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Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Furosemide G.E. GRANERO,1 M.R. LONGHI,1 M.J. MORA,1 H.E. JUNGINGER,2 K.K. MIDHA,3 V.P. SHAH,4 S. STAVCHANSKY,5J.B. DRESSMAN,6 D.M. BARENDS7 1Chemical Sciences Faculty, Pharmacy Department, National University of Co´rdoba, Co´rdoba, Argentina 2Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand 3University of Saskatchewan, Saskatoon, Saskatchewan, Canada 4International Pharmaceutical Federation FIP, The Hague, the Netherlands 5Pharmaceutical Division, College of Pharmacy, University of Texas at Austin, Austin, Texas 6Institute of Pharmaceutical Technology, J.W. Goethe University, Frankfurt, Germany 7RIVM—National Institute for Public Health and the Environment, Bilthoven, the Netherlands Received 29 July 2009; accepted 29 October 2009 Published online 3 December 2009 in Wiley InterScience ( DOI 10.1002/jps.22030 ABSTRACT: Literature and new experimental data relevant to the decision to allow a waiver ofin vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosageforms containing furosemide are reviewed. The available data on solubility, oral absorption, andpermeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharma-ceutics Classification System (BCS). Furosemide’s therapeutic use and therapeutic index, itspharmacokinetic properties, data related to the possibility of excipient interactions and reportedBE/bioavailability (BA) problems are also taken into consideration. In view of the data available,it is concluded that the biowaiver procedure cannot be justified for either the registration of newmultisource drug products or major postapproval changes (variations) to existing drug products.
ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2544–2556, 2010Keywords: furosemide; absorption; bioequivalence; Biopharmaceutics Classification System (BCS); permeability; solubility; regulatory science new multisource products, are evaluated underconsideration of its biopharmaceutical and clinical A biowaiver monograph of furosemide based on properties. This evaluation refers to drug products literature data, together with additional experimen- containing furosemide as the single active pharma- tal data, is presented. The risks of basing a ceutical ingredient (API). The purpose and scope of bioequivalence (BE) assessment on in vitro rather this series of monographs have been previously than in vivo study results for the approval of new IR discussed.1 Summarized in few words, the aim is to solid oral dosage forms containing furosemide (‘‘bio- evaluate all pertinent data available from literature waiving’’), including both reformulated products and sources for a given API to assess the risks associatedwith a biowaiver. For these purposes, risk is definedin terms of the probability of an incorrect biowaiver A project of the International Pharmaceutical Federation FIP, decision as well as the consequences of an incorrect Special Interest Group BCS and Biowaiver,
decision in terms of public health and individual This article reflects the scientific opinion of the authors and not the policies of regulating agencies, the International Pharmaceu- patient risks. On the basis of these considerations, tical Federation (FIP) and the World Health Organization (WHO).
a recommendation can be made as to whether a Correspondence to: D.M. Barends (Telephone: 31-30-2744209; biowaiver is advisable or not. It is pointed out that Fax: 31-30-2744462; E-mail: these monographs do not simply apply the various Journal of Pharmaceutical Sciences, Vol. 99, 2544–2556 (2010)ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association regulatory documents, but also serve as a critical JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 evaluation of these documents. Biowaiver mono- headache, hypotension, muscle cramps, dry mouth, graphs have already been published for acetamino- thirst, weakness, etc.20 There is generally no need to phen (INN: paracetamol),2 acetazolamide,3 aciclovir,4 amitriptyline,5 atenolol,1 chloroquine,6 cimetidine,7diclofenac,8 doxycyline hyclate,9 ethambutol,10 ibu- profen,11 isoniazid,12 metoclopramide,13 predniso-lone,14 prednisone,15 pyrazinamide,16 propranolol,1 quinidine,17 ranitidine,18 rifampicin,19 and verapa-mil.1 They are also available on-line at www.fip.
The aqueous solubility of furosemide at room temperature has been reported to be 0.01825 mg/mL.21 Its aqueous solubility increases as function ofthe pH of the medium from 0.18 mg/mL at pH 2.3 to 13.36 mg/mL at pH 10.22 Martindale reports thatfurosemide is practically insoluble in water, corre- profile of furosemide at 308C showed a minimum of Chemical name: 4-chloro-N-furfuryl-5-sulphamoy- 0.010 mg/mL at pH 2.0 and a maximum of 21.9 mg/mL lanthranilic acid or 5-(aminosulfonyl)-4-chloro-2[(2- at pH 8.0, followed by a marginal decrease to about furanylmethyl)amino] benzoic acid. Its structure is 18 mg/mL above pH 8.0.23 Other workers reported a saturation solubility at pH 4.6 and 378C of 0.008 mg/mL.24 The equilibrium solubility of furosemide at Therapeutic Indication, Therapeutic Index, and Toxicity 378C in Krebs Ringer buffer at pH 5.0 was 0.33 mg/mL,increasing to $1.5 mg/mL at pH 6.5 and 1.9 mg/mL Furosemide is a loop diuretic that is used orally in the at pH 7.4.25 New solubility data at pH values within treatment of edematous states associated with the ranges required by the various Guidances26–29 cardiac, renal, and hepatic failure and the treatment were measured1 in triplicate at pH 1.0; 2.8; 3.8; 4.8; and 7.5 using the standard USP shake-flask method, The usual dosage is 40–120 mg/day. For the with stirring for 48 h at 378C. A summary of the treatment of mild cases of edema, doses as low as literature data as well as the new data are presented 20 mg can be effective, whereas for severe cases of in Table 1. No data on the stability of furosemide in edema doses as high as 600 mg/day may be required.20 human gastric and intestinal fluids were found in the For the treatment of chronic renal impairment the dose can be as high as 1.5 g/24 h. Furosemide inhibitsthe reabsorption of sodium and chloride in the ascending limb of the loop of Henle and also in the A furosemide sodium salt is known, but is used only in early distal tubules. Excretion of sodium, potassium, parenterals, such as furosemide for injection USP.30 calcium, and chloride ions is increased and water Seven polymorphic forms are known: four true excretion enhanced.20 Most adverse effects of furose- polymorphs (I, II, III, IV), two solvates (IV—DMS mide occur at high doses and/or prolonged use.
and V—dioxane) and one amorphous form,31–34 but Serious effects are uncommon, the most common polymorph-dependent bioavailability (BA) has not being fluid and electrolyte imbalance, including been reported to date in the literature.
hyponatraemia, hypokalaemia, and hypochloraemicalkalosis. Signs of electrolyte imbalance include Furosemide is a weak acid with an acidic pKa value of3.8 (carboxylic acid).35 Log P (n-octanol/water) values of 2.2935 and 1.8136have at pH values of 7.39, 5.86, and 2.58 have beenreported to be À1.20, À0.10, and 1.78, respectively.36A log D (pH 7.4) value of À0.69 has been measured.35Kasim et al.37 calculated log n-octanol/water partition 1Experiments performed at the Pharmacy Department, Chemi- cal Sciences Faculty, National University of Co´rdoba, Argentina.
The pH was measured after the addition of the drug.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 Table 1. Solubility (mg/mL) of Furosemide: Literature Data and New Experimental Data. Also shown: the CorrespondingDose/Solubility Ratio (D/S) (mL) at 378C for three tablet strengths aCalculated from the solubility data at 378C; the critical limit is 250 mL.26–29 bStrength on WHO essential medicines list.38 cA D/S value exceeding the critical limit.
coefficients for furosemide using two different tions, Lasix1 and Furix1, each in a dose of 40 mg, and methods, finding values of 1.9 and 0.74, respectively.
also after intravenous (i.v.) administration in eight For metoprolol, following the same methodologies, healthy subjects. Absolute BA was reported to be 56% the authors reported values of 1.35 and 1.72, for Lasix1 and 55% for Furix1, with a range of 20– 84% between individuals and 20–61% within anindividual, indicating extensive variability after oral administration. Extensive variability was also The WHO recommended oral dosage form strength is observed in mean absorption time and urinary 40 mg.38 Table 2 shows IR furosemide tablets with a excretion. The intra-subject variability was thought marketing authorization (MA) in Germany (DE),39 to depend mainly on the absorption process, since Denmark (DK),40 Finland (FI),41 France (FR),42 The repeated i.v. doses showed only marginal intra- Netherlands (NL),43 Norway (NO),44 Spain (ES),45 subject variability, but, as this study was severely Sweden (SE),46 United Kingdom (UK),47 and the underpowered, it is not possible to draw robust United States (US).48 These MAs cover a very wide range of strengths: from 20 mg up to 500 mg.
The hypothesis that furosemide exhibits site- specific absorption was investigated in the rat model.
In this animal model, Chungi et al.54 reported absorption to be biexponential and rapid whenadministered to the stomach but slower when administered to the small intestine. The most rapid Furosemide is fairly rapidly absorbed from the absorption occurred after administration to the gastrointestinal (GI) tract. Its BA was reported to stomach at a pH of 3. In man, the absorption of be about 60–70%, but the absorption is variable and furosemide is also site-specific and takes place erratic.20 Others report a poorer oral BA of 50%49–51 primarily in the upper parts of the small intestine.
or 37–51%.52 Peak serum concentrations (Cmax) occur Clear et al.55 released furosemide using an Intelisite1 between 60 and 90 min with concentrations falling capsule at specific sites in the GI tract, finding that below the limit of detection between 3 and 4 h after the absorption window of furosemide in the upper GI ingestion. The rate and extent of absorption show tract is narrow: when drug release took place in the large inter- and intra-subject variabilities. Absorp- proximal intestine instead of the stomach, the area tion following oral administration is influenced by the under the concentration time curve (AUC) for dosage form, underlying disease processes, and by furosemide decreased markedly, by 29%. From these the presence of food.50 Grahne´n et al.53 investigated studies it was concluded that, in humans, furosemide the intra-subject variation in BA with respect to rate is most rapidly absorbed from the upper GI tract and extent of absorption between two tablet formula- following dissolution in the stomach.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 Absorptive behavior differences were reported The pharmacokinetics of furosemide are reported to between dosage forms. Hammarlund et al.51 studied be linear over the oral dosage range of 20–80 mg.61 in 8 subjects the mean time for the different steps in Furosemide plasma profiles often exhibit secondary absorption for i.v. and different modes oral adminis- or multiple peaks following either oral or i.v.
tration of furosemide. The mean absorption times for administration.52,62,63 These phenomena have been all oral doses were significantly longer than the mean attributed to enterohepatic cycling of the drug.50 absorption times after i.v. administration, indicating However, furosemide is mainly excreted in the urine, absorption rate-limited kinetics. Absorptive behavior largely unchanged. There is some excretion via the differences were also reported between solutions bile and nonrenal elimination, but the small amount versus tablets. Waller et al.56studied two furosemide of furosemide reabsorbed after biliary elimination is tablets and an aqueous solution in 21 healthy adult not sufficient to account for the secondary peaks.20 males. The peak plasma furosemide concentration Other authors explain the multiple plasma peaks obtained with the solution was significantly greater with an erratic absorption behavior.64 However, this than with the tablet formulations. Also, the time to hypothesis is not consistent with multiple peaks after peak occurred significantly earlier with the solution.
This finding was confirmed by McNamara et al.57 evaluating the relative BA of five tablets and an oralsolution in 12 normal volunteers in a crossover Several authors report permeability data of furose- design; compared to the solution, all tablets formula- mide; 25,65–72 they are shown in Table 3. Furosemide tions exhibited lower peak furosemide concentration.
is a known substrate of efflux transporters.65 Motz25 Absorptive behavior differences were also reported applied a proton gradient between an apical to between the fasting and nonfasting state. In the study basolateral compartment (A-B) transport study with of Hammarlund et al.,51 food delayed the absorption A ¼ pH 6.5 and B ¼ pH 7.4, respectively, resulting in a on average by 60 min. When a 40 or 80 mg tablet of flux–efflux high ratio of $50. The large directional furosemide was taken orally by healthy adults in the differences in transport rates in the Caco-2 cells have fasting state, a detectable concentration of drug been attributed to the secretion of this API by efflux appears in the serum within 10 min and peaks systems such as the P-glycoproteins on the one hand between 60 and 90 min at a level of 1–3 mg/mL,58,59 and to a significant paracellular contribution to but when taken in close proximity to a meal, there is a delay in its appearance in plasma, and a lower peak It has been reported that apparent permeability concentration of about 1 mg/mL was reported after ( Papp) of furosemide can be affected by the presence of $2 h.60 Despite the difference in peak serum con- the excipient Tween-801 (polysorbate 80). Rege centrations the total amount of furosemide absorbed et al.70 reported an increase in the apical-to-baso- is similar.60 Kelly et al.52 also found that postprandial lateral (A-B) transport of furosemide in the presence administration of furosemide results in delayed of Tween-801, which neutralized the asymmetry in appearance of the drug in serum, lowered Cmax and transport. Polysorbate 80 is a known P-glycoprotein more prolonged concentrations. Beermann and Mid- skov60 reported a reduced but parallel plasma effect, observing not only an increase in Papp (A-B) concentration versus time profile between the fasting but also a decrease in Papp basolateral-to-apical (B-A) in a Caco-2 cell model. Motz25 also found that vitamin When metoprolol was included as a reference, its permeability is also reported.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 E d-alpha-tocopheryl poly(ethylene glycol)succinate, different brands of 40 mg furosemide tablets available another P-glycoprotein inhibitor,73 increased Papp in Thailand was evaluated. Only four brands passed (A-B) of furosemide, while Papp(B-A) was reduced.
the specification for dissolution (apparatus 2 at50 rpm in pH 7.4 phosphate buffer). The original Distribution, Metabolism, and Elimination brand (brand A) and the three local brands (brand B, Furosemide is up to 99% bound to plasma proteins.30 C, and D) which showed differences in dissolution The clearance of furosemide is generally reported to characteristics were selected for a BA study in eight be in the range of 0.09–0.18 L/h/kg. The half-life of healthy subjects. Plasma furosemide concentrations furosemide is in the range of 30–120 min and it is and urine output, and sodium, chloride, and potas- mainly excreted in the urine, largely unchanged.20 In sium excretion were measured. The relative BA of end-stage renal disease the half-life may reach almost furosemide with respect to brand A was 70% (brand 10 h and in neonates the half-life is also prolonged, B), 113% (brand C), and 95% (brand D); these since renal function is not yet mature at birth. As well differences were deemed not statistically significant as renal elimination there is also some excretion different at a 95% confidence level, but certainly at via the bile, with the role of nonrenal elimination least brand A would not have met the current 0.80– considerably greater in renal impairment.50 1.25 criterion for the AUC. As the clinical response in Furosemide has two metabolites, furosemide glu- terms of diuresis and electrolyte excretion between the four brands was not significantly different at a95% confidence level, the authors concluded that theformulations were clinically equivalent. Here again, the power of the study was likely too weak toappropriately detect differences.
Excipients and/or Manufacturing Variations Awad et al.80 estimated the BE of Diusemide versus Reports of BE studies between furosemide IR drug Lasix, each containing 40 mg of furosemide, in 20 products show inconsistent results.74–78 However, healthy volunteers. The compositions of the products most of these studies were carried out 20–30 years were not reported. No significant differences were ago, when BE was not defined according to the found in AUC, Cmax, tmax, cumulative urine volume, current biostatistical standards. Nowadays drug products are considered bioequivalent if, with high Although this analysis led the authors to conclude probability, the hypothesis that two formulations to BE between the two products, the power of the are bioinequivalent can be rejected,26–29 whereas at study was undoubtedly too weak to conclude that the the time most of the literature studies were con- products were bioequivalent using today’s BE stan- ducted, two formulations were considered bioequiva- lent if no significant differences in pharmacokinetic Nakib et al.81 reported BE of a brand of furosemide parameters were observed. As a result, in several 40 mg tablets versus Lasix1. The compositions of the early studies formulations were reported to be products were not reported. The study included 24 bioequivalent, even though by current biostatistical fasting, healthy, male volunteers and 90% confidence intervals of the ratios of AUC0–t, AUC0–1, and Cmax of met BE criteria due to insufficient power in the the two formulations were within the 80–125% range.
study design. Additionally, most references do not Applying current BE standards, the two products report results in sufficient detail to allow recalcula- tion of the data according to current biostatistical Cuadrado et al.82 studied two 40 mg furosemide formulations versus a reference, the identity of which not was revealed. The compositions of the products marketed brands of furosemide, Impugan1 (A/S were also not reported. The study included 24 healthy Dumex, Copenhagen, DK) and Lasix1 (Hoechst volunteers; plasma furosemide concentrations, urine AG, Frankfurt (M), DE), in five healthy volunteers.
output and sodium, chloride, and potassium excre- The compositions of the products were not reported.
tions were measured. AUC0–1, and Cmax and were Although time of the peak levels, AUC and the tested for BE after ln-transformation and ratios of urinary recovery after the oral administration did not tmax were evaluated nonparametrically. Ninety per- differ significantly using Student’s paired t-test, the cent confidence intervals for AUC0–1 were 0.94–1.19; power of the study was undoubtedly too weak to for Cmax 0.96–1.31 and for tmax 0.55–1.00, respectively conclude that the two products were bioequivalent.
and BE between both formulations was concluded by A Thai study79 compared the in vitro dissolution the authors for all parameters except for tmax. The and clinical response among marketed furosemide methodology used was in line with current standards, drug products. The compositions of the products were but many regulatory authorities would conclude that not reported. The in vitro dissolution of thirteen these formulations do not meet current BE criteria, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 since for Cmax an acceptance criteria of 0.8–1.25 is Rubinstein and Rughani85 studied furosemide 40 mg tablets, prepared with four different binders: Grahne´n et al.53 reported a study of two tablet polyvinylpyrrolidone, starch mucilage, stearic acid, formulations, Lasix1 and Furix1, each at a dose of and methylhydroxyethyl cellulose. BA was assessed 40 mg, in eight healthy subjects. For these subjects in four healthy males with reference to an oral the products were demmed nonequivalent, based solution. The tablets containing polyvinylpyrrolidone on AUC: However, after extending the study to and methylhydroxyethyl cellulose showed point 16 subjects, the authors considered the products to be estimate of relative BA values of 72% and 72%, bioequivalent, based on a <6% probability that there respectively, while the starch mucilage formulation was a >20% difference in AUC. This criterion does not and the stearic acid formulation showed relative BA values of 54% and 35%, respectively. This consider- Studies suggesting bioinequivalence2 between fur- able decrease of the BA of furosemide by starch and osemide tablets have also been reported. Wolf- stearic acid was not confirmed by other excipient Coporda et al.84 evaluated two oral preparations of interaction data, see below. As this study was furosemide, a Croatian test product and the reference severely underpowered, it is not possible to draw preparation, Lasix1 (Hoechst AG), at a dose of 500 mg any robust conclusions from the data.
in 15 healthy male volunteers. The compositions Table 2 shows the excipients present in IR of the products were not reported. The test product furosemide tablets with an MA in various countries.
showed a considerably higher Cmax; statistically As over the years the criteria for BE have been significant shorter tmax and significantly higher changed, it cannot be assumed that all these drug AUC than the reference preparation. The relative products successfully had passed an in vivo BE study BA of the test product was 129% and thus not that would be in conformity with the present equivalent to the reference according to current BE regulations. However, in view of their MA, there standards. These products maybe even bioinequiva- can be little doubt on their clinically efficacy and lent, in view of the large differences in the point safety. It can therefore be argued that the excipients estimates of these pharmacokinetic parameters. The present in these drug products do not exert a brand with the highest Cmax also showed the fastest significant effect on the rate and extent of absorption in vitro dissolution but the test conditions used were of furosemide. Table 2 includes polysorbate 80, an excipient which showed an effect on the Caco-2 McNamara et al.57 evaluated three brands of 40 mg permeability of furosemide.70 This suggests that the furosemide tablets, one of which was Lasix1, and one Caco-2 excipient interaction studies may have over- oral solution in 12 volunteers. For two brands, discriminated. Table 2 also includes starch and including Lasix1, two different batches were included stearic acid, excipients which were reported by in the study, one of which was designated as Rubinstein and Rughani to decrease the BA of reference. The compositions of the formulations were furosemide considerably is possible that the amounts not reported. Plasma and cumulative urine concen- used were quite different between the test formula- trations of furosemide were measured, as well as the tions and those described in Table 2.
in vitro dissolution of the tablets in USP Apparatus II Dissolution and In Vitro–In Vivo Correlations (IVIVCs) (paddle) at 50 rpm in acetate buffer pH 4.6 and 5.6.
With respect to the usual pharmacokinetic para- The USP 32 specification for dissolution of furosemide meters, all tablet formulations were significantly tablets is not <80% (Q) dissolved in 60 min in 900 mL different from the reference at the 95% confidence of pH 5.8 phosphate buffer, using the paddle level, with point estimate BA ranging from 70% to 91%. This study also reported a wide intra-subject There are some reports describing successful variability from oral dosage forms. Applying current IVIVCs for furosemide drug products.82–86 Rubinstein BE standards, it would most probably be concluded and Rughani85 reported that the observed differences that all tested tablet formulations failed to meet the in BA of furosemide tablets with different exci- BE criteria; some of these formulations might even be pients were reflected in in vitro drug release in distilled water. Stu¨ber et al.86 studied the BA of sixcommercial tablet preparations in six volunteers. Theidentities and the composition of the tested tabletswere not reported. One tablet reached only 80% of the AUC of the reference tablet; its Cmax was lower and its Bioinequivalence implies that the regulatory defined confidence interval of one, or more, BE attributes (AUC, Cmax, Tmax) falls fully tmax longer. The tablet with the lowest BA in term of outside of their regulatory acceptance range, whereas failure to AUC, Cmax, and tmax also showed lower in vitro meet BE criteria implies that the regulatory defined confidence dissolution than the reference tablet in each of four interval of one, or more, BE attributes does not fully fall inside theirregulatory acceptance range.83 different methods: pH 7.8/paddle 25 rpm; pH 7.8/ JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 paddle 50 rpm; pH 5.3/paddle 50 rpm and flow- through cell/pH 7.8. The difference in vitro dissolu-tion was most pronounced at pH 5.3/paddle 50 rpm; under this condition the time needed to reach 50% Solubility criteria defined in present regulatory dissolution for the tablet with the low BA was 4.4 guidances26–29 for classifying an API as highly soluble require the highest dosage strength to be soluble at Investigating the dissolution of two brands of 378C in 250 mL aqueous solution over the pH range of furosemide tablets Prasad et al.87 found negligible 1.0–6.8, according to the EU28,29 and WHO26 gui- differences at pHs higher than 4.6; the brand dances, or 1.0–7.5 according to the FDA guidance.27 dissolving poorly at pH 4.6 also had an inferior BA The dose to solubility ratio (D/S) at 378C of the most with respect to both Cmax and AUC. In a study of four often used strength, 40 mg, exceeds the critical value commercial and two experimental furosemide tablets of 250 mL at pH 4.8 and below; the 500 mg tablet Kingsford et al.88 reported a good correlation between exceeds the critical D/S value at pH 5.0 and below, see the percentage dissolved in 30 min in buffer pH 5.0 at Table 1. Hence, furosemide is not highly soluble.
378C in the rotating basket and the percentage offurosemide recovered in the urine.
McNamara et al.57 tested five lots of furosemide tablets for dissolution in acetate buffer at pH values of The FDA defines highly permeable as having a 4.6 and 5.6, using a USP paddle apparatus at 50 rpm fraction dose absorbed of not <90%.27 The WHO at pH 4.6 and 5.6. The products dissolved faster Guideline set a limit of not <85% of the fraction dose and more completely at pH 5.6. Correlations of absorbed.90 The EMEA Note for Guidance presently mean in vivo parameters with in vitro dissolution in force is less precise, stating that ‘‘linear and approached statistical significance, with a somewhat complete absorption indicating high permeability higher correlation with the parameters derived from reduces the possibility of an IR dosage form influen- dissolution at pH 4.6 than at pH 5.6. However, since cing the BA.’’28 The draft revision to that Guidance two products showing only small differences in states that an extent of absorption !85% is generally differences in dissolution at pH 4.6, the authors Furosemide is incompletely absorbed after oral concluded that this medium was overly discriminat- administration to healthy subjects and also in ing and that the pH 5.6 medium would be more patients with various diseases.59,91 Additionally, appropriate for assuring batch uniformity and BE of Attachment A of the FDA Guidance classifies Waller et al.56 compared tablets in vivo and in vitro Caco-2 data are in line with that classification. For of identical composition but produced by a slightly drug transport in Caco-2 monolayers, a cutoff point different manufacturing method. The in vivo study in for highly permeable APIs of Papp ¼ 10À5 cm/s, was 21 healthy human volunteers showed the relative proposed to ensure a fraction dose absorbed higher BAs of two tablets to be 89% and 101% compared to than 95%.92 Similarly, a cutoff limit of Papp from the solution, respectively, as determined by AUC, and 2 Â 10À6 to 10À5 cm/s as a boundary of highly perme- these were reported to be not different at a 95% able were proposed by Rinaki et al.93 Other workers confidence level. After 30 min dissolution testing proposed that a cutoff limit of Papp of 2 Â 10À6 cm/s in at pH 5.8 in the paddle apparatus operated at Caco-2 is commensurate with 100% absorption.94 The 50 rpm, one tablet showed 83% dissolution, the other apical-to-basolateral, that is, the absorptive Papp tablet 49% dissolution. Under the same conditions, values reported for furosemide, being in the range but using a medium composed at pH 4.6, the of 0.1–0.5 Â 10À6 cm/s, are a factor of 4–20 below these same tablets released 41% and 17%, respectively.
boundary values. It can be questioned if absolute Since the two products show only small differences Caco-2 permeability data are not so laboratory in pharmacokinetic parameters, but marked differ- specific that a general limit cannot be set. However, ences in dissolution at pH 5.8, and even larger Table 3 shows that in all studies where metoprolol differences at pH 4.6, this study suggested that was included as a reference, the permeability of dissolution testing of furosemide tablets tends to furosemide was far lower than the permeability of be overly discriminating, particularly at pH 4.6.
metoprolol; metoprolol is the reference substance in Qureshi and McGilveray89 reported a collaborative classifying any other substance as highly permeable study on the in vitro dissolution of 40-mg furosemide or not highly permeable. And the log P and C log P tablets in buffer pH 5.8 and buffer at pH 4.6. About values are likewise in line with the classification of 20–38% of the variability in dissolution was not furosemide as not highly permeable, although corre- product related but came from the dissolution test lations of log P values with human intestinal perme- ability show both false positives and negatives.37 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 Patient’s Risks Associated With Nonequivalence The most recent WHO Guideline,90 as well as Kasim The regulations of the FDA, the WHO, and also the et al.37 and Lindenberg et al.,95 all classify furosemide draft Guideline on BE of the EU exclude Narrow as Biopharmaceutics Classification System (BCS) Class IV. Moreover, Wu and Benet96 classified ing.26,27,29 The therapeutic plasma concentration furosemide as Class IV in their Biopharmaceutics for furosemide ranges from 1 to 6 mg/mL, with toxicity Drug Disposition Classification System (BDDCS), a occurring in the range 25–30 mg/mL.97 According to system using the disposition characteristics of an API the FDA definition of NTI,98 furosemide is not a NTI as an estimate of its GI permeability. On the basis of drug, since there is more than a twofold difference literature data presented in this monograph, new between the minimum toxic concentration (25 mg/mL) data generated, as well as the classification of and the minimum effective plasma concentration furosemide by other groups, it can be concluded that (1 mg/mL). The Pan American Health Organization PAHO classified furosemide as an intermediatehealth-risk drug in view of the margin between the Risk of Nonequivalence Caused by Excipients nontoxic maximum and effective minimum concen- trations and its adverse effects. This organizationclassified furosemide as having an intermediate Many studies reported in the literature asserted that probability of a minor complication of the disease the drug products studied were bioequivalent, but and/or mild adverse reactions at plasma concentra- most studies used small subject numbers and tions outside the therapeutic window of the drug.99 statistical methods that do not meet current require- The current EU regulation does not mention the ments. Only the Nakib et al.81 and Cuadrado et al.82 concept of NTI, but states that noncritical therapeutic studies appeared to have reached a BE conclusion range should be considered, defined as requirements based on currently accepted methodology. On the of special precautions with respect to precision and other hand, in the Thai,79 Wolf-Coporda et al.,84 accuracy of dosing, for example, the need for critical McNamara et al.,57 and Rubinstein and Rughani85 studies, at least one of the products showed such large Furosemide is used for serious indications such as differences in pharmacokinetic parameters from cardiac insufficiency and pulmonary hypertension. In those of the comparator that it is most likely that many therapeutic situations, including edema of that product would be declared bioinequivalent after varying severity and oliguria, dose titration in the application of statistical testing. Although most of individual patient is recommended.20 This is partly these products were exploratory or test formulations, because furosemide shows large intra- and inter- the results indicate that changes in composition and/ subject variabilities in BA after oral administration or variations in manufacturing techniques can indeed and partly due to variability in patient response to have an impact on the BA of furosemide.
furosemide. Although a bioinequivalence betweentwo furosemide drug products could easily bemasked Surrogate Techniques for In Vivo BE Testing by the large intra- and inter-subject variabilities inBA and the dose titration, approving drug products A variety of dissolution test conditions have been used which cannot meet BE criteria is not an option for to link in vitro to in vivo performance. In general, the results indicate that dissolution in media with a pH inthe range of pH 5.0 to 5.8, that is, the pH of the USPdissolution test, will detect differences in BA. Testing in more acidic dissolution media, such as pH 4.6,tends to be overly discriminating, whereas tests in Furosemide is BCS Class IV, so both the in vivo more alkaline media, such as pH 7.8, tend to lose dissolution and the in vivo permeability can be critical discrimatory power. To date, however, there are not to in vivo performance of oral furosemide drug enough data with any one set of in vitro test products. No data are available in the literature conditions to allow a firm conclusion on its reliability about its stability in human gastric and intestinal as a predictor for in vivo performance.
fluids. Likewise, no surrogate methods have been Further, there are hints in the literature data that identified in the literature that would reliably in vitro permeability of furosemide may show an forecast the in vivo performance of oral furosemide excipient interaction and there is not enough products. Further, in vivo excipient effects on evidence to rule out the possibility of such an permeability of furosemide cannot fully be ruled interaction in vivo. It is noted that in vitro dissolution out. Therefore, a biowaiver for the approval of testing is not indicative for in vivo permeability new multisource IR solid oral products containing furosemide is inappropriate and BE should be JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 6, JUNE 2010 established with an in vivo BE study. This conclusion man JB, Barends DM. 2009. Biowaiver monographs for supports current regulatory guidances26–29 which do immediate release solid oral dosage forms: Diclofenac sodium not allow biowaivers for new multisource drug and diclofenac potassium. J Pharm Sci 98:1206–1219.
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changes may be approvable without an in vivo BE Biowaiver monographs for immediate release solid oral dosage study. The FDA describes such postapproval changes forms: Ethambutol dihydrochloride. J Pharm Sci 97:1350– as SUPAC level 1 and level 2.100 The EU has a comparable system.101 When a change to an approved 11. Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, furosemide IR drug product falls into such category, Shah VP, Vogelpoel H, Barends DM. 2005. Biowaiver mono-graphs for immediate release solid oral dosage forms: Ibupro- the data presented in this monograph (including the excipient table for products with an MA) can be 12. Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, helpful to assess how critical the change is to product Midha KK, Shah VP, Stavchansky S, Barends DM. 2007.
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