liberation Army, the military arm of the Chinese Communist Party. The bill claims WuXi AppTec sponsored military-civil events and received military-civil fusion funding.

Richard Connell, the chief operating officer of WuXi AppTec in the United States and Europe, said the company participates in community events, which do not “imply any association with or endorsement of a government institution, political party or policy such as military-civil fusion.” He also said shareholders do not have control over the company or access to nonpublic information.

Last month, after a classified briefing with intelligence staff, the Senate homeland security committee advanced a bill by a vote of 11 to 1: It would bar companies from receiving government contracts for work with Wuxi, but would allow the companies to still obtain contracts for unrelated projects. Government contracts with drugmakers are generally limited, though they were worth billions of dollars in revenue to companies that responded to the Covid-19 pandemic.

Mr. Connell defended the company’s record, saying the proposed legislation “relies on misleading allegations and inaccurate assertions against our company.”

WuXi operates in a highly regulated environment by “multiple U.S. federal agencies — none of which has placed our company on any sanctions list or designated it as posing a national security risk,” Mr. Connell said. WuXi Biologics did not respond to requests for comment.

Smaller biotech companies, which tend to rely on government grants and have fewer reserves, are among the most alarmed. Dr. Jonathan Kil, the chief executive of Seattle-based Sound Pharmaceuticals, said WuXi has worked alongside the company for 16 years to develop a treatment for hearing loss and tinnitus, or ringing in the ear. Finding another contractor to make the drug could set the company back two years, he said.

“What I don’t want to see is that we get very anti-Chinese to the point where we’re not thinking correctly,” Dr. Kil said.

It is unclear whether a bill targeting WuXi will advance at all this year. The Senate version has been amended to protect existing contracts and limit supply disruptions. Still, the scrutiny has prompted some drug and biotechnology companies to begin making backup plans.

Peter Kolchinsky, managing partner of RA Capital Management, estimated that half of the 200 biotech companies in his firm’s investment portfolio work with WuXi.

“Everyone is likely considering moving away from Wuxi and China more broadly,” he said in an email. “Even though the current versions of the bill don’t create that imperative clearly, no one wants to be caught flat-footed in China if the pullback from China accelerates.”

The chill toward China extends beyond drugmakers. U.S. companies are receiving billions of dollars in funding under the CHIPS Act, a federal law aimed at bringing semiconductor manufacturing stateside.

For the last several years, U.S. intelligence agencies have been warning about Chinese biotech companies in general and WuXi in particular. The National Counterintelligence and Security Center, the arm of the intelligence community charged with warning companies about national security issues, raised alarms about WuXi’s acquisition of NextCODE, an American genomic data company.

Though WuXi later spun off that company, a U.S. official said the government remains skeptical of WuXi’s corporate structure, noting that some independent entities have overlapping management and that there were other signs of the Chinese government’s continuing control or influence over WuXi.

Aides from the Senate homeland security committee said their core concerns are about the misuse of Americans’ genomic data, an issue that’s been more closely tied to other companies named in the bill.

Aides said the effort to discourage companies from working with WuXi and others was influenced by the U.S. government’s experience with Huawei, a Chinese telecommunications giant. By the time Congress acted on concerns about Huawei’s access to Americans’ private information, taxpayers had to pay billions of dollars to tear Huawei’s telecommunication equipment out of the ground.

Yet WuXi has far deeper involvement in American health care than has been discussed in Congress. Supply chain analytics firms QYOBO and Pharm3r, and some public records, show that WuXi and its affiliates have made the active ingredients for critical drugs.

They include Imbruvica, a leukemia treatment sold by Janssen Biotech and AbbVie that brought in $5.9 billion in worldwide revenue in 2023. WuXi subsidiary factories in Shanghai and Changzhou were listed in government records as makers of the drug’s core ingredient, ibrutinib.

Dr. Mikkael A. Sekeres, chief of hematology at the University of Miami Health System, called that treatment for chronic lymphocytic leukemia “truly revolutionary” for replacing highly toxic drugs and extending patients’ lives.

Janssen Biotech and AbbVie, partners in selling the drug, declined to comment.

WuXi Biologics also manufactures Jemperli, a GSK treatment approved by the Food and Drug Administration last year for some endometrial cancers. In combination with standard therapies, the drug improves survival in patients with advanced disease, said Dr. Amanda Nickles Fader, president of the Society of Gynecologic Oncology.

“This is particularly important because while most cancers are plateauing or decreasing in incidence and mortality, endometrial cancer is one of the only cancers globally” increasing in both, Dr. Fader said.

GSK declined to comment.

The drug that possibly captures WuXi’s most significant impact is Trikafta, manufactured by an affiliate in Shanghai and Changzhou to treat cystic fibrosis, a deadly disease that clogs the lungs with debilitating, thick mucus. The treatment is credited with clearing the lungs and extending by decades the life expectancy of about 40,000 U.S. residents. It also had manufacturers in Italy, Portugal and Spain.

The treatment has been so effective that the Make-A-Wish Foundation stopped uniformly granting wishes to children with cystic fibrosis. Trikafta costs about $320,000 a year per patient and has been a boon for Boston-based Vertex Pharmaceuticals and its shareholders, with worldwide revenue rising to $8.9 billion last year from $5.7 billion in 2021, according to a securities filing .

Trikafta “completely transformed cystic fibrosis and did it very quickly,” said Dr. Meghan McGarry, a University of California San Francisco pulmonologist who treats children with the condition. “People came off oxygen and from being hospitalized all the time to not being hospitalized and being able to get a job, go to school and start a family.”

Vertex declined to comment.

Two industry sources said WuXi plays a role in making Eli Lilly’s popular obesity drugs. Eli Lilly did not respond to requests for comment. WuXi companies also make an infusion for treatment-resistant H.I.V., a drug for advanced ovarian cancer and a therapy for adults with a rare disorder called Pompe disease.

WuXi is known for helping biotech firms from the idea stage to mass production, Dr. Kolchinsky said. For example, a start-up could hypothesize that a molecule that sticks to a certain protein might cure a disease. The company would then hire WuXi chemists to create or find the molecule and test it in petri dishes and animals to see whether the idea works — and whether it’s safe enough for humans.

“Your U.S. company has the idea and raises the money and owns the rights to the drug,” Dr. Kolchinsky said. “But they may count on WuXi or similar contractors for almost every step of the process.”

WuXi operates large bioreactors and manufactures complex peptide, immunotherapy and antibody drugs at sprawling plants in China.

WuXi AppTec said it has about 1,900 U.S. employees. Officials in Delaware gave the company $19 million in tax funds in 2021 to build a research and drug manufacturing site that is expected to employ about 1,000 people when fully operational next year, public records and company reports show.

Mayor Kenneth L. Branner Jr. of Middletown, Del., called it “one of those once-in-a-lifetime opportunities to land a company like this,” according to a news report when the deal was approved.

In 2022, the lieutenant governor of Massachusetts expressed a similar sentiment when workers placed the final steel beam on a WuXi Biologics research and manufacturing plant in Worcester. Government officials had approved roughly $11.5 million in tax breaks to support the project. The company announced this year that it would double the site’s planned manufacturing capacity in response to customer demand.

And in Philadelphia, a WuXi Advanced Therapies site next to Iovance Biotherapeutics was approved by regulators to help process individualized cell therapies for skin cancer patients. Iovance has said it is capable of meeting demand for the therapies independently.

By revenue, WuXi Biologics is one of the top five drug development and manufacturing companies worldwide, according to Statista , a data analytics company. A WuXi AppTec annual report showed that two-thirds of its revenue came from U.S. work.

Stepping away from WuXi could cause a “substantial slowdown” in drug development for a majority of the 105 biotech companies surveyed by BioCentury , a trade publication. Just over half said it would be “extremely difficult” to replace China-based drug manufacturers.

BIO, a trade group for the biotechnology industry, is also surveying its members about the impact of disconnecting from WuXi companies. John F. Crowley, BIO’s president, said the effects would be most difficult for companies that rely on WuXi to manufacture complex drugs at commercial scale. Moving such an operation could take five to seven years.

“We have to be very thoughtful about this so that we first do no harm to patients,” Mr. Crowley said. “And that we don’t slow or unnecessarily interfere with the advancement of biomedical research.”

Julian E. Barnes contributed reporting, and Susan C. Beachy contributed research.

Christina Jewett covers the Food and Drug Administration, which means keeping a close eye on drugs, medical devices, food safety and tobacco policy. More about Christina Jewett

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