Wednesday 24 February 2016

Fidaxomicin


Fidaxomicin.svg

Fidaxomicin (C52H74Cl2O18, Mr = 1058.0 g/mol)
Launched - 2011 MERCK, Clostridium difficile-associated diarrhea
CUBIST ....INNOVATOR
OPT-80
PAR-101
Also tiacumicin B or lipiarmycin A3,
A bacterial RNA polymerase inhibitor as macrocyclic antibiotic used to treat clostridium difficile-associated diarrhea (CDAD).
SYNTHESIS

str1
REFERENCES
US 4918174
WO 2006085838
J ANTIBIOTICS 1987, 40, PG 567-574 AND 575-588

Idaxomicin(trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrum macrocyclic antibiotic drugs.[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.[5] [6]
Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011.
First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals, now part of Cubist (now, Merck & Co.), is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant
In 2014 Astellas initiated in Europe a phase III clinical study for the treatment of Clostridium difficile infection in pediatric patients. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection.


The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.
It is marketed by Cubist Pharmaceuticals after acquisition of its originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection.
In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. In October 2013, Optimer Pharmaceuticals was acquired by Cubist.
Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient's clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350.[7]
Fidaxomicin (also known as OPT-80 and PAR-101 ) is a novel antibiotic agent and the first representative of a new class of antibacterials called macrocycles. Fidaxomicin is a member of the tiacumicin family, which are complexes of 18-membered macrocyclic antibiotics naturally produced by a strain of Dactylosporangium aurantiacum isolated from a soil sample collected in Connecticut, USA.
The major component of the tiacumicin complex is tiacumicin B. Optically pure R-tiacumicin B is the most active component of Fidaxomicin. The chiral center at C(19) of tiacumicinB affects biological activity, and R-tiacumicin B has an R-hydroxyl group attached at this position. The isomer displayed significantly higher activity than other tiacumicin B-related compounds and longer post-antibiotic activity.
Tiacumicins are a family of structurally related compounds that contain the 18-membered macrolide ring shown below.
Figure imgf000002_0001
At present, several distinct Tiacumicins have been identified and six of these
(Tiacumicin A-F) are defined by their particular pattern of substituents R1, R2, and R3 (US Patent No. 4,918,174; J. Antibiotics, 1987, 575-588).
The Lipiarmycins are a family of natural products closely related to the Tiacumicins. Two members of the Lipiarmycin family (A3 and B3) are identical to Tiacumicins B and C respectively (J. Antibiotics, 1988, 308-315; J. Chem. Soc. Perkin Trans 1, 1987, 1353-1359).
The Tiacumicins and the Lipiarmycins have been characterized by numerous physical methods. The reported chemical structures of these compounds are based on spectroscopy (UV-vis, IR and !H and 13C NMR), mass spectrometry and elemental analysis (See for example: J. Antibiotics, 1987, 575-588; J. Antibiotics, 1983, 1312-
1322).
Tiacumicins are produced by bacteria, including Dactylosporangium aurantiacum subspecies hamdenensis, which may be obtained from the ARS Patent Collection of the Northern Regional Research Center, United States Department ofAgriculture, 1815 North University Street, Peoria, IL 61604, accession number NRRL
18085. The characteristics of strain AB 718C-41 are given in J. Antibiotics, 1987,567-574 and US Patent No. 4,918,174.
Lipiarmycins are produced by bacteria including Actinoplanes deccanensis (US Patent No. 3,978,211). Taxonomical studies of type strain A/10655, which has been deposited in the ATCC under the number 21983, are discussed in J. Antibiotics,1975, 247-25.
Tiacumicins, specifically Tiacumicin B, show activity against a variety of bacterial pathogens and in particular against Clostridium difficile, a Gram-positive bacterium (Antimicrob. Agents Chemother. 1991, 1108-1111). Clostridium difficile is an anaerobic spore-forming bacterium that causes an infection of the bowel.
As per WIPO publication number 2006085838, Fidaxomicin is an isomeric mixture of the configurationally distinct stereoisomers of tiacumicin B, composed of 70 to 100% of R-tiacumicin B and small quantities of related compounds, such as S-tiacumicin B and lipiarmycin A4. Fidaxomicin was produced by fermentation of the D aurantiacum subspecies hamdenensis (strain 718C-41 ). It has a narrow spectrum antibacterial profile mainly directed against Clostridium difficile and exerts a moderate activity against some other gram-positive species.
Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins. The drug product is poorly absorbed and exerts its activity in the gastrointestinal (Gl) tract, which is an advantage when used in the applied indication, treatment of C. difficile infection (CDI) (also known as C. difficile-associated disease or diarrhoea [CDAD]). Fidaxomicin is available as DIFICID oral tablet in US market.
Its CAS chemical name is Oxacyclooctadeca-3,5,9, 13, 15-pentaen-2-one, 3-[[[6-deoxy-4-0-(3,5dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-0-methyl-P-D-manno pyranosyl]oxy]methyl]-12[[6-deoxy-5-C-methyl-4-0-(2-methyl-1 -oxopropyl)- -D-lyxo-hexo pyranosyl]oxy]-1 1 -ethyl-8-hydroxy-18-[(1 R)-1 -hydroxyethyl] -9,13,15-trimethyl-, (3E.5E, 8S.9E.1 1 S.12R.13E, 15E.18S)-.
Structural formula (I) describes the absolute stereochemistry of fidaxomicin as determined by x-ray.

(I)
WIPO publication number 2004014295 discloses a process for preparation of Tiacumicins that comprises fermentation of Dactylosporangium aurantiacum NRRL18085 in suitable culture medium. It also provides process for isolation of tiacumicin from fermentation broth using techniques selected from the group consisting of: sieving and removing undesired material by eluting with at least one solvent or a solvent mixture; extraction with at least one solvent or a solvent mixture; Crystallization; chromatographic separation; High-Performance Liquid Chromatography (HPLC); MPLC; trituration; and extraction with saturated brine with at least one solvent or a solvent mixture. The product was isolated from /so-propyl alcohol (IPA) having a melting point of 166-169 °C.
U.S. Patent No. 7378508 B2 discloses polymorphic forms A and B of fidaxomicin, solid dosage forms of the two forms and composition thereof. As per the ‘508 patent form A is obtained from methanol water mixture and Form B is obtained from ethyl acetate.
J. Antibiotics, vol. 40(5), 575-588 (1987) discloses purification of Tiacumicins using suitable solvents wherein tiacumicin B exhibited a melting point of 143-145 °C.
PCT application WO2013170142A1 describes three crystalline forms of Fidaxomicn namely, Form-Z, Form-Z1 and Form-C. IN2650/CHE/2013 describes 6 crystalline polymorphic forms of Fidaxomicin namely, Forms I, Form la, Form II, Form Ha, Form III and Form Ilia).

Mechanism

Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNAP polymerase. Switch motion is important for opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but especially during opening of double standed DNA during transcription initiation.[8] It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.[3]

Clinical trials

Good results were reported by the company in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection (CDI)[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks.[12]
Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Approvals and indications

For the treatment of Clostridium difficile-associated diarrhea (CDAD), the drug won an FDA advisory panel's unanimous approval on April 5, 2011[14] and full FDA approval on May 27, 2011.[15]

PAPER
Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B
Angew Chem Int Ed 2015, 54(6): 1929
Enantioselective Synthesis of Putative Lipiarmycin Aglycon Related to Fidaxomicin/Tiacumicin B (pages 1929–1932)
Dr. William Erb, Dr. Jean-Marie Grassot, Dr. David Linder, Dr. Luc Neuville and Prof. Dr. Jieping Zhu
Article first published online: 24 NOV 2014 | DOI: 10.1002/anie.201409475
Thumbnail image of graphical abstract
Chain gang: In the synthesis of the title compound, the ene-diene ring-closing metathesis was used for the formation of the 18-membered macrolactone and the stereogenic centers of the molecule were installed by Brown's alkoxyallylboration, allylation, and an Evans aldol reaction, while iterative Horner–Wadsworth–Emmons reactions were used for chain elongation.
http://onlinelibrary.wiley.com/doi/10.1002/anie.201409475/full
http://onlinelibrary.wiley.com/store/10.1002/anie.201409475/asset/supinfo/anie_201409475_sm_miscellaneous_information.pdf?v=1&s=75d40b6f8b214578d5a65518e7f384f03f377c35

PAPER
Total synthesis of the glycosylated macrolide antibiotic fidaxomicin
Org Lett 2015, 17(14): 3514
http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b01602
http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b01602/suppl_file/ol5b01602_si_001.pdf
Abstract Image
The first enantioselective total synthesis of fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is reported. This novel glycosylated macrolide antibiotic is used in the clinic for the treatment of Clostridium difficile infections. Key features of the synthesis involve a rapid and high-yielding access to the noviose, rhamnose, and orsellinic acid precursors; the first example of a β-selective noviosylation; an effective Suzuki coupling of highly functionalized substrates; and a ring-closing metathesis reaction of a noviosylated dienoate precursor. Careful selection of protecting groups allowed for a complete deprotection yielding totally synthetic fidaxomicin.
The identity of the synthetic compound to an authentic sample of fidaxomicin (1) was confirmed by coinjection on RP-HPLC and an equimolar mixed NMR-sample with an authentic sample. Rƒ = 0.44 (MeOH/CH2Cl2 1/10).
HRMS ESI calcd. for [C52H74Cl2NaO18] + [M+Na]+ : 1079.4144; found:1079.4151.
1H NMR (600 MHz, Methanol-d4 , containing HCOO- ) δ 7.23 (d, J = 11.5 Hz, 1H), 6.60 (dd, J = 14.9, 11.8 Hz 1H), 5.95 (ddd, J = 14.7, 9.5, 4.8 Hz, 1H), 5.83 (s, 1H), 5.57 (ap t, J = 8.2 Hz, 1H), 5.14 (ap d, J = 10.7, 1H), 5.13 (dd, J = 9.7 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 4.74-4.70 (m, 1H), 4.71 (s, 1H), 4.64 (s, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.22 (ap s, 1H), 4.02 (p, J = 6.3 Hz, 1H), 3.92 (dd, J = 3.2, 1.2 Hz, 1H), 3.75 (ddd, J = 13.9, 10.2, 3.3 Hz, 1H) 3.71 (d, J = 9.7 Hz 1H), 3.58-3.52 (m, 2H) 3.54 (s, 3H), 3.15-3.06 (m, 1H), 3.04-2.95 (m, 1H), 2.76-2.66 (m, 3H), 2.60 (hept, J= 7.0 Hz, 1H), 2.49 (ddd, J = 14.9, 9.5, 4.4 Hz, 1H), 2.43 (ddd, J = 13.8, 8.8, 4.5 Hz, 1H), 2.05-1.98 (m, 1H), 1.82 (d, J = 1.3 Hz, 3H), 1.76 (ap s, 3H), 1.66 (ap s, 3H), 1.32-1.27 (m, 4H), 1.22-1.15 (m, 12H), 1.15 (s, 3H), 1.13 (s, 3H), 0.88 (t, J = 7.4 Hz, 3H).
RP-HPLC tR = 14.87 min (A: H2O+0.1% HCOOH; Solvent B: MeCN+0.1% HCOOH; 1 mL/min; T = 20°C; B[%] (tR [min])= 10 (0 to 3); 100 (15).
PATENT
WO 2004014295
http://www.google.co.in/patents/WO2004014295A2?cl=en
The term "Tiacumicin B" refers to molecule having the structure shown below:
Figure imgf000008_0002
Example 1
Dactylosporangium aurantiacum subsp. hamdenensis AB 718C-41 NRRL 18085 (-20 °C stock), was maintained on 1 mL of Medium No. 104 (Table 1). After standard sterilization conditions (30 min., 121 °C, 1.05 kg/cm2) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C-41 NRRL 18085 on a shaker (set @ 250 rpm) at 30 °C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was then transferred aseptically to a fermentation flask containing the same ingredients as in Table 1.
Table 1: Ingredients of Medium No. 104
Figure imgf000013_0001
Fermentation flasks were incubated on a rotary shaker at 30 °C for 3 to 12 days. Samples of the whole culture fermentation broth were filtered. The filter cake was washed with MeOH and solvents were removed under reduced pressure. The residue was re-constituted in methanol to the same volume of the original fermentation broth. Analysis was performed using a Waters BREEZE HPLC system coupling with Waters 2487 2-channel UV/Vis detector. Tiacumincins were assayed on a 50 x 4.6 μm I.D., 5 μm YMC ODS-A column (YMC catalog # CCA AS05- 0546WT) with a mobile phase consisting of 45% acetonitrile in water containing 0.1% phosphoric acid at a flow rate of 1.5 mL/minute. Tiacumicins were detected at 266 nm. An HPLC chromatogram of a crude product (Tiacumicin B retention time @ 12.6 minutes) is shown in Fig. 1. In this example the crude yield of Tiacumicin B was about 250 mg/L after 7 days. After purification by HPLC, the yield of Tiacumicin B was about 100 mg/L.
Example 2
After standard sterilization conditions (30 min, 121 °C, 1.05 kg/cm2) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C- 41 NRRL 18085 and incubated on a shaker (set @ 250 rpm) at 30° C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was transferred aseptically to a seed flask containing the same ingredients as in Table 1 and was incubated on a rotary shaker at 30 °C for 72 hr. Five percent inoculum from the second passage seed flasks was then used to inoculate with AB 718C-41 NRRL 18085 in a 5-liter fermenter containing Medium No. 104 (2.5 L). Excessive foam formation was controlled by the addition of an antifoaming agent (Sigma A-6426). This product is a mixture of non-silicone organic defoamers in a polyol dispersion.
Glucose consumption was monitored as a growth parameter and its level was controlled by the addition of the feeding medium. Feeding medium and conditions in Example 2 were as follows:
Feeding medium:
Figure imgf000014_0001
Fermenter Medium: No. 104
Fermenter Volume: 5 liters
Sterilization: 40 minutes, 121° C, 1.05 kg/cm2
Incubation Temperature: 30 °C.
Aeration rate: 0.5-1.5 volumes of air per culture volume and minute
Fermenter Agitation: 300-500 rpm
The fermentation was carried out for 8 days and the XAD-16 resin was separated from the culture broth by sieving. After washing with water the XAD-16 resin was eluted with methanol (5-10 x volume of XAD-16). Methanol was evaporated and the oily residue was extracted three times with ethyl acetate. The extracts were combined and concentrated under reduced pressure to an oily residue. The oily residue was dried and washed with hexane to give the crude product as a pale brown powder and its HPLC chromatogram (Tiacumincin B rete tion time @ 11.8 minutes) is shown in Figure 2. This was purified by silica gel column (mixture of ethyl acetate and hexane as eluent) and the resultant material was further purified by RP-HPLC (reverse phase HPLC) to give Tiacumicin B as a white solid. The purity was determined to be >95% by HPLC chromatography and the chromatogram (Tiacumincin B retention time @ 12.0 minutes) is shown in Figure 3. Analysis of the isolated Tiacumincin B gave identical !H and 13C NMR data to those reported in J. Antibiotics, 1987, 575-588, and these are summarized below. Tiacumicin B: mp 129-140 °C (white powder from RP-HPLC); mp 166-169 °C (white needles from isopropanol); [α]D 20-6.9 (c 2.0, MeOH); MS m/z (ESI) 1079.7(M + Na)+; H NMR (400 MHz, CD3OD) δ 7.21 (d, IH), 6.59 (dd, IH), 5.95 (ddd, IH), 5.83 (br s, IH), 5.57 (t, IH), 5.13 (br d, IH), 5.09 (t, IH), 5.02 (d, IH), 4.71 (m, IH), 4.71 (br s, IH), 4.64 (br s, IH), 4.61 (d, IH), 4.42 (d, IH), 4.23 (m, IH), 4.02 (pentet, IH), 3.92 (dd, IH), 3.73 (m, 2H), 3.70 (d, IH), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, IH), 2.49 (ddd, IH), 2.42 (ddd, IH), 2.01 (dq, IH), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, IH), 1.20 (t, 3H), 1.19 (d, 3 H), 1.17 (d, 3H), 1.16 (d, 3H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H); 13C NMR (100 MHz, CD3OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.
PATENT
http://www.google.com/patents/US7378508
macrolide of Formula I:
Figure US07378508-20080527-C00001
 
Structure of R-Tiacumicin B
The structure of the R-Tiacumicin B (the major most active component) is shown below in Formula I. The X-ray crystal structure of the R-Tiacumicin B was obtained as a colorless, parallelepiped-shaped crystal (0.08×0.14×0.22 mm) grown in aqueous methanol. This x-ray structure confirms the structure shown below. The official chemical name is 3-[[[6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]-methyl]-12(R)-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one.
Figure US07378508-20080527-C00009
7.2.1 Analytical Data of R-Tiacumicin B
The analytical data of R-Tiacumicin B (which is almost entirely (i.e., >90%) R-Tiacumicin).
mp 166-169° C. (white needle from isopropanol);
[α]D 20-6.9 (c 2.0, MeOH);
MS m/z (ESI) 1079.7(M+Na)+;
1H NMR (400 MHz, CD3OD) δ 7.21 (d, 1H), 6.59 (dd, 1H), 5.95 (ddd, 1H), 5.83 (br s, 1H), 5.57 (t, 1H), 5.13 (br d, 1H), 5.09 (t, 1H), 5.02 (d, 1H), 4.71 (m, 1H), 4.71 (br s, 1H), 4.64 (br s, 1H), 4.61 (d, 1H), 4.42 (d, 1H), 4.23 (m, 1H), 4.02 (pentet, 1H), 3.92 (dd, 1H), 3.73 (m, 2H), 3.70 (d, 1H), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, 1H), 2.49 (ddd, 1H), 2.42 (ddd, 1H), 2.01 (dq, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, 1H), 1.20 (t, 3H), 1.19 (d, 3H), 1.17 (d, 3H), 1.16 (d, 3 H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H);
13C NMR (100 MHz, CD3OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.
 
 
 PATENT
WO2013170142
 EXAMPLES
Example 1; General procedure for the preparation of crude Fidaxomycin
Fidaxomycin was prepared by:
i) culturing a microorganism in a nutrient medium to accumulate Fidaxomycin in the nutrient medium;
ii) isolating crude Fidaxomycin from the nutrient medium by methods known from the art;
iii) purifying Fidaxomycin by reversed phase chromatography using a mixture of acetonitrile, water and acetic acid as eluent; and iv) isolating the purified Fidaxomycin from the fractions.
Actionplanes deccanenesis was used during the cultivation. The nutrient medium comprises the following combination based on weight: from about 0% to about 5% Sucrose; from about 0% to about 3% Starch; from about 0.1% to about 1.0 % Soy peptone; from about 2% to about 5% Cotton seed meal; from about 0.01% to about 0.1% Potassium-dihydrogen Phosphate; from about 0.05% to about 0.5% Dipotassium-hydrogen Phosphate; from about 0.05% to about 0.5% Antifoam agent; from about 0% to about 2% Amberlite XAD-16N resin. The preferred temperature of the cultivation is from 28 to 32°C, and the pH is between 6.0 and 8.0. During the cultivation C-source is continuously fed.
 The Fidaxomycin fermentation production can also be done by the following procedure:
The Fidaxomycin fermentation production can include a step of inoculation followed by fermentation as follows:
 Inoculation: Actinoplanes deccanenesis strain is inoculated into the seed medium. The inoculation parameters are adjusted and maintained until the inoculum transferred to the main fermentation. The inoculum medium comprises: from about 0 to about 5% glucose, from about 0 to about 1% yeast extract, from about 0 to about 1% soy peptone, from about 0 to about 0.5% CaCo3, from about 0 to about 0.2% MgS0 -7H20, from about 0 to about 0.2% K2HP04, from about 0 to about 0.2% KC1, from about 0 to about 0.3% Polypropylene glycol. The pH is adjusted by adding Hydrochloric acid and/or Sodium/potassium hydroxide.
 Inoculation parameters :
Inoculation time: 40-48 ± 24 hours.
At the end of the inoculation, the inoculum (or a part of it) is transferred into the sterile fermentation medium at a ratio of 8-15 ± 5 %.
Fermentation: the fermentation medium comprises: from about 0 to aboutl0% Sucrose/Hydrolyzed Starch, from about 0 to about 1% Soy peptone, from about 0 to about 5% Cotton seed meal, from about 0 to about 0.3% K2HP04, from about 0 to about 0.2% KH2P04, from about 0 to aboutl% KC1, from about 0 to about 0.5% Polypropylene glycol (PPG). The pH is adjusted by adding Hydrochloric acid and/or Sodium/potassium hydroxide.
The sterile fermentation medium is seeded with the inoculum.
 Feeding:
C-source is fed during the fermentation, For C-source feeding sucrose or hydrolyzed-starch can be applied. Total amount of fed C-source is 0 - 15% related to the initial volume.
 Fermentation parameters :
In case of foaming, sterile antifoaming agent should be added.
 Fermentation time: 168-192 ± 24 hours.
 The inoculation/fermentation medium may also include from about 0% to about 2% Amberlite XAD-16N resin.
Upon completion of fermentation, the Fidaxomycin is extracted from the fermented broth with an organic solvent such as, for example, ethyl acetate, isobutyl acetate or isobutanol. The organic phase is concentrated and the Fidaxomycin is precipitated by addition of an antisolvent such as, for example, n-hexane. Optionally the precipitate can be suspended in a second antisolvent. After filtration and drying, crude Fidaxomycin is obtained.
 
DIFICID (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-Omethyl- β-D- mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxohexopyranosyl] oxy]-11-ethyl-8 -hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-,(3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.
Figure 1: Structural Formula of Fidaxomicin

str1
Image result for Fidaxomicin


Patent
WO 2016024243, New patent, Dr Reddy’s Laboratories Ltd, Fidaxomicin
WO2016024243,  FIDAXOMICIN POLYMORPHS AND PROCESSES FOR THEIR PREPARATION
DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana State, India Hyderabad 500034 (IN)
CHENNURU, Ramanaiah; (IN).
PEDDY, Vishweshwar; (IN).
RAMAKRISHNAN, Srividya; (IN)
Aspects of the present application relate to crystalline forms of Fidaxomicin IV, V & VI and processes for their preparation. Further aspects relate to pharmaceutical compositions comprising these polymorphic forms of fidaxomicin
front page image

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physico-chemical properties.
Polymorphs are different solid materials having the same molecular structure but different molecular arrangement in the crystal lattice, yet having distinct physico-chemical properties when compared to other polymorphs of the same molecular structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21 , 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
There remains a need for additional polymorphic forms of fidaxomicin and for processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.

G.V. Prasad, chairman, Dr Reddy’s Laboratories
EXAMPLES
Example 1 : Preparation of fidaxomicin Form IV:
Fidaxomicin (0.5 g) and a mixture of 1 ,4-Dioxane (10 mL), THF (10 ml) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature: 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-IV.
Example 2: Preparation of fidaxomicin Form V:
Fidaxomicin (1 g) and a mixture of propylene glycol (10 mL) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.
Example 3: Preparation of fidaxomicin Form VI:
Fidaxomicin (0.5 mg) and MIBK (10 mL) were charged in Easy max reactor (Mettler Toledo) and the mixture was heated to 80°C. n-heptane (20 mL) was added to the solution at the same temperature. The mixture was stirred for 1 hour. The reaction mass was then cooled to 25°C. Solid formed was filtered at 25°C and dried at 40°C in air tray dryer (ATD) to a constant weight to produce crystalline fidaxomicin form VI.
Example 4: Preparation of fidaxomicin Form V:
Fidaxomicin (500 mg) and a mixture of R-propylene glycol (5 mL) and water (15 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 2 hours.
After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.
Example 5: Preparation of fidaxomicin Form V:
Fidaxomicin (1 g) and a mixture of S-propylene glycol (3 ml_) and water (30 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 2 hours.
After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.
Example 6: Preparation of fidaxomicin Form V:
Fidaxomicin (40 g) and a mixture of propylene glycol (400 mL) and water (1600 mL) were charged in Chem glass reactor. The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.


The 10-member board at pharmaceutical major Dr Reddy’s thrives on diversity. Liberally sprinkled with gray hairs, who are never quite impressed with powerpoint presentations, “they want information to be pre-loaded so that the following discussions (at the board level) are fruitful,” says Satish Reddy, Chairman, Dr Reddy’s. That said, the company has now equipped its board members with a customized application (that runs on their tablets) to manage board agenda and related processes.
see at
http://articles.economictimes.indiatimes.com/2014-10-31/news/55631761_1_board-members-board-agenda-dr-reddy-s

Dr. Reddy’s Laboratories Managing Director and Chief Operating Officer Satish Reddy addressing


References

 
ARNONE A ET AL: "STRUCTURE ELUCIDATION OF THE MACROCYCLIC ANTIBIOTIC LIPIARMYCIN", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1987 (1987-01-01), pages 1353-1359, XP000578201, ISSN: 0300-922X, DOI: 10.1039/P19870001353
Fidaxomicin
Fidaxomicin.svg
Systematic (IUPAC) name
3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
Clinical data
Trade namesDificid, Dificlir
Licence dataUS FDA:link
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
BioavailabilityMinimal systemic absorption[1]
Biological half-life11.7 ± 4.80 hours[1]
ExcretionUrine (<1%), faeces (92%)[1]
Identifiers
CAS Number873857-62-6 Yes
ATC codeA07AA12
PubChemCID 11528171
ChemSpider8209640 
UNIIZ5N076G8YQ 
KEGGD09394 Yes
ChEBICHEBI:68590 
ChEMBLCHEMBL1255800 
SynonymsClostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B
Chemical data
FormulaC52H74Cl2O18
Molar mass1058.04 g/mol
US491817426 Sep 198617 Apr 1990Abbott LaboratoriesTiacumicin compounds
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WO2014023616A1 *30 Jul 201313 Feb 2014Olon SpaProcedure for the production of tiacumicin b
WO2014111254A114 Jan 201424 Jul 2014Astellas Pharma Europe LtdComposition of tiacumicin compounds
WO2015091851A118 Dec 201425 Jun 2015Xellia Pharmaceuticals ApsProcess for the preparation of tiacumicin
WO2015169451A111 May 201512 Nov 2015Astellas Pharma Europe LtdTreatment regimen tiacumicin compound
CN101128114B31 Jan 200528 Mar 2012浩鼎生技公司18-membered macrocycles and analogs thereof
CN102614207B *31 Jan 200513 Jan 2016默克夏普&多梅有限公司18元环大环化合物及其类似物
EP1848273A1 *31 Jan 200531 Oct 2007Optimer Pharmaceuticals, Inc.18-membered macrocycles and analogs thereof
EP2070530A113 May 200517 Jun 2009Optimer Pharmaceuticals, Inc.Treatment of diseases associated with the use of antibiotics
EP2125850A122 Jan 20082 Dec 2009Optimer Pharmaceuticals, Inc.Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
EP2305244A113 May 20056 Apr 2011Optimer Pharmaceuticals, Inc.Treatment of diseases associated with the use of antibiotics
EP2305245A113 May 20056 Apr 2011Optimer Pharmaceuticals, Inc.Treatment of diseases associated with the use of antibiotics
EP2468761A122 Jan 200827 Jun 2012Optimer Pharmaceuticals, Inc.Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US737850831 Jul 200727 May 2008Optimer Pharmaceuticals, Inc.Polymorphic crystalline forms of tiacumicin B
US786324911 Apr 20084 Jan 2011Optimer Pharmaceuticals, Inc.Macrolide polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US790648931 Jul 200715 Mar 2011Optimer Pharmaceuticals, Inc.18-membered macrocycles and analogs thereof
US804403028 Nov 200825 Oct 2011Optimer Pharmaceuticals, Inc.Antibiotic macrocycle compounds and methods of manufacture and use thereof
US858655131 Aug 200919 Nov 2013Optimer Pharmaceuticals, Inc.18-membered macrocycles and analogs thereof
US885951022 Jan 200814 Oct 2014Optimer Pharmaceuticals, Inc.Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US88839864 Mar 200911 Nov 2014Optimer Pharmaceuticals, Inc.Macrolide polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US891652715 Mar 201323 Dec 2014Optimer Pharmaceuticals, Inc.Antibiotic macrocycle compounds and methods of manufacture and use thereof
US20110166090 * 7 Jul 2011Youe-Kong Shue18-Membered Macrocycles and Analogs Thereof
US20140107054 *21 Dec 201217 Apr 2014Optimer Pharmaceuticals, Inc.Method of treating clostridium difficile-associated diarrhea
US3978211 *Oct 31, 1974Aug 31, 1976Gruppo Lepetit S.P.A.Lipiarmycin and its preparation
US4918174Sep 26, 1986Apr 17, 1990Abbott LaboratoriesTiacumicin compounds
US5583115May 9, 1995Dec 10, 1996Abbott LaboratoriesDialkyltiacumicin compounds
US5767096Jul 12, 1996Jun 16, 1998Abbott LaboratoriesBromotiacumicin compounds
US20060257981 *Jul 15, 2003Nov 16, 2006Optimer Pharmaceuticals, Inc.Tiacumicin production
US20070173462 *May 13, 2005Jul 26, 2007Optimer Pharmaceuticals, Inc.Treatment of diseases associated with the use of antibiotics
WO2004014295A2Jul 15, 2003Feb 19, 2004Optimer Pharmaceuticals IncTiacumicin production
WO2005112990A2May 13, 2005Dec 1, 2005Optimer Pharmaceuticals IncTreatment of diseases associated with the use of antibiotics

WO2006085838A1 *Jan 31, 2005Aug 17, 2006Optimer Pharmaceuticals Inc18-membered macrocycles and analogs thereof
DE2455230A1 *Nov 21, 1974May 28, 1975Lepetit SpaLipiarmycin, verfahren zu seiner herstellung, mikroorganismus zur durchfuehrung des verfahrens und arzneimittel
EP2125850A1Jan 22, 2008Dec 2, 2009Optimer Pharmaceuticals, Inc.Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US7378508Jul 31, 2007May 27, 2008Optimer Pharmaceuticals, Inc.Polymorphic crystalline forms of tiacumicin B
Braga et al., "Making crystals from crystals: a green route tocrystal engineering and polymorphism" Chemical Communications (2005) pp. 3635-3645.
2*Chemical Abstracts registry entry 56645-60-4, Tiacumicin B, Copyright 2007, American Chemical Society, p. 1-2.
3*Dean, J., Analytical Chemistry Handbook, Published bt McGraw-Hill, Inc., pp. 10.23-10.26.
4 J.E. Hochlowski et al., Tiacumicins, A Novel Complex of 18-Membered Macrolides, J. Antibiotics, vol. XL, No. 5, pp. 575-588 (May 1987).
5*Jain et al., "Polymorphism in Pharmacy" Indian Drugs (1986) vol. 23, No. 6, pp. 315-329.
6*Pharmaceutical Dosage Forms: Tablets, vol. 2, Published by Marcel Dekker, Inc., ed. by Lieberman, Lachman, and Schwartz, pp. 462-472.
7*Polymorphism in Pharmaceutical Solids, published 1999 by Marcel Dekker Inc, ed. by Harry G. Brittain, pp. 1-2.
8 Robert N. Swanson et al., In Vitro and In Vivo Evaluation of Tiacumicins B and C against Clostridium difficile, Antimicrob. Agents Chemother., Jun. 1991, pp. 1108-1111.
9*The Condensed Chemical Dictionary, Tenth Edition, published 1981 by the Van Nostrand Reinhold Company, revised by Gessner G. Hawley, p. 35 and 835.
///////////Fidaxomicin, OPT-80, PAR-101
CC[C@H]1/C=C(/[C@H](C/C=C/C=C(/C(=O)O[C@@H](C/C=C(/C=C(/[C@@H]1O[C@H]2[C@H]([C@H]([C@@H](C(O2)(C)C)OC(=O)C(C)C)O)O)\C)\C)[C@@H](C)O)\CO[C@H]3[C@H]([C@H]([C@@H]([C@H](O3)C)OC(=O)C4=C(C(=C(C(=C4O)Cl)O)Cl)CC)O)OC)O)\C

Sunday 7 February 2016

Patiromer


Patiromer
1260643-52-4 FREE FORM
CAS 1208912-84-8
(C10 H10 . C8 H14 . C3 H3 F O2 . 1/2 Ca)x
2-​Propenoic acid, 2-​fluoro-​, calcium salt (2:1)​, polymer with diethenylbenzene and 1,​7-​octadiene
RLY5016
RELYPSA INNOVATOR

Patiromer is a powder for suspension in water for oral administration, approved in the U.S. as Veltassa in October, 2015. Patiromer is supplied as patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol. Patiromer sorbitex calcium is an amorphous, free-flowing powder that is composed of individual spherical beads.
Veltassa is a powder for suspension in water for oral administration. The active ingredient is patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion.

Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol.

Mechanism of Action

Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.
patiromer1
Treatment of Hyperkalemia
Hyperkalemia is usually asymptomatic but occasionally can lead to life-threatening cardiac arrhythmias and increased all-cause and in-hospital mortality, particularly in patients with CKD and associated cardiovascular diseases (Jain et al., 2012; McMahon et al., 2012; Khanagavi et al., 2014). However, there is limited evidence from randomized clinical trials regarding the most effective therapy for acute management of hyperkalemia (Khanagavi et al., 2014) and a Cochrane analysis of emergency interventions for hyperkalemia found that none of the studies reported mortality or cardiac arrhythmias, but reports focused on PK (Mahoney et al., 2005). Thus, recommendations are based on opinions and vary with institutional practice guidelines (Elliot et al., 2010; Khanagavi et al., 2014). Management of hyperkalemia includes reducing potassium intake, discontinuing potassium supplements, treatment of precipitating risk factors, and careful review of prescribed drugs affecting potassium homeostasis. Treatment of life-threatening hyperkalemia includes nebulized or inhaled beta-agonists (albuterol, salbutamol) or intravenous (IV) insulin-and-glucose, which stimulate intracellular potassium uptake, their combination being more effective than either alone. When arrhythmias are present, IV calcium might stabilize the cardiac resting membrane potential. Sodium bicarbonate may be indicated in patients with severe metabolic acidosis. Potassium can be effectively eliminated by hemodialysis or increasing its renal (loop diuretics) and gastrointestinal (GI) excretion with sodium polystyrene sulfonate, an ion-exchange resin that exchanges sodium for potassium in the colon. However, this resin produces serious GI adverse events (ischemic colitis, bleeding, perforation, or necrosis). Therefore, there is an unmet need of safer and more effective drugs producing a rapid and sustained PK reduction in patients with hyperkalemia.
In this article we review two new polymer-based, non-systemic oral agents, patiromer calcium (RLY5016) and zirconium silicate (ZS-9), under clinical development designed to induce potassium loss via the GI tract, particularly the colon, and reduce PK in patients with hyperkalemia.
1. Patiromer calcium
This metal-free cross-linked fluoroacrylate polymer (structure not available) exchanges cations through the gastrointestinal (GI) tract. It preferentially binds soluble potassium in the colon, increases its fecal excretion and reduces PK under hyperkalemic conditions.
The development program of patiromer includes several clinical trials. An open-label, single-arm study evaluated a titration regimen for patiromer in 60 HF patients with CKD treated with ACEIs, ARBs, or beta blockers (clinicaltrials.gov identifier: NCT01130597). Another open-label, randomized, dose ranging trial determined the optimal starting dose and safety of patiromer in 300 hypertensive patients with diabetic nephropathy treated with ACEIs and/or ARBs, with or without spironolactone (NCT01371747). The primary outcomes were the change in PK from baseline to the end of the study. Unfortunately, the results of these trials were not published.
In a double-blind, placebo-controlled trial (PEARL-HF, NCT00868439), 105 patients with a baseline PK of 4.7 mmol/L and HF (NYHA class II-III) treated with spironolactone in addition to standard therapy were randomized to patiromer (15 g) or placebo BID for 4 weeks (Pitt et al., 2011). Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on day 15 if PK was ≤5.1 mmol/L. Patients were eligible for the trial if they had either CKD (eGFR <60 ml/min) or a history of hyperkalemia leading to discontinuation of RAASIs or beta-blockers. Compared with placebo, patiromer decreased the PK (-0.22 mmol/L, while PK increased in the placebo group +0.23 mmol/L, P<0.001), and the incidence of hyperkalemia (7% vs. 25%, P=0.015) and increased the number of patients up-titrated to spironolactone 50 mg/day (91% vs. 74%, P=0.019). A similar reduction in PK and hyperkalemia was observed in patients with an eGFR <60 ml/min. Patiromer produced more GI adverse events (flatulence, diarrhea, constipation, vomiting: 21% vs 6%), hypokalemia (<4.0 mmol/L: 47% vs 10%, P<0.001) and hypomagnesaemia (<1.8 mg/dL: 24% vs. 2.1%), but similar adverse events leading to study discontinuation compared to placebo. Unfortunately, recruited patients had normokalemia and basal eGFR in the treatment group was 84 ml/min. Thus, this study did not answer whether patiromer is effective in reducing PK in patients with CKD and/or HF who develop hyperkalemia on RAASIs.
A two-part phase 3 study evaluated the efficacy and safety of patiromer in the treatment of hyperkalemia (NCT01810939). In a single-blind phase (part A) 243 patients with hyperkalemia and CKD (102 with HF) on RAASIs were treated with patiromer BID for 4 weeks: 4.2 g in patients with mild hyperkalemia (5.1-<5.5 mmol/L, n=92) and 8.4 g in patients with moderate-to-severe hyperkalemia (5.5-<6.5 mmol/L, n=151). Part B was a placebo-controlled, randomized, withdrawal phase designed to confirm the maintained efficacy of patiromer and the recurrent hyperkalemia following that drug’s withdrawal. Patients (n=107) who completed phase A with a normal PK were randomized to continue on patiromer (27 with HF) or placebo (22 with HF) besides RAASIs for 8 weeks. The primary endpoint was the difference in mean PK between the patiromer and placebo groups from baseline to the end of the study or when the patient first had a PK <3.8 or ≥5.5 mmol/L. In part A patiromer produced a rapid reduction in PK that persisted throughout the study in patients with and without HF (-1.06 and -0.98 mmol/L, respectively; both P<0.001 vs. placebo); three-fourths of patients in both groups had normal PK (3.8-<5.1 mmol/L) at 4 weeks. In part B patiromer reduced PK (-0.64 mmol/L) in patients with or without HF (P<0.001). As compared with placebo, fewer patients, with or without HF, presented recurrent hyperkalemia in the patiromer group or required RAASI discontinuation regardless of HF status (Pitt, 2014). Patiromer was well-tolerated, with a safety profile similar to placebo even in HF patients. The most common adverse events were nausea, diarrhea, and hypokalemia.

INDICATIONS AND USAGE

Veltassa is a potassium binder indicated for the treatment of hyperkalemia.
Veltassa should not be used as an emergency treatment for lifethreatening hyperkalemia because of its delayed onset of action.
Patiromer (USAN, trade name Veltassa) is a drug used for the treatment of hyperkalemia (elevated blood potassium levels), a condition that may lead to palpitations and arrhythmia (irregular heartbeat). It works by binding potassium in the gut.[1][2]

Medical uses

Patiromer is used for the treatment of hyperkalemia, but not as an emergency treatment for life-threatening hyperkalemia, because it acts relatively slowly.[2] Such a condition needs other kinds of treatment, for example calcium infusions, insulin plus glucose infusions, salbutamol inhalation, and hemodialysis.[3]
Typical reasons for hyperkalemia are renal insufficiency and application of drugs that inhibit the renin–angiotensin–aldosterone system (RAAS) – e.g. ACE inhibitors, angiotensin II receptor antagonists, or potassium-sparing diuretics – or that interfere with renal function in general, such as nonsteroidal anti-inflammatory drugs (NSAIDs).[4][5]

Adverse effects

Patiromer was generally well tolerated in studies. Side effects that occurred in more than 2% of patients included in clinical trials were mainly gastro-intestinal problems such as constipation, diarrhea, nausea, and flatulence, and also hypomagnesemia (low levels of magnesium in the blood) in 5% of patients, because patiromer binds magnesium in the gut as well.[2][6]

Interactions

No interaction studies have been done in humans. Patiromer binds to many substances besides potassium, including numerous orally administered drugs (about half of those tested in vitro). This could reduce their availability and thus effectiveness,[2] wherefore patiromer has received a boxed warning by the US Food and Drug Administration (FDA), telling patients to wait for at least six hours between taking patiromer and any other oral drugs.[7]

Pharmacology

Mechanism of action

Patiromer works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange, thus lowering the amount of potassium available for absorption into the bloodstream and increasing the amount that is excreted via the feces. The net effect is a reduction of potassium levels in the blood serum.[2][4]
Lowering of potassium levels is detectable 7 hours after administration. Levels continue to decrease for at least 48 hours if treatment is continued, and remain stable for 24 hours after administration of the last dose. After this, potassium levels start to rise again over a period of at least four days.[2]

Pharmacokinetics

Patiromer is not absorbed from the gut, is not metabolized, and is excreted in unchanged form with the feces.[2]

Physical and chemical properties

The substance is a cross-linked polymer of 2-fluoroacrylic acid (91% in terms of amount of substance) with divinylbenzenes (8%) and 1,7-octadiene (1%). It is used in form of its calcium salt (ratio 2:1) and with sorbitol (one molecule per two calcium ions or four fluoroacrylic acid units), a combination called patiromer sorbitex calcium.[8]
Patiromer sorbitex calcium is an off-white to light brown, amorphous, free-flowing powder. It is insoluble in water, 0.1 M hydrochloric acid, heptane, and methanol.[2][8]
Hyperkalemia Is a Clinical Challenge
Hyperkalemia may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or conditions that reduce potassium excretion, including CKD, hypertension, diabetes mellitus, or chronic heart failure (HF) (Jain et al., 2012). Additionally, drugs and nutritional/herbal supplements (Table 1) can produce hyperkalemia in up to 88% of hospitalized patients by impairing normal potassium regulation (Hollander-Rodríguez and Calvert, 2006; Khanagavi et al., 2014).
Although the prevalence of hyperkalemia in the general population is unknown, it is present in 1-10% of hospitalized patients depending on how hyperkalemia is defined (McMahon et al., 2012; Gennari, 2002). Hyperkalemia is a common problem in patients with conditions that reduce potassium excretion, especially when treated with beta-adrenergic blockers that inhibit Na+,K+-ATPase activity or RAAS inhibitors (RAASIs) [angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists or renin inhibitors] that decrease aldosterone excretion (Jain et al., 2012; Weir and Rolfe, 2010). The incidence of hyperkalemia with RAASIs in monotherapy is low (≤2%) in patients without predisposing factors, but increases with dual RAASIs (5%) and in patients with risk factors such as CKD, HF, and/or diabetes (5-10%) (Weir and Rolfe, 2010). Thus, hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs.

History

Studies

In a Phase III multicenter clinical trial including 237 patients with hyperkalemia under RAAS inhibitor treatment, 76% of participants reached normal serum potassium levels within four weeks. After subsequent randomization of 107 responders into a group receiving continued patiromer treatment and a placebo group, re-occurrence of hyperkalemia was 15% versus 60%, respectively.[9]

Approval

The US FDA approved patiromer in October 2015.[7] The drug is not approved in Europe as of January 2016.


PATENT
PATENT

References


  • 1 Henneman, A; Guirguis, E; Grace, Y; Patel, D; Shah, B (2016). "Emerging therapies for the management of chronic hyperkalemia in the ambulatory care setting". American Journal of Health-System Pharmacy 73 (2): 33–44. doi:10.2146/ajhp150457. PMID 26721532.
  • 2FDA Professional Drug Information for Veltassa.
  • 3Vanden Hoek TL, Morrison LJ, Shuster M, Donnino M, Sinz E, Lavonas EJ, Jeejeebhoy FM, Gabrielli A; Morrison; Shuster; Donnino; Sinz; Lavonas; Jeejeebhoy; Gabrielli (2010-11-02). "Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation 122 (18 Suppl 3): S829–61. doi:10.1161/CIRCULATIONAHA.110.971069. PMID 20956228.
  • 4Esteras, R.; Perez-Gomez, M. V.; Rodriguez-Osorio, L.; Ortiz, A.; Fernandez-Fernandez, B. (2015). "Combination use of medicines from two classes of renin-angiotensin system blocking agents: Risk of hyperkalemia, hypotension, and impaired renal function". Therapeutic Advances in Drug Safety 6 (4): 166. doi:10.1177/2042098615589905. PMID 26301070.
  • 5Rastegar, A; Soleimani, M (2001). "Hypokalaemia and hyperkalaemia". Postgraduate Medical Journal 77 (914): 759–64. doi:10.1136/pmj.77.914.759. PMC 1742191. PMID 11723313.
  • 6Tamargo, J; Caballero, R; Delpón, E (2014). "New drugs for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors -- hype or hope?". Discovery medicine 18 (100): 249–54. PMID 25425465.
  • 7"FDA approves new drug to treat hyperkalemia". FDA. 21 October 2015.
  • 8RxList: Veltassa.
  • 9Weir, Matthew R.; Bakris, George L.; Bushinsky, David A.; Mayo, Martha R.; Garza, Dahlia; Stasiv, Yuri; Wittes, Janet; Christ-Schmidt, Heidi; Berman, Lance; Pitt, Bertram (2015). "Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors". New England Journal of Medicine 372 (3): 211. doi:10.1056/NEJMoa1410853. PMID 25415805.



Patiromer skeletal.svg
Systematic (IUPAC) name
2-Fluoropropenoic acid, cross-linked polymer with diethenylbenzene and 1,7-octadiene
Clinical data
Trade namesVeltassa
AHFS/Drugs.comentry
Legal status
Routes of
administration
Oral suspension
Pharmacokinetic data
BioavailabilityNot absorbed
MetabolismNone
Onset of action7 hrs
Duration of action24 hrs
ExcretionFeces
Identifiers
CAS Number1260643-52-4
1208912-84-8 (calcium salt)
ATC codeNone
PubChemSID 135626866
DrugBankDB09263
UNII1FQ2RY5YHH
KEGGD10148
ChEMBLCHEMBL2107875
SynonymsRLY5016
Chemical data
Formula[(C3H3FO2)182·(C10H10)8·(C8H14)10]n
[Ca91(C3H2FO2)182·(C10H10)8·(C8H14)10]n (calcium salt)
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Thursday 4 February 2016

The Year In New Drugs ..........Speedier development and regulatory process contributed to a peak in product approvals in 2015

 09405-cover-graph

 
SURGE
New drug approvals have risen sharply in recent years. SOURCE: FDA

The Year In New Drugs

Speedier development and regulatory process contributed to a peak in product approvals in 2015
 
 
read at 
 Chemical & Engineering News
Volume 94 Issue 5 | pp. 12-17
Issue Date: February 1, 2016

http://cen.acs.org/articles/94/i5/Year-New-Drugs.html
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