Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Meropenem products, pharmaceutical form, license number, batch, and manufacturer

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques:

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Primary pharmacodynamics parameters and mathematical quality of respective nonlinear regressions obtained from the dose-response relationships of the different animal models a

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Drug discovery

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of three generics compared with the innovator of meropenem against the WT strain P. aeruginosa GRP-0019 (MIC, 1 mg/liter) in the neutropenic guinea pig soleus infection model (panels correspond to separate experiments). The hydrolytic activity of cDHP-I against meropenem was very close to that of hDHP-I, making this species useful to model the PD in a human-like environment and without protecting the antibiotic with cilastatin. All products fit the Hill equation without faults; gMer-A and gMer-C required 91% (A) and 122% (B) greater doses to attain bacteriostasis than iMer, respectively. gMer-B, on the other hand, was indistinguishable (P = 0.88) from iMer (B).

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Drug discovery, Infection, Activity Assay

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of three generics compared with the innovator of meropenem against P. aeruginosa strains GRP-0019 (WT; A and B) and GRP-0049 (MDR; C and D) in the neutropenic mouse meningoencephalitis model. Without cilastatin, and using a dose-range encompassing the T>MIC from 12.4% to 100% (in serum) against GRP-0019, it was possible to obtain flawless fits for gMer-B, gMer-C, and iMer to the Hill model, demonstrating therapeutic equivalence of gMer-B and therapeutic nonequivalence of gMer-C (A). With cilastatin, only a 1:3 M:C ratio gave gMer-A a clean regression that, compared with iMer, required 47% more drug to achieve bacteriostasis (B). GRP-0049 was untreatable in this model without cilastatin (data not shown); with a 1:1 M:C ratio, gMer-A gave an accurate nonlinear regression but iMer did not (C), as seen in the thigh model with this MDR strain. A 1:3 M:C ratio gave an impeccable regression for both products, demonstrating that gMer-A required 56% more meropenem than iMer to attain bacteriostasis in vivo (D). These findings suggest that the innovator is preferentially hydrolyzed by GRP-0049, a strain that evolved in our hospital under the selective pressure of iMer (discussed in the text).

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Drug discovery, In Vivo

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of three generics compared with the innovator of meropenem against the WT strain K. pneumoniae GRP-0107 (MIC, 0.06 mg/liter) in the neutropenic mouse pneumonia model. mDHP-I is very active in this tissue, providing a good model to test meropenem under a highly hydrolytic environment. Without cilastatin, a T>MIC range from 22.8% to 100% (2.5 to 80 mg/kg/day) was not enough to reach maximal efficacy, and the data did not fit the Hill equation (A). Increasing the dose to 640 mg/kg provided much higher serum concentrations of meropenem (30- to 897-fold above the MIC) during 100% of the dosing interval, allowing gMer-B and iMer to reach their maximal effect and fit the Hill equation (P = 0.13 for comparison by CFA); gMer-C could not be included in the analysis because it did not fit the model, suggesting greater susceptibility to mDHP-I (B). When the dose range was narrowed to 5 to 160 mg/kg (%T>MIC, 42.8 to 100%), the addition of cilastatin up to a 1:3 M:C ratio did not help gMer-A or iMer (C); under a 1:5 M:C ratio, only iMer generated a flawless regression, suggesting that gMer-A is more susceptible to mDHP-I (D).

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Drug discovery, Comparison, Generated

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Single-dose serum PK parameters ± standard error computed by non compartmental analysis) of three generic and the innovator product of meropenem, after subcutaneous injection to neutropenic mice infected in the thighs with P. aeruginosa GRP-0019 (three dose levels, 10, 40 and 160 mg/kg, 6 mice per dose)*

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Injection, Infection

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Meropenem hydrolysis by mDHP-I: detection by HPLC-UV (left panels) and microbiological assay (right panels) of the remaining fraction of meropenem products with time after incubation at 37°C with mDHP-I extract for 4.5 h. The control curve (dotted) corresponds to meropenem incubated without DHP-I and shows the spontaneous degradation of the carbapenem. Both products were hydrolyzed by the enzyme, but gMer-A degraded much faster than iMer at all concentrations tested.

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Microbial Assay, Incubation, Control

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Quantification of enzymatic degradation of meropenem products by mDHP-I, determined by HPLC-UV and microbiological assay a

Article Snippet: Cilastatin was donated by Merck (Whitehouse Station, NJ). table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Meropenem product (code) Ampule presentation a License no. Batch(es) Manufacturer Analytical standard Meropenem trihydrate powder, 500 mg CAS no. 119478-56-7 106K0046V Sigma-Aldrich, St. Louis, MO Generic A (gMer-A) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2004M-0003819 B5305032, B5305052, B040687, C100752, C010806, C050994 Vitalis S.A.C.I., Bogotá, Colombia Generic B (gMer-B) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2006M-0005526 {"type":"entrez-nucleotide","attrs":{"text":"ES270220","term_id":"140295061","term_text":"ES270220"}} ES270220 , {"type":"entrez-nucleotide","attrs":{"text":"ES230084","term_id":"138228768","term_text":"ES230084"}} ES230084 Procaps S.A., Barranquilla, Colombia Generic C (gMer-C) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2010M-0010487 {"type":"entrez-nucleotide","attrs":{"text":"ES200261","term_id":"164138793","term_text":"ES200261"}} ES200261 Farmioni (Procaps S.A.), Barranquilla, Colombia Innovator (iMer) Meropenem trihydrate powder + Na 2 CO 3 , 500 mg INVIMA 2007M-006423-R1 DY001, DF465, CS686, CN859, CH277, HF501, FF201 AstraZeneca, Macclesfield, Cheshire, UK Open in a separate window a Only the analytical standard was devoid of the excipient, sodium carbonate (Na 2 CO 3 ).

Techniques: Microbial Assay, Control

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Meropenem products, pharmaceutical form, license number, batch, and manufacturer

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques:

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Primary pharmacodynamics parameters and mathematical quality of respective nonlinear regressions obtained from the dose-response relationships of the different animal models a

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques:

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of three generics compared with the innovator of meropenem against the WT strain P. aeruginosa GRP-0019 (MIC, 1 mg/liter) in the neutropenic guinea pig soleus infection model (panels correspond to separate experiments). The hydrolytic activity of cDHP-I against meropenem was very close to that of hDHP-I, making this species useful to model the PD in a human-like environment and without protecting the antibiotic with cilastatin. All products fit the Hill equation without faults; gMer-A and gMer-C required 91% (A) and 122% (B) greater doses to attain bacteriostasis than iMer, respectively. gMer-B, on the other hand, was indistinguishable (P = 0.88) from iMer (B).

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Infection, Activity Assay

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of one generic product (gMer-A) compared with the innovator of meropenem against the MDR strain P. aeruginosa GRP-0049 (MIC, 2 mg/liter) in the neutropenic mouse thigh infection model. Against this organism, a 1:1 M:C ratio was insufficient to protect meropenem from mDHP-I hydrolysis, and it was necessary to accumulate data from three identical experiments to obtain a valid nonlinear regression for gMer-A; persistent multicollinearity of both products prevented their statistical comparison, but their PD profiles looked quite different (A). With a 1:3 M:C ratio, both products fit the Hill equation with a single experiment without faults, dropping the T>MIC to 18.1% (B); increasing the M:C ratio to 1:5 made both products even more potent (T>MIC, 16.8%), suggesting additional hydrolysis of meropenem caused by this strain, probably by an enzyme other than mDHP-I but still susceptible to cilastatin inhibition (C). Increasing concentrations of cilastatin made products identical, with overlapping PD curves (compare panel A with panels B and C).

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Infection, Inhibition

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of three generics compared with the innovator of meropenem against P. aeruginosa strains GRP-0019 (WT; A and B) and GRP-0049 (MDR; C and D) in the neutropenic mouse meningoencephalitis model. Without cilastatin, and using a dose-range encompassing the T>MIC from 12.4% to 100% (in serum) against GRP-0019, it was possible to obtain flawless fits for gMer-B, gMer-C, and iMer to the Hill model, demonstrating therapeutic equivalence of gMer-B and therapeutic nonequivalence of gMer-C (A). With cilastatin, only a 1:3 M:C ratio gave gMer-A a clean regression that, compared with iMer, required 47% more drug to achieve bacteriostasis (B). GRP-0049 was untreatable in this model without cilastatin (data not shown); with a 1:1 M:C ratio, gMer-A gave an accurate nonlinear regression but iMer did not (C), as seen in the thigh model with this MDR strain. A 1:3 M:C ratio gave an impeccable regression for both products, demonstrating that gMer-A required 56% more meropenem than iMer to attain bacteriostasis in vivo (D). These findings suggest that the innovator is preferentially hydrolyzed by GRP-0049, a strain that evolved in our hospital under the selective pressure of iMer (discussed in the text).

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: In Vivo

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Pharmacodynamics of three generics compared with the innovator of meropenem against the WT strain K. pneumoniae GRP-0107 (MIC, 0.06 mg/liter) in the neutropenic mouse pneumonia model. mDHP-I is very active in this tissue, providing a good model to test meropenem under a highly hydrolytic environment. Without cilastatin, a T>MIC range from 22.8% to 100% (2.5 to 80 mg/kg/day) was not enough to reach maximal efficacy, and the data did not fit the Hill equation (A). Increasing the dose to 640 mg/kg provided much higher serum concentrations of meropenem (30- to 897-fold above the MIC) during 100% of the dosing interval, allowing gMer-B and iMer to reach their maximal effect and fit the Hill equation (P = 0.13 for comparison by CFA); gMer-C could not be included in the analysis because it did not fit the model, suggesting greater susceptibility to mDHP-I (B). When the dose range was narrowed to 5 to 160 mg/kg (%T>MIC, 42.8 to 100%), the addition of cilastatin up to a 1:3 M:C ratio did not help gMer-A or iMer (C); under a 1:5 M:C ratio, only iMer generated a flawless regression, suggesting that gMer-A is more susceptible to mDHP-I (D).

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Generated

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Single-dose serum PK parameters ± standard error computed by non compartmental analysis) of three generic and the innovator product of meropenem, after subcutaneous injection to neutropenic mice infected in the thighs with P. aeruginosa GRP-0019 (three dose levels, 10, 40 and 160 mg/kg, 6 mice per dose)*

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Injection, Infection

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Meropenem hydrolysis by mDHP-I: detection by HPLC-UV (left panels) and microbiological assay (right panels) of the remaining fraction of meropenem products with time after incubation at 37°C with mDHP-I extract for 4.5 h. The control curve (dotted) corresponds to meropenem incubated without DHP-I and shows the spontaneous degradation of the carbapenem. Both products were hydrolyzed by the enzyme, but gMer-A degraded much faster than iMer at all concentrations tested.

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Microbial Assay, Incubation

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: Quantification of enzymatic degradation of meropenem products by mDHP-I, determined by HPLC-UV and microbiological assay a

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Microbial Assay

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

doi: 10.1128/AAC.00350-13

Figure Lengend Snippet: LC/MS scan mode (range, m/z 100 to 1,000) of the pharmaceutical forms of one generic and the innovator of meropenem (fresh samples). The left (innovator) and right (generic) panels show above the spectrogram and, under it, the centroids graphs describing the composition masses of each peak numbered. There were no differences in the analyte signal (peak 2 in both panels), demonstrating that the active pharmaceutical ingredient (m/z 384) is present in both products at the same concentration, in compliance with current regulations. However, the generic product exhibited one additional peak, detected at 10 min (peak 3, right panel), with a main molecular mass of m/z 359 [M + 1] that was absent in the mass spectra of the innovator.

Article Snippet: Innovator (iMer) , Meropenem trihydrate powder + Na 2 CO 3 , 500 mg , INVIMA 2007M-006423-R1 , DY001, DF465, CS686, CN859, CH277, HF501, FF201 , AstraZeneca, Macclesfield, Cheshire, UK.

Techniques: Liquid Chromatography with Mass Spectroscopy, Concentration Assay