Biowaiver monographs for immediate release solid oral dosage forms

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levofloxacin MARCELLE O. KOEPPE,1 RODRIGO CRISTOFOLETTI,1 EDUARDO F. FERNANDES,1 SILVIA STORPIRTIS,2 HANS E. JUNGINGER,3 SABINE KOPP,4 KAMAL K. MIDHA,5 VINOD P. SHAH,6 SALOMON STAVCHANSKY,7 JENNIFER B. DRESSMAN,8 DIRK M. BARENDS9 1

Brazilian Health Surveillance Agency (Anvisa), Division of Bioequivalence, Brazil

2

Faculty of Pharmaceutical Sciences, University of São Paulo, Brazil

3

Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand

4

World Health Organization, Geneva, Switzerland

5

University of Saskatchewan, Saskatoon, Saskatchewan, Canada

6

International Pharmaceutical Federation FIP, The Hague, the Netherlands

7

Pharmaceutics Division , College of Pharmacy, University of Texas at Austin, Austin, Texas 78712

8

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany

9

RIVM—National Institute for Public Health and the Environment, Bilthoven, the Netherlands

Received 13 September 2010; revised 2 November 2010; accepted 2 November 2010 Published online 21 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22413 ABSTRACT: Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levofloxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the current Biopharmaceutics Classification System, levofloxacin can be assigned to Class I. No problems with BE of IR levofloxacin formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. In addition, levofloxacin has a wide therapeutic index. On the basis of this evidence, a biowaiver is recommended for IR solid oral dosage forms containing levofloxacin as the single API provided that (a) the test product contains only excipients present in IR levofloxacin drug products that have been approved in International Conference on Harmonization (ICH) or associated countries and which have the same dosage form; (b) both the test and comparator dosage form are “very rapidly dissolving” or “rapidly dissolving” with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8; and (c) if the test product contains polysorbates, it should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1628–1636, 2011 Keywords: levofloxacin; absorption; Biopharmaceutics Classification System (BCS); permeability; regulatory science; solubility

INTRODUCTION Correspondence to: D.M. Barends (Telephone: 31-30-274-4209; Fax: 31-30-2744462; E-mail: [email protected]) A project of the International Pharmaceutical Federation FIP, Special Interest Group BCS & Biowaiver, www.fip.org/bcs. This article reflects the scientific opinion of the authors and not necessarily the policies of regulating agencies, the International Pharmaceutical Federation (FIP) and the World Health Organization (WHO), nor the Brazilian Health Surveillance Agency (Anvisa). Journal of Pharmaceutical Sciences, Vol. 100, 1628–1636 (2011) © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

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A biowaiver monograph based on literature data is presented on levofloxacin, with respect to its biopharmaceutical properties and the risk of waiving in vivo bioequivalence (BE) testing in the approval of new immediate release (IR) solid oral dosage forms containing levofloxacin, including both reformulated products and new multisource drug products. This evaluation refers to drug products containing

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011

BIOWAIVER MONOGRAPH FOR LEVOFLOXACIN

levofloxacin as the only active pharmaceutical ingredient (API) and not to combination products. The purpose and scope of this series of monographs have been previously discussed.1 Summarized in few words, the aim is to evaluate all pertinent data available from literature sources for a given API to assess the risks associated with a biowaiver. For these purposes, risk is defined as the probability of an incorrect biowaiver decision as well as the consequences of the decision in terms of public health and individual patient risks. On the basis of these considerations, a recommendation can be made as to whether a biowaiver approval is advisable or not. This systematic approach to recommend or advise against a biowaiver decision is referred to in the recently published World Health Organization (WHO) guideline.2 These monographs do not intend to simply apply the WHO,2 United States Food and Drug Administration (FDA),3 and/or European Medicine Agency (EMA) Guidance,4 but aim also as a critical evaluation of these and other countries’ regulatory documents. Biowaiver monographs have already been published for several APIs, also available online at www.fip.org/bcs.5

Experimental Literature data were obtained from Web of Science, PubMed, and Micromedex databases up to December 2009. The keywords used for searching were levofloxacin, intestine absorption, linear absorption, absolute bioavailability (BA), BE, log P, solubility, permeability, and lipophilicity. Information was also obtained from regulatory documents published by the WHO,2 the FDA,3 and the EMA.4

GENERAL CHARACTERISTICS Levofloxacinum/Levofloxacin (INN),6 (-)-(S)-9-fluoro2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid.6,7 The molecule exists as a zwitterion at the pH conditions in the small intestine. The commercially available drug substance is the hemihydrate with the empirical formula C18 H20 FN3 O4 · 21 H2 O and containing 97.6% levofloxacin by mass.8 Its structure is shown in Figure 1. Stereochemistry Levofloxacin is the S-(-) isomer of the racemic drug substance ofloxacin; it is significantly more active against bacterial pathogens than R-(+)-ofloxacin.6,7 Therapeutic Indication Levofloxacin has a broad spectrum of in vitro activity against Gram-positive and Gram-negative bacteria.8,9 In Brazil, its labeled indications include treatment of adults (≥ 18 years old) with mild, modDOI 10.1002/jps

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Figure 1. Structure of levofloxacin hemihydrate (Molecular weight = 370.38).

erate, and severe infections caused by susceptible strains such as upper and lower respiratory tract infection, infection of skin and/or subcutaneous tissue, urinary tract infection, acute pyelonephritis, osteomyelitis, related septicemia/bacteremia, intraabdominal infections, prostatitis, and nosocomial pneumonia.10 In the United States (US) in addition to the above-mentioned indications, levofloxacin has been approved to treat infection caused by inhaled anthrax (prophylaxis or postexposure).11 Also, according to the 16th edition of WHO’s Essential Medicines List, levofloxacin may be used as an alternative to ofloxacin in the treatment of multidrug resistant tuberculosis.12 Therapeutic Index and Toxicity Levofloxacin exhibits a low potential for acute toxicity. The median lethal dose (LD50 ) values were around 1800 mg/kg for mice, 1500 mg/kg for rats, and more than 250 mg/kg in female monkeys.13 Generally, its serum and tissue levels do not require routine monitoring.9–11 Depending on the indication, the dosage regimen can vary from 250 mg daily for 3 days to 500 mg daily for 28 days. Daily doses can be as high as 750 mg.8–13 The most common adverse reactions (≥ 3%) in humans are nausea, headache, diarrhea, insomnia, constipation, and dizziness.19 Dysglycemia20–23 and liver disorders24,25 in association with levofloxacin have been reported in the literature. Disturbances of blood glucose levels are labeled in the product monograph.9 As with other quinolones, disturbances of blood glucose, including symptomatic hyper and hypoglycemia, have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide/ glibenclamide) or with insulin. In these patients, careful monitoring of blood glucose is recommended.8–11 Postmarketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. The majority of fatal hepatotoxicity reports occurred in patients with 65 years old or older and most were not associated with hypersensitivity.19,25–29 Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011

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resulting in paresthesias, hypoesthesias, dysesthesias, weakness, and infrequent cases of arrhythmia have been reported.8–11 Clinical pharmacologic studies performed with supratherapeutic doses also showed an increase in QT intervals.10,19 The risk of developing levofloxacin-associated tendinitis and tendon rupture is further increased in older patients (usually defined as over 60 years old), in those taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants. In this case the therapy should be discontinued.19,26

CHEMICAL PROPERTIES Solubility The solubility of levofloxacin in water is around 25 mg/mL (temperature not reported, presumably ambient).19–33 Levofloxacin shows pH-dependent solubility. Over the pH range of 2–5, the solubility is essentially constant, approximately 200 mg/mL; above pH 5.5, the solubility increases to a maximum value of approximately 300 mg/mL at about pH 6.5, whereas above pH 6.5, the solubility decreases and reaches its minimum value of approximately 30 mg/mL at about pH 7.5. All these data were taken at 20◦ C.34 Polymorphs Three polymorphic forms (anhydrous ", $, () and two pseudopolymorphic forms (hemihydrate and monohydrate) of levofloxacin occurs, depending on the temperature used in the manufacturing process.35,36 Polymorph-dependent BA has not been reported. Partition Coefficient (log P) Log P and log D (pH 7) values of 1.49 ± 0.79 and −1.35, respectively, were calculated for levofloxacin by using the software Solaris v4.67 (ACD/Labs, Toronto, Canada).37 The temperature was not reported, presumably ambient. Other authors reported a log P of −0.40 without reporting the experimental conditions.34 PKa Levofloxacin is a zwitterion at physiological pH,38 possessing a carboxylic group with pKa = 5.5, a piperazinyl group with pKa = 8.0 and another protonaccepting function with pKa = 6.8 ± 0.3.37 Available Dosage Form Strengths The WHO Essential Medicines List includes levofloxacin as an alternative for ofloxacin, based on availability and programme considerations; however, no dosage form and dosage form strengths are given.39 Other WHO documents report 500 mg40 and 250 mg, 500 mg and 750 mg tablets, respectively.41 CommerJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011

cially available are tablets of 250, 500, and 750 mg (Table 1).

PHARMACOKINETIC PROPERTIES Absorption and BA The pharmacokinetics of levofloxacin is well described by a linear two-compartment open model with firstorder elimination. Plasma concentrations in healthy volunteers reach a mean peak drug plasma concentration (Cmax ) of approximately 2.8 and 5.2 mg/L within 1–2 h after oral administration of levofloxacin 250 and 500 mg tablets, respectively.8 The BA of oral levofloxacin is very rapid and approaches 100% and is little affected by administration with food.8,10,19,34,42–45 Frick et al.34 calculated the in vivo dissolution of levofloxacin tablets by numerical deconvolution from the plasma concentrations measured in a BA study comparing intravenous infusion versus oral administration, and estimated that more than 80% of the oral dose had been absorbed after 1 h, which was interpreted as indicating that gastric emptying controls the absorption rate. Single oral doses of levofloxacin from 50 to 1000 mg produce a mean Cmax and area under the plasma concentration–time curve (AUC) from approximately 0.6 to 9.4 mg/L and 4.7 to 108 mg·h/ L, respectively, both increasing linearly in a doseproportional fashion.8,19 The pharmacokinetics of levofloxacin is similar during multiple- and single-dose regimens.8,19,41,46 Although chelation of levofloxacin by divalent cations can occur, it is less marked than with other fluoroquinolones.47,48 The BA of oral levofloxacin (100 mg) was reduced significantly during concomitant administration of aluminum hydroxide 1 g (by 44%), magnesium oxide 500 mg (by 22%), and ferrous sulfate 160 mg (by 19%).49 Permeability The log P values reported differ widely. However, as human BA data are available, partition coefficient data can be disregarded for the permeability classification of levofloxacin. Because levofloxacin is a zwitterionic compound, passive diffusion may not fully explain the high intestinal absorption.46 In Caco-2 cells the apical influx clearance value at pH 6 was much greater than the basolateral influx clearance value, suggesting uptake across the apical membrane in Caco-2 cells to be mediated by a specific transport system.50 A good correlation was found between the expression levels of organic anion transporting polypeptide 1A2 (OATP 1A2) and levofloxacin influx clearance in Caco-2 cells.46 The in vitro permeability of levofloxacin was evaluated using a suitable Caco2 assay according to the criteria in the Biopharmaceutics Classification System (BCS) Guidance.3,51,52 Metoprolol, labetalol, and atenolol served as high DOI 10.1002/jps


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Table 1. Excipientsa Present in Levofloxacin IR Solid Oral Drug Products with a Marketing Authorization (MA)b in a Number of Countriesc and the Minimal and Maximal Amount of that Excipient Present Pro Dosage Unit in Solid Oral Drug Products with a MA in the US

Excipient

Drug products containing that excipient with a MA granted by the named country

Cellulose

BR (1,2) CA (3–11) CZ (12–15) DE (16) DK (17–19) ES (20–29) FI (30,31) FR (32,33) HU (34–36) IE (37–40) IL (41) NL (42–48) SE (49–51) UK (52) US (53,54) Copovidone CA (9–11) DK (17,19) ES (21) FI (30) HU (35) IE (37) Croscarmellose sodium BR (55) CA (5,56,57) CZ (58) DK (59) ES (60–62) HU (63–65) IE (66,67) NL (68,69) Crospovidone BR (1,2) CA (3,4,6–11) CZ (12–15) DE (16) DK (17–19) ES (20–29) FI (30,31) FR (32,33) HU (34–36) IE (37–40) IL (41) NL (42–48) SE (49–51) UK (52) US (53,54) Glycerol dibehenate BR (55) CA (57) CZ (58) DK (59) ES (60–62) HU (64,65) IE (66) NL (68) Hydroxypropylcellulose BR (55) CA (3,8,56,57) CZ (14) DK (18) ES (22) HU (63) IE (38,67) NL (43–47,69) SE (49,51) Hypromellose BR (1,2,55) CA (4–8,10,56,57) CZ (12,13,15) DE (16) ES (20,23–29) FI (31) FR (32,33) HU (34,36) IE (39,40) IL (41) NL (42,48) SE (50) UK (52) US (53,54) Lactose BR (55) CA (57) CZ (58) DK (59) ES (60–62) HU (64,65) IE (66) NL (68) Macrogols BR (1,2,55) CA (4–11,56,57) DE (16) ES (20,23,26,27) FR (32,33) US (53,54) Magnesium stearate BR (2 ) CA (4–11,56) CZ (12–14) DK (18) ES (20,22–24,26,27) FI (31) HU (63) IE (38,67) NL (43–48,69) SE (49,51) US (53,54) Methylcellulose CA (56) Polydextrose CA (7,10) Polysorbates CA (4,6) US (53,54) Poly(vinylalcohol) CA (9,11) Povidone BR (55) CA (5,57) CZ (58) DK (59) ES (60–62) HU (64,65) IE (66) NL (68) Silica BR (55) CA (3,9–11,56,57) CZ (12,13,58) DK (17,19,59) ES (20,21,23,24,26,27,60–62) FI (30,31) HU (35,63–65) IE (37,66,67) NL (68,69) Sodium starch BR (55) CA (57) CZ (58) DK (59) ES (60–62) HU (63–65) IE (66,67) NL (68,69) glycolate Sodium stearyl BR (1) CA (3) CZ (15) DE (16) DK (17,19) ES (21,25,28,29) FI (30) FR (32,33) fumarate HU (34-36) IE (37,39,40) IL (41) NL (42) SE (50) UK (52) Starch CA (5) Stearic acid CA (56) CZ (12,13) ES (20,23,24,26,27) FI (31) Talc BR (1,55) CA (9,11,57) CZ (12,13,58) DE (16) DK (59) ES (20,23,24,26,27,60–62) FI (31) FR (32,33) HU (63–65) IE (66,67) NL (48,68,69) Triacetin CA (7,10)

Range present in solid oral dosage forms with a MA in the US (mg) 4.6–1385d

357–854 2–180 4.4–792d

2.5–14 4–132 0.8–537 23–1020d 0.12–961d 0.15–401d 2.8–184 3.8–8.1 0.4–418d 0.7–20 0.17–80 0.50–100 2–876d 1.2–26 0.44–1135d 0.9–72d 0.10–220d 0.72–15

R 1. TAVANIC levofloxacino. 2. Levaquin comprimido revestido 500 mg [Janssen-Cilag]. 3. CO LEVOFLOXACIN (levofloxacin tablets 250/500/750 mg). 4. LEVAQUIN (levofloxacin tablets 250/500/750 mg). 5. Mylan-Levofloxacin (levofloxacin tablets 250/500 mg). 6. NOVO-LEVOFLOXACIN (levofloxacin tablets 250 mg). 7. NOVO-LEVOFLOXACIN (levofloxacin tablets 500 mg). 8. NOVO-LEVOFLOXACIN (levofloxacin tablets 750 mg). 9. pms-LEVOFLOXACIN (levofloxacin tablets 250 mg). 10. pms-LEVOFLOXACIN (levofloxacin tablets 500 mg). 11. pms-LEVOFLOXACIN (levofloxacin tablets 750 mg). 12. Aflobax 250/500 mg, potahované tablety. 13. Levofloxacin Liconsa 250/500 mg potahované tablety. 14. Levofloxacin Mylan 250/500 mg. 15. TAVANIC 250/500 mg. 16. Tavanic 250/-500 mg Filmtabletten. 17. Levofloxacin “Nucleus”, filmovertrukne tabletter (250/500 mg). 18. Voflan, filmovertrukne tabletter (levofloxacin tablets 250/500 mg). 19. Felvosin, filmovertrukne tabletter (levofloxacin 250/500 mg). 20. ASEY 500 mg comprimidos recubiertos con pel´ıcula EFG. 21. Levofloxacino Actavis 250/500 mg comprimidos recubiertos con pel´ıcula EFG. 22. Levofloxacino MYLAN 250/500 mg comprimidos recubiertos con pel´ıcula EFG. 23. LEVOFLOXACINO NORMON 500 mg Comprimidos recubiertos con pel´ıcula EFG. 24. Levofloxacino Pensa 500 mg comprimidos recubiertos con pel´ıcula EFG. 25. Levofloxacino ratiopharm 500 mg comprimidos recubiertos con pel´ıcula EFG. 26. Levofloxacino STADA 500 mg comprimidos recubiertos con pel´ıcula EFG. 27. LEVOFLOXACINO SUPPORT PHARMA 250/500 mg comprimidos recubiertos con pel´ıcula EFG. 28. PRIXAR 250/500 mg comprimidos ¨ recubiertos con pel´ıcula. 29. TAVANIC 250/500 mg comprimidos recubiertos con pel´ıcula. 30. Levofloxacin Actavis 250/500 mg tabletti, kalvopa¨ allysteinen. 31. ¨ Levofloxacin Liconsa 250/500 mg tabletit, kalvopa¨ allysteiset. 32. TAVANIC 500 mg cp pellic séc [Pharma Lab]. 33. TAVANIC 500 mg cp pellic séc [Sanofi-Aventis France]. 34. LevoWin 250/500 mg filmtabletta. 35. Levoxa 250/500 mg filmtabletta. 36. Tavanic 250/500/750 mg filmtabletta. 37. Levofloxacin Actavis 250/500 mg film-coated tablets. 38. Tavager 250/500 mg film-coated tablets. 39. Tavanic 250/500 mg film-coated tablets [sanofi-aventis Ireland Ltd]. 40. R Tavanic 500mg Film-coated tablets [PCO Manufacturing Ltd]. 41. TAVANIC 500 and 250 mg tablets. 42. Tavanic 250/500 mg, filmomhulde tabletten 250/500 mg. 43. Levofloxacine Mylan 250/500 mg, filmomhulde tabletten 250/500 mg. 44. Levofloxacine 250/500 mg Mylan, filmomhulde tabletten 250/500 mg. 45. Levofloxacine Mylan 250/500 mg, filmomhulde tabletten 250/500 mg. 46. Levofloxacine Mylan 250/500 mg, filmomhulde tabletten 250/500 mg. 47. Levofloxacine 250/500 mg Mylan, filmomhulde tabletten 250/500 mg. 48. Levofloxacine advisors 250/500 mg filmomhulde tabletten. 49. Levofloxacin Mylan 250/500 mg filmdragerad tablett. 50. Tavanic 250/500 mg filmdragerad tablett. 51. Voflan 250/500 mg tablett. 52. Tavanic 250/500 mg film-coated tablet. 53. LEVAQUIN (levofloxacin) tablet, film coated (250/500/750 mg)[McNeil Pharmaceuticals]. 54. LEVAQUIN (levofloxacin) tablet, film coated (250/500/750 mg)[Ortho-McNeil-Janssen Pharmaceuticals Inc.]. 55. Levofloxacino 250 mg e 500 mg. 56. APO-LEVOFLOXACIN (levofloxacin tablets 250/500/750 mg). 57. SANDOZ LEVOFLOXACIN (levofloxacin tablets 250/500/750 mg). 58. Levofloxacin “ZAK” 250/500 mg potahované tablety. 59. Levofloxacin “Lek”, filmovertrukne tabletter (levofloxacin tablets 250/500 mg). 60. Levofloxacino Acost 500 mg comprimidos recubiertos con pel´ıcula EFG. 61. Levofloxacino Bexal 500 mg comprimidos recubiertos con pel´ıcula EFG. 62. Levofloxacino Sandoz 500 mg comprimidos recubiertos con pel´ıcula EFG. 63. Leflokin 250/500 mg filmtabletta. 64. Levofloxacin 1 A Pharma 500 mg filmtabletta. 65. Levofloxacin Sandoz 250/500 mg filmtabletta. 66. Levofloxacin 250/500 mg film-coated tablets. 67. Levofloxacin Teva 250/500 mg Film-Coated Tablets. 68. Levofloxacine Sandoz 250/500 mg, filmomhulde tabletten. 69. Levofloxacine 250/500 mg PCH, filmomhulde tabletten. a Colorants,

flavors, and ingredients present in the coating and/or the printing ink are not included. approval of a drug product by the local regulatory authority. Also the terms Drug approval and registration, are used. c Abbreviations of the countries: see, text. d The upper range value reported is unusually high for solid oral dosage forms and the authors doubt its correctness. b The

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permeability and low permeability reference standards and an apparent permeability coefficient (Papp ) of levofloxacin of 28.36 ± 1.93 10−6 cm/s was reported. In the same study, metoprolol, labetalol, and atenolol showed Papp values of 29.88 ± 3.17 10−6 cm/ s, 18.05 ± 1.90 10−6 cm/s, and 1.86 ± 0.47 10−6 cm/ s, respectively; hence, levofloxacin was classified as highly permeable. The authors also concluded that levofloxacin is an efflux protein substrate, although its efflux ratio was only 4:1.52 According to the Biopharmaceutical Drug Disposition Classification System (BDDCS), extensive metabolism of an API indicates a high permeability.53,54 Levofloxacin is mainly eliminated by renal excretion of the unaltered drug, hence not extensively metabolised,8,19,55–57 suggesting levofloxacin not to be highly permeable.53,54 However, BDDCS was developed as a surrogate system for situations in which no BA data are available, which is not so for levofloxacin. Moreover, discrepancies between BCS and BDDCS have been observed.53,54,58–60 Distribution, Metabolism, and Elimination Levofloxacin is widely distributed throughout the body, with a mean volume of distribution of 1.1 L/ kg and penetrates well into most body tissues and fluids. It is approximately 24%–38% bound to serum plasma proteins (primarily albumin).8,19 The drug undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. The only metabolites identified in humans are the desmethyl and N-oxide inactive metabolites, which account for less than 5% of a dose.19 Following oral administration in healthy volunteers or patients with complicated urinary infections or pyelonephritis, approximately 80%–87% of an administered dose was recovered as unchanged drug in urine,8,19,55–57 whereas less than 4% of the dose was recovered in feces.19 The excretion occurs through glomerular filtration and tubular secretion. Renal clearance and total body clearance are highly correlated with creatinine clearance (Clcr ), and dosage adjustments are required in patients with significant renal dysfunction.8,19 The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 h following single or multiple doses of levofloxacin given orally or intravenously.8,19

DOSAGE FORM PERFORMANCE BE Studies Two reports in the literature have demonstrated BE of two different generic formulation of oral levR ofloxacin (500 mg) marketed in Mexico and Tavanic 61,62 (500 mg). In the first report, 26 healthy volunJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011

teers (14 men and 12 women) were enrolled and the 90% confidence intervals (CIs) for log-transformed Cmax , AUC0–24 , and AUC0-∞ were 94.48%–106.22%, 90.01%–116.44%, and 85.11%–114.00%, respectively. The composition of the formulation was not reported.61 In the second report, BE was assessed in 27 male healthy subjects. The CIs for log-transformed Cmax , AUC0–24 , and AUC0-∞ were 95.57%–111.97%, 102.73%–106.36%, and 102.04%–106.75%, respectively. The composition of formulation was not reported.62 All the results meet the current BE criteria.

Excipients Excipients present in IR levofloxacin tablets with a marketing authorization (MA)∗ in BR63 , Canada (CA)64 , Czech Republic (CZ)65 , Germany (DE)66 , Denmark (DK)67 , Spain (ES)68 , Finland (FI)69 , France (FR)70 , Hungary (HU)71 , Ireland (IE)72 , Israel (IL)73 , the Netherlands (NL)74 , Sweden (SE)75 , United Kingdom (UK),76 and US77 are summarized in Table 1. In view of their MAs and national regulations, it can be inferred that the drug products listed in Table 1 successfully passed an in vivo BE study or clinical trial. Because one formulation will most probably be registered in several countries, these drug products correspond to a far lower number of formulations. Also, it cannot be taken for granted that each and every registered drug product has successfully met the current in vivo BE criteria.78 Nevertheless, it seems safe to conclude that the risk of bioinequivalence caused by an excipient effect is low for excipients present in a large number of registered drug products, when the excipient is present in amounts not exceeding its normal use in IR tablets. Table 1 shows the range of that excipients present in solid oral dosage forms with a MA in the US.79 ∗ The approval of a drug product by the local regulatory authority. Also, the terms Drug Approval and Registration are used.

Dissolution A dissolution method for levofloxacin tablets is not included in present editions of the USP, European Pharmacopoeia, British Pharmacopoeia, or the International Pharmacopoeia,80–83 but the dissolution methods database of the FDA contains a test for levofloxacin tablets: USP Apparatus I (basket), 100 rpm, medium—900 mL of 0.1 N HCl at 37◦ C.84 In the pharmacokinetic study of Frick et al.,34 the drug product showing more than 80% of the dose absorbed after 1 h was also tested by in vitro dissolution; more than 80% of the dose was dissolved in 30 min under the following conditions: basket, 100 rpm, 900 mL of 0.1 N HCl. DOI 10.1002/jps


DISCUSSION Solubility According to the current regulatory guidances, an API is highly soluble if its dose/solubility ratios (D/S) is 250 mL or less at the pH range of 1.0–6.82,4 or 1.0–7.53 at 37◦ C, in which “dose” is to be understood as highest dose strength2,3 or highest single dose administered.4 Levofloxacin’s D/S at pH 1.0–7.5 are over the range from 2.5 to 25 mL, based on 750 mg of levofloxacin as the highest dosage strength and also the highest single dose administered, and thus far less than the D/S cut-off for the “high solubility” biowaiver criteria. However, these data refer to 20◦ C, not at 37◦ C.2–4 But, if levofloxacin, like most APIs, has an endothermic heat of solution, it can be assumed that it will exhibit a higher solubility at 37◦ C. Therefore, it seems safe to conclude that levofloxacin is highly soluble according to BCS criteria.2–4 Permeability Because its BA is nearly complete following oral administration, levofloxacin is highly permeable according to all BCS criteria.2–4,8,19,42–45,55–57 Data from Caco-2 studies support this classification.34,52 BCS Classification According to all current BCS class definitions,2–4 levofloxacin can be assigned to BCS I. Frick et al.34 and the WHO40,85,86 reached the same classification. Risks with Respect to Excipient and/or Manufacturing Variations No study directly investigating the influence of excipients on the absorption of levofloxacin has been reported. Moreover, there is no report of bioinequivalence seen in the literature. Surrogate Techniques for in vivo BE Testing In the highly unlikely case that a test product is bioinequivalent, and that this is caused by a large difference in in vivo desintegration and/or in vivo dissolution between test product and comparator, it is most likely that comparative in vitro dissolution of the test product versus its comparator in the three biowaiver-relevant media2–4 will be able to detect the difference. There is presently no surrogate technique for in vivo BE testing able to detect BE caused by a difference in in vivo permeability between test product and comparator, but this risk will be low if the test product contains only excipients also present in IR levofloxacin drug products approved in ICH or associated countries in the same dosage form, as listed on Table 1.

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However, one of the excipients listed in Table 1, polysorbates,87 may have an effect on the in vivo permeability. Also, levofloxacin has been reported to be a substrate of uptake transporters like OATP1A246 and efflux transporters,52 and in view of these more critical permeability characteristics, more stringent criteria are recommended when polysorbates are present in the test product. In that case, the test product should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content.4 Patient’s Risks Associated with Bioinequivalence According to the Code of Federal Regulations, an API has a narrow therapeutic index when there is less than a twofold difference in LD50 and median effective dose (ED50 ) values, and/or safe and effective use of the drug products requires careful dosage titration and patient monitoring.88 Because the LD50 in rats is 1500 mg/kg13 and the ED50 range in rats is 0.18–16.3 mg/kg,89 resulting in an almost 10-fold difference, and there is generally no need to monitor blood levels, levofloxacin can be considered as a wide therapeutic index drug, according to the US FDA.88 Furthermore, Health Canada published a guidance including drugs which commonly exhibit adverse effects that limit the therapeutic use to doses close to those required for the therapeutic effect (e.g., “narrow therapeutic range drugs”) or drugs for which the therapeutic use may result in dose or concentrationdependent adverse effects, which are persistent, irreversible or slowly-reversible, or life threatening (e.g., “highly toxic drugs”), and this list does not include levofloxacin.90 Further, levofloxacin is not on the list of Narrow Therapeutic Range Drugs of the Japanese Health Authorities.91 Despite the low potential of levofloxacin for acute toxicity19 and its acceptance as a wide therapeutic index drug, it is nonetheless advisable to monitor blood glucose levels in diabetic patients and monitor hepatic functions in patients 60 years old or older taking levofloxacin.19

CONCLUSION A biowaiver for IR solid oral dosage forms containing levofloxacin is scientifically justified, provided that (a) the test product contains only excipients present in IR levofloxacin drug products approved in ICH or associated countries in the same dosage form; (b) both the test and comparator dosage form are very rapidly dissolving or rapidly dissolving with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8; and (c) if the test product contains polysorbates, it should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content.


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ACKNOWLEDGMENTS Arthur da Silva, Camila Costa, Camila Rediguieri, Cristina Serra, Diana Nunes, Jacqueline de Souza, Kelen Soares, Varley Sousa, Taina Nunes, and Valentina Porta are acknowledged for helping the construction of this monograph that is a product from the work of Brazilian Biowaiver Working Group. Kik Groot, RIVM, is acknowledged for producing Table 1.

REFERENCES 1. Vogelpoel H, Welink J, Amidon GL, Junginger HE, Midha KK, Möller H, Olling M, Shah VP, Barends DM. 2004. Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: Verapamil hydrochloride, propranolol hydrochloride, and atenolol. J Pharm Sci 93:1945–1956. 2. WHO. 2006. Proposal to waive in vivo bioequivalence requirements for WHO model list of essential medicines immediaterelease, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert Committee on Specifications for Pharmaceutical Preparations. Accessed November 20, 2009, at: http://whqlibdoc.who. int/trs/ WHO TRS 937 eng.pdf. 3. US Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research (CDER). 2000. Guidances for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System. Accessed November 20, 2009, at: http://www.fda.gov/ CDER/GUIDANCE/3618fnl. pdf. 4. European Medicines Agency (EMA), Committee for Proprietary Medicinal Products (CPMP). 2001. Note for Guidance on the Investigation of Bioavailability and Bioequivalence. Accessed November August 05, 2010, at: http://www.ema.europa.eu/docs/en GB/document library/ Scientific guideline/2010/01/WC500070039.pdf. 5. International Pharmaceutical Federation (FIP). 2009. Special Interest Group on BCS & Biowaiver. Accessed November 20, 2009, at: http://www.fip.org/bcs. 6. World Health Organization (WHO). 1990. Guidance on INN. Accessed November 20, 2009, at: http://www.who.int/ medicines/services/inn/innquidance/en. 7. Martindale. 2006. The Complete Drug Reference, Electronic Version. Accessed November 20, 2009, at: http:// www.medicinescomplete.com/mc/martindale/2006. 8. Fish DN, Chow AT. 1997. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet 32(2):101–119. 9. Levaquin (levofloxacin) [product monograph]. 2006. Toronto: Janssen-Ortho Inc. ´ 10. Bulario eletrônico – ANVISA. Accessed November 10, 2009, at: http://www.anvisa.gov.br/bularioeletronico. R 11. Micromedex Healthcare Series. Accessed November 20, 2009, at: https://www.thomsonhc.com/hcs/librarian/CS/ EA2F61/PFActionId/pf.HomePage/ssl/true. 12. World Health Organization (WHO). 2009. WHO Model Lists of Essential Medicines, 16th ed. Accessed August 05, 2010, at: http://www.who.int/medicines/publications/ essentialmedicines/Updated sixteenth adult list en.pdf. 13. Kato M, Furuhama K, Yoshida M, Akahane K, Takayama S. 1992. Acute oral toxicity of the new quinolone antibacterial agent levofloxacin in mice, rats, and monkeys. Arzneimittelforschung 43(3A):365–366. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 5, MAY 2011

14. Davis R, Bryson HM. 1994. Levofloxacin: A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 4:677–700. 15. Martin SJ, Meyer JM, Chuck SK, Jung R, Messick CR, Pendland SL. 1998. Levofloxacin and sparfloxacin: New quinolone antibiotics. Ann Pharmacother 32:320–336. 16. Martin SJ, Jung R, Garvin CG. 2001. A risk-benefit assessment of levofloxacin in respiratory, skin and skin structure, and urinary tract infections. Drugs 24:199–222. 17. Croom KF, Goa KL. 2003. Levofloxacin: A review of its use in the treatment of bacterial infections in the United States. Drugs 63:2769–2802. 18. Anderson VR, Perry CM. 2008. Levofloxacin: A review of its use as a high-dose, short-course treatment for bacterial infection. Drugs 68:535–565. 19. Food and Drug Administration (FDA). 2009. Levaquin label. Accessed November 20, 2009, at: http://www.accessdata. fda.gov/drugsatfda docs/label/2008/021721s020 020635s57 020634s52 lbl.pdf. 20. Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, Dresser L, Low DE, Mamdani MM. LY 2006 Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 354(13):1352–1361. 21. Friedrich LV, Dougherty R. 2004. Fatal hypoglycemia associated with levofloxacin. Pharmacotherapy 24(12):1807–1812. 22. Garon N, Cloutier I. 2001. Une hypoglycémie associée a` la lévofloxacine (Levaquin). Québec Pharmacie 48(1):71–74. 23. Saraya A, Yokokura M, Gonoi T, Seino S. 2004. Effects of fluoˆ roquinolones on insulin secretion and a-cell ATP-sensitive K+ channels. Eur J Pharmacol 497(1):111–117. 24. Papastavros T, Dolovich LR, Holbrook A, Whitehead L, Loeb M. 2002. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ 167(2):131–136. 25. Schwalm JD, Lee CH. 2003. Acute hepatitis associated with oral levofloxacin therapy in hemodialysis. CMAJ 168(7):847–848. 26. Petri WA. 2001. Goodman & Gilman’s. The pharmacological basis of therapeutics, 10th ed. New York: McGraw-Hill MedicalPublishing Division. 27. Kaplowitz N. 2004. Drug-induced liver injury. Clin Infect Dis 38(Suppl 2):S44–S48. 28. Canadian Adverse Reaction Newsletter, Volume 17(1), January 2007. 29. World Health Organization (WHO). 2007. The International Pharmacopoeia: Draft Proposal for the International Pharmacopoeia (October 2006). WHO Drug Information Vol 21, No. 1, 2007 Recent Publications, Information, and Events. Accessed at: http://whqlibdoc.who.int/druginfo/21 1 2007.pdf. 30. Beyer R, Pestova E, Millichap JJ, Stosor V, Noskin GA, Peterson LR. 2000. A convenient assay for estimating the possible involvement of efflux of fluoroquinolones by Streptococcus pneumoniae and Staphylococcus aureus: Evidence for diminished moxifloxacin, sparfloxacin, and trovafloxacin efflux. Antimicrob Agents Chemother 44:798–801. ¨ ¨ 31. Puustjarvi T, Terasvirta M, Nurmenniemi P, Lokkila J, Uusitalo H. 2006. Penetration of topically applied levofloxacin 0.5% and ofloxacin 0.3% into the vitreous of the non-inflamed human eye. Graefe’s Arch Clin Exp Ophthalmol 244:1633–1637. 32. Fukuda M, Sasaki K. 1995. In vitro topically applied fluoroquinolone penetration into the anterior chamber. Nippon Ganka Gakkai Zasshi 99(5):532–536. 33. Robertson SM, Curtis MA, Schlech BA, Rusinko A, Owen GR, Dembinska O, Liao J, Dahlin DC. 2005. Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans. Surv Ophthalmol 50(Suppl 1):S32–S35. 34. Frick A, Moller H, Wirbitzki E. 1998. Biopharmaceutical characterization of oral immediate release drug products. DOI 10.1002/jps


35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

In vitro/in vivo comparison of phenoxymethylpenicillin potassium, glimepiride and levofloxacin. Eur J Pharm Biopharm 46(3):305–311. Solubility data were read from Fig 1. Niddam-hildesheim V, Gershon N, Amir E, Wizel S. 2006. Patent EP1451194. Preparation of levofloxacin hemihydrate. Teva Pharmaceutical Industries Ltd. Accessed November 23, 2009, at: http://www.freepatentsonline.com/ EP1451194B1.html. Kitaoka H, Wada C, Moroi R, Hakusui H. 1995. Effect of dehydration on the formation of Levofloxacine Pseudopolymorphs. Chem Pharm Bull 43(4):649–653. Michot JM, Seral C, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM. 2005. Influence of efflux transporters on the accumulation and efflux of four quinolones (ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin) in J774 macrophages. Antimicrob Agents Chemother 49(6):2429–2437. Yano I, Ito T, Takano M, Inui K. 1997. Evaluation of renal tubular secretion and reabsorption of levofloxacin in rats. Pharm Res 14(4):508–511. World Health Organization (WHO). 2009. WHO Model Lists of Essential Medicines, 16th ed. Accessed November 20, 2009, at: http://www.who.int/selection medicines/committees/ expert/17/sixteenth adult list en.pdf. World Health Organization (WHO). 2009. Biopharmaceutics Classification System (BCS)-based biowaiver applications: Anti-tuberculosis medicines. Accessed November 20, 2009, at: http://apps.who.int/prequal/info applicants/BE/ BW TB 2009February.pdf. World Health Organization (WHO). 2009. Recommended comparator products: anti-tuberculosis medicines. Accessed November 20, 2009, at: http://apps.who.int/prequal/ info applicants/BE/Comparators-TB2009--28September.pdf. Chulavatnatol S, Chindavijak B, Vibhagool A, Wananukul W, Sriapha C, Sirisangtragul C. 1999. Pharmacokinetics of levofloxacin in healthy Thai male volunteers. J Med Assoc Thai 82(11):1127–35. Furlanut M, Brollo L, Lugatti E, Di Qual E, Dolcet F, Talmassons G, Pea F. 2003. Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with lower respiratory tract infections. J Antimicrob Chemother 51(1):101–106. Chien SC, Rogge MC, Gisclon LG, Curtin C, Wong F, Natarajan J, Williams RR, Fowler CL, Cheung WK, Chow AT. 1997. Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrob Agents Chemother 41(10):2256–2260. Rodvold KA, Neuhauser M. 2001. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Pharmacotherapy 21(10 Pt 2):233S–252S. Maeda T, Takahashi K, Ohtsu N, Oguma T, Ohnishi T, Atsumi R, Tamai I. 2007. Identification of influx transporter for the quinolone antibacterial agent levofloxacin. Mol Pharm 4:85–94. Tanaka M, Kurata T, Fujisawa C, Ohshima Y, Aoki H, Okazaki O, Hakusui H. Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide. 1993. Antimicrob Agents Chemother 37(10):2173–2178. Shiba K, Saito A, Miyahara T, Tachizawa H, Fujimoto T. 1988. Effect of aluminum hydroxide, an antacid, on the pharmacokinetics of new quinolones in humans. Xenobiot Metab Dispos 3:717–722. Shiba K, Sakai O, Shimada J, Okazaki O, Aold H, Hakusui H. 1992. Effect of antacids, ferrous sulfate, and ranitidine on absorption of DR-3355 in humans. Antimicrob Agents Chemother 36:2270–2274. Takaai M, Suzuki H, Ishida K, Tahara K, Hashimoto Y. 2007. Pharmacokinetic analysis of transcellular transport of lev-

DOI 10.1002/jps

51.

52. 53.

54.

55.

56.

57.

58.

59. 60.

61.

62.

63. 64. 65. 66. 67. 68. 69. 70.

1635

ofloxacin across LLC-PK1 and Caco-2 cell monolayers. Biol Pharm Bull 30:2167–2172. Volpe DA, Ciavarella AB, Asafu-Adjaye EB, Ellison CD, Faustino PJ, Yu LX. 2001. Method suitability of a Caco-2 cell model for drug permeability classification. AAPS PharmSci 3(S1). Accessed November 20, 2009, at: http://www. aapspharmaceutica.com/search/abstract view.asp?id=385&ct =01Abstracts. Volpe DA. 2004. Permeability classification of representative fluoroquinolones by a cell culture method. AAPS J 6(2):1–6. Wu CH, Benet LZ. 2005. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 22(1):11–23. Shugarts S, Benet LZ. 2009. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res 26(9):2039–2054. Wagenlehner FM, Kinzig-Schippers M, Sörgel F, Weidner W, Naber KG. 2006. Concentrations in plasma, urinary excretion and bactericidal activity of levofloxacin (500 mg) versus ciprofloxacin (500 mg) in healthy volunteers receiving a single oral dose. Int J Antimicrob Agents 28(6):551–559. Wagenlehner FM, Wagenlehner C, Redman R, Weidner W, Naber KG. 2009. Urinary bactericidal activity of Doripenem versus that of levofloxacin in patients with complicated urinary tract infections or pyelonephritis. Antimicrob Agents Chemother 53(4):1567–73. Wagenlehner FM, Kinzig-Schippers M, Tischmeyer U, Wagenlehner C, Sörgel F, Dalhoff A, Naber KG. 2006. Pharmacokinetics of ciprofloxacin XR (1000 mg) versus levofloxacin (500 mg) in plasma and urine of male and female healthy volunteers receiving a single oral dose. Int J Antimicrob Agents 27(1):7–14. ¨ H, Polli JE, Benet LZ, Amidon GL, Barends DM, Lennernas Shah VP, Stavchansky SA, Yu LX. 2008. The use of BDDCS in classifying the permeability of marketed drugs. Pharm Res 25(3):483–8. Chen ML, Yu L. 2009. The use of drug metabolism for prediction of intestinal permeability (dagger). Mol Pharm 6(1):74–81. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. 2006. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol Pharm 3:631–643. Galan-Herrera JF, Poo JL, Rosales-Sanchez O, Fuentes˜ L, Burke-Fraga V, Namur S, Parra MG. Fuentes E, Carino 2009. Bioavailability of two oral formulations of a single dose of levofloxacin 500 mg: An open-label, randomized, two-period crossover comparison in healthy Mexican volunteers. Clin Ther 31(8):1796–803. Carrasco-Portugal MDC, Flores-Murrieta F. 2009. Comparative bioavailability of two oral formulations of levofloxacin in healthy Mexican volunteers. Int J Clin Pharmacol Ther 47(4):283–286. Brazilian Agency of Health Surveillance. Accessed June 16, 2010, at: www.anvisa.gov.br. Health Canada. Accessed June 14, 2010, at: www.webprod.hcsc.gc.ca. State Institute for Drug Control. Accessed June 15, 2010, at: www.sukl.cz. Rote List. Arzneimittelinformationen fur Deutschland. Accessed June 14, 2010, at: www.rote-liste.de. Danish Medicines Agency. Accessed June 14, 2010, at: www.dkma.dk. ˜ Agencia Espanola de Medicamentos y Productos Sanitarios. Accessed November 20, 2009, at: www.agemed.es. Finnish Medicines Agency. Accessed June 15, 2010, at: www.nam.fi. Vidal. Accessed June 15, 2010, at: www.vidal.fr.


1636

KOEPPE ET AL.

71. National Institute of Pharmacy. Accessed June 18, 2010, at: www.ogyi.hu. 72. Irish Medicines Board. Accessed June 15, 2009, at: www.imb.ie. 73. Ministry of Health of Israel. Accessed June 15, 2010, at: www.health.gov.il. 74. Medicines Evaluation Board. Accessed June 14, 2010, at: www.cbg-meb.nl. 75. Medical Products Agency. Accessed June 15, 2010, at: www.lakemedelsverket.se. 76. Electronic Medicines Compendium. Accessed June 15, 2010, at: www.medicines.org.uk. 77. DailyMed. Accessed June 15, 2010, at: www.dailymed. nlm.nih.gov. 78. Olivera ME, Manzo RH, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM. 2010. Biowaiver monographs for immediate release solid oral dosage forms: Ciprofloxacin hydrochloride. J Pharm Sci Published online 02 07 2010 as DOI: 10.1002/jps.22259. 79. FDA. Inactive Ingredients Database. Accessed, August 3, 2010, at: http://www.fda.gov/Drugs/InformationOnDrugs/ ucm113978.htm. 80. The United States Pharmacopeia – The National Formulary (USP 32/NF 27), edition. Rockville, MD: The United States Pharmacopeial Convention, Inc. 81. The European Pharmacopoeia (Ph.Eur.). 2010. 6th ed., Strasbourg, France: European Directorate for the Quality of Medicines, Council of Europe. 82. The British Pharmacopoeia (B.P.). 1993. ed., London, the United Kingdom: The British Pharmacopoeia Secretariat. 83. The World Health Organization (WHO). 2008. The International Pharmacopoeia4th ed. Accessed November 20, 2009, at: http://apps.who.int/phint/en/p/about/. 84. Food and Drug Administration (FDA). 2009. Dissolution methods database. Accessed November 23, 2009,


85.

86.

87.

88.

89.

90.

91.

at: http://www.accessdata.fda.gov/scripts/cder/dissolution/ dsp SearchResults Dissolutions.cfm. World Health Organization (WHO). 2009. General notes on Biopharmaceutics Classification System (BCS)based biowaiver applications. Accessed November 23, 2009, at: http://apps.who.int/prequal/info applicants/BE/ BW general 2009February.pdf. World Health Organization (WHO). 2009. Substances on the Complementary list of WHO Essential Medicines List (EML). Accessed November 23, 2009, at: http://www.who. int/medicines/services/expertcommittees/pharmprep/QAS04 109Rev1 Waive invivo bioequiv.pdf. Rege BD, Kao JP, Polli JE. 2002. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci 16(4–5):237–246. Food and Drug Administration (FDA). 2009. Title 21—Food and Drugs, Chapter I—Subchapter D—Drugs for Human Use—Part 320—Bioavailability and Bioequivalence Requirements. Accessed November 23, 2009, at: http://www. accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=320&showFR=1. Klesel N, Geweniger KH, Koletzki P, Isert D, Limbert M, Markus A, Riess G, Schramm H, Iyer P. 1995. Chemotherapeutic activity of levofloxacin (HR 355, DR-3355) against systemic and localized infections in laboratory animals. J Antimicrob Chemother 35(6):805–819. Health Canada. 2009. Critical dose drugs. Accessed November 23, 2009, at: http://www.hc-sc.gc.ca/dhp-mps/alt formats/ pdf/prodpharma/applic-demande/guide-ld/bio/critical dose critique-eng.pdf. National Institute of Health Sciences (NIHS). 2010. Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms. Accessed November 20, 2009, at: http://www.nihs.go.jp/drug/be-guide(e)/strength/strength. html.

DOI 10.1002/jps