Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fluconazole

doi:10.1002/jps.24181

Journal of Pharmaceutical Sciences

Volume 103, Issue 12, December 2014, Pages 3843-3858

https://doi.org/10.1002/jps.24181 Get rights and content

ABSTRACT:

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug–excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Section snippets

INTRODUCTION

Fluconazole is an orally active bis-triazole derivative used for the prophylaxis and treatment of superficial and systemic fungal infections, mainly candidiasis and cryptococcal meningitis, which are prevalent in immunocompromised patients.1., 2., 3. It is well tolerated in adults and children, including seriously ill patients, and the safety of the drug has been proven in clinical studies.4., 5., 6., 7., 8. Fluconazole has favorable pharmacokinetic (PK) properties: because of its low plasma

Literature Search

Literature data published in PubMed, Micromedex, and Web of Science databases up to September 2013 were accessed by using the following keywords: fluconazole, indication, solubility, polymorphism, intestinal absorption, distribution, metabolism, excretion, dissolution, therapeutic index, linear PK, absolute bioavailability (BA), bioequivalence (BE), log P, permeability, mass balance, and radiolabeled studies. Information was also obtained from the WHO,¹¹ US-FDA,¹² and EMA¹³ regulatory guidance

Name and Structure

INN: Fluconazole.¹⁶ IUPAC: 2-(2,4-difluorophenyl)-1,3-bis-(1H-1.2.4-triazol-1-yl)-propan-2-ol.15., 16. Chemically, fluconazole is a triazole derivative as shown in Figure 1 with a molecular formula C₁₃H₁₂F₂N₆O and a molecular weight of 306.27 g/mol.¹⁶

Therapeutic Indications and Dose

Fluconazole selectively inhibits fungal cytochrome P450-dependent lanosterol 14-α-demethylase enzyme, and thereby prevents conversion of lanosterol to ergosterol. Ergosterol is an essential component of the fungal cytoplasmic membrane. The

Salt and Polymorphs

Fluconazole is used as the free base in pharmaceutical dosage formulations. It exists mainly in three polymorphic forms, namely I, II, and III.47., 48., 49., 50., 51., 52., 53., 54., 55. There is a report indicating superior BA of fluconazole polymorph III in comparison with forms I and I–III (50:50); however, no further information about experimental conditions was published.⁵¹ After digitizing the PK profiles, it was identified that C_max (maximum plasma concentration) as well as AUC for

Absorption and Permeability

Fluconazole is well absorbed after oral administration and plasma levels (systemic BA) of more than 90% are achieved in comparison with intravenous administration.17., 25., 63. Its PK properties after administration by the intravenous or oral routes are similar.17., 25., 63. It shows linear PK over the 50–400 mg dose range. Concomitant food intake does not affect its oral absorption.17., 25., 63., 64. When administered under fasting conditions, peak plasma concentrations are reached between 0.5

Excipients

Table 3 shows the excipients present in IR fluconazole products with a MA in Australia and ICH countries. In view of their MAs, it is presumed that these products successfully passed the in vivo BE criteria.

One report detected the occurrence of chemical interaction of fluconazole with lactose by using differential scanning calorimetry and X-ray diffraction.⁷⁸ But as many marketed formulations of fluconazole contain lactose (Table 3, Table 4), this interaction may be pharmacokinetically

Solubility

Active pharmaceutical ingredients with a dose/solubility ratio of ≤ 250 mL in the pH range 1.0–6.811., 13. or 1.0–7.5¹² at 37 °C are considered highly soluble. The highest dose strength available is 200 mg and the highest single dose recommended varies from 50 to 400 mg depending on the severity and type of fungal infection.²⁵ The maximum loading dose of 800 mg is recommended for invasive candidiasis in SmPC.¹⁷

The dose/solubility ratio values corresponding to the solubility values determined at 37 °C

CONCLUSIONS

Fluconazole in polymorphic forms II and III is a BCS class I drug with a broad therapeutic index. It does not produce any severe adverse effects. The BCS-based biowaiver is therefore highly recommended for fluconazole IR solid oral dosage forms provided that (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the test product contains only excipients present in IR fluconazole drug products approved in ICH or associated countries in the

ACKNOWLEDGMENTS

This biowaiver monograph is part of a project of the FIP, Focus Group BCS and Biowaiver, www.fip.org/bcs. This article reflects the scientific opinion of the authors and not necessarily reflects the policies of the regulating agencies, the FIP, RIVM, ANVISA, or the WHO.

REFERENCES (119)

M.L. MacMillan et al.
Fluconazole to prevent yeast infections in bone marrow transplantation patients: A randomized trial of high versus reduced dose, and determination of the value of maintenance therapy
Am J Med
(2002)
M.R. Caira et al.
Preparation and crystal characterization of a polymorph, a monohydrate, and an ethyl acetate solvate of the antifungal fluconazole
J Pharm Sci
(2004)
A.K. Dash et al.
Fluconazole
F.X. Mathy et al.
Fluconazole distribution in rat dermis following intravenous and topical application: A microdialysis study
J Pharm Sci
(2005)
W.J. Steinbach
Antifungal agents in children
Pediatr Clin N Am
(2005)
C.S. Chaw et al.
The effect of pH change on the gastric emptying of liquids measured by electrical impedance tomography and pH-sensitive radiotelemetry capsule
Int J Pharm
(2001)
P. Paixão et al.
Prediction of the in vitro permeability determined in Caco-2 cells by using artificial neural networks
Eur J Pharm Sci
(2010)
J. Faergemann
Pharmacokinetics of fluconazole in skin and nails
J Am Acad Dermatol
(1999)
B.D. Rege et al.
Effect of common excipients on Caco-2 transport of low-permeability drugs
J Pharm Sci
(2001)
V. Porta et al.
Evaluation of the bioequivalence of capsules containing 150 mg of fluconazole
Int J Pharm
(2005)

D. Jovanović et al.

A randomized, open-label pharmacokinetic comparisonof two oral formulations of fluconazole 150 mg in healthy adult volunteers

Clin Ther

(2005)

K.L. Goa et al.

Fluconazole

An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs

(1995)

S.M. Grant et al.

Fluconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential, in superficial and systemic mycoses

Drugs

(1990)

A.M. Sugar

Treatment of fungal infections in patients infected with the human immunodeficiency virus

Pharmacotherapy

(1990)

I.H. Osterloh

Safety

W. Inman et al.

Safety of fluconazole in the treatment of vaginal candidiasis. A prescription-event monitoring study, with special reference to the outcome of pregnancy

Eur J Clin Pharmacol

(1994)

W. Inman et al.

PEM Report Number 3. Fluconazole

Pharmacoepidemiol Drug Safety

(1993)

P. Munoz et al.

Fluconazole-related hepatotoxicity in patients with acquired immunodeficiency syndrome

Arch Intern Med

(1991)

V. Novelli et al.

Safety and tolerability of fluconazole in children

Antimicrob Agents Chemother

(1999)

D. Debruyne et al.

Clinical pharmacokinetics of fluconazole

Clin Pharmacokinet

(1993)

P.G. Pappas et al.

Guidelines for treatment of candidiasis

Clin Infect Dis

(2004)

World Health Organization (WHO)

Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms

US Department of Health and Human Services et al.

Guidances for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System

European Medicines Evaluation Agency (EMEA) et al.

Note for guidance on the investigation of bioavailability and bioequivalence

International Pharmaceutical Federation (FIP)

Biopharmaceutics Classification System (BCS)

USP 36-NF 31

The United States Pharmacopoeia—The National Formulary

(2013)

International non-proprietary names for pharmaceutical substances

World Health Organization

(1986)

Summary of product characteristics

Diflucan 200 mg hard capsules, Pfizer Limited

(2013)

R. Cha et al.

Fluconazole for the treatment of candidiasis: 15 years experience

Exp Rev Anti Infect Ther

(2004)

F. Menichetti et al.

High-dose fluconazole therapy for cryptococcal meningitis in patients with AIDS

Clin Infect Dis

(1996)

N. Longley et al.

Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in Southwestern Uganda

Clin Inf Dis

(2008)

A.J. Berry et al.

Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS

Antimicrob Agents Chem

(1992)

J.L. Goodman et al.

A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation

N Engl J Med

(1992)

M.A. Slavin et al.

Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—A prospective, randomized double-blind study

J Infect Dis

(1995)

Diflucan. Product information

Pfizer, NY 10017

(2013)

J.D. Sobel

Fluconazole maintenance therapy in recurrent vulvovaginal candidiasis

Int J Gynaecol Obstet

(1992)

R.J. Hay et al.

Dandruff and seborrhoeic dermatitis: Causes and management

Clin Exp Derm

(1997)

R.J. Hamill

Free fluconazole for cryptococcal meningitis: Too little of a good thing?

Clin Inf Dis

(2006)

E.J. Anaissie et al.

Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections

J Inf Dis

(1995)

H. Chen et al.

High-versus low-dose fluconazole therapy for empiric treatment of suspected invasive candidiasis among high-risk patients in the intensive care unit: A cost-effectiveness analysis

Curr Med Res Opin

(2007)

E. Milefchik et al.

Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis

Med Mycol

(2008)

K.H. Duswald et al.

High-dose therapy with fluconazole > 800 mg day − 1

Mycoses

(1997)

A. Voss et al.

High-dose fluconazole therapy in patients with severe fungal infections

Eur J Clin Microbiol Infect Dis

(1999)

National Committee for Clinical Laboratory Standards

Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard NCCLS document M27-A

Wayne, Pennsylvania: National Committee for Clinical Laboratory Standards

(1997)

J.H. Rex et al.

Development of interpretive breakpoints for antifungal susceptibility testing: Conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections

Clin Infect Dis

(1997)

C.J. Clancy et al.

In vitro susceptibility of breakthrough Candida bloodstream isolates correlates with daily and cumulative doses of fluconazole

Antimicrob Agents Chemother

(2006)

C.J. Clancy et al.

Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia

Antimicrob Agents Chemother

(2005)

K.C. Wade et al.

Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants

Pediatr Infect Dis J

(2009)

K.C. Wade et al.

Population pharmacokinetics of fluconazole in young infants

Antimicrob Agents Chemother

(2008)

L. Piper et al.

Fluconazole loading dose pharmacokinetics and safety in infants

Infect Dis J

(2011)

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In the crystallization and search for higher multicomponent forms of fluconazole (FLZ), a metastable FLZ polymorph (concomitant) that manifests in the same crystallization system and transforms into the stable FLZ form (II) after the lyophilization process was observed. In this report, we demonstrated and showed how this FLZ polymorph 10 (Mw = 306.79 g/mol) of the monoclinic C2 space group was detected and reproduced through a controlled lyophilized experiment, and modeled differentiation between vibrational and absorption modes of FLZ functionalities like C=O, OH, –CH₂ and –NH. The FLZ polymorph shows strong O–H···N and weak C−H···X (X = N, and F) hydrogen bond and the presence of pi-pi bond interactions in the overlapping triazole rings. The combination of vibrational spectroscopic techniques (Raman/FT-IR) and principal component analysis (PCA) aid the development of important models for polymorph screening and identification. In addition, X-ray diffraction (powder and single crystal) techniques support the polymorph characterization and structure depiction. The PCA models and X-ray diffraction analyses confirmed the newness of FLZ polymorph 10, and further solid-state characterization using thermal techniques (DSC and TGA) affirmed its uniqueness and novelty. Finally, the thermal stability and solubility studies on the new FLZ polymorph were determined to understand its structure properties and compare these with previously reported polymorphs of FLZ.
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Despite having adequate solubility properties, bioequivalence (BE) studies performed on immediate release formulations containing BCS1/3 drugs occasionally fail. By systematically evaluating a set of 17 soluble drugs where unexpected BE failures have been reported and comparing to a set of 29 drugs where no such reports have been documented, a broad assessment of the risk factors leading to BE failure was performed. BE failures for BCS1/3 drugs were predominantly related to changes in C_max rather than AUC. C_max changes were typically modest, with minimal clinical significance for most drugs. Overall, drugs with a sharp plasma peak were identified as a key factor in BE failure risk. A new pharmacokinetic term (t½C_max) is proposed to identify drugs at higher risk due to their peak plasma profile shape. In addition, the analysis revealed that weak acids, and drugs with particularly high gastric solubility are potentially more vulnerable to BE failure, particularly when these features are combined with a sharp C_max peak. BCS3 drugs, which are often characterised as being more vulnerable to BE failure due to their potential for permeation and transit to be altered, particularly by excipient change, were not in general at greater risk of BE failures. These findings will help to inform how biowaivers may be optimally applied in the future.
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Fluconazole (FCZ) is a broad spectrum anti-fungal drug and categorized as a BCS class-I molecule because of its readily soluble and highly permeable properties. Oral delivery of FCZ is associated with teratogenic effects. Thus, other routes of administration needs to be investigated for improved efficacy of the drug. The purpose of this study was to prepare and characterize FCZ loaded thermosensitive system (FCZ-TSS) for rectal administration with sustained release and improved bioavailability. The ingredients of FCZ-TSS were optimised by preparing different formulations using various concentrations of Poloxamer 407 (P-407), Poloxamer 188 (P-188), Tween 80 (Tw-80) and FCZ. The FCZ-TSS was liquid at room temperature and converted into gel at body temperature. The rheological properties of the FCZ-TSS were determined including, gelation temperature, gel strength, gelation time and mucoadhesive force. In vitro release and in vivo pharmacokinetic studies of the optimised formulation was performed and compared with the drug solution. P-407 and Tw-80 reduced the gelation time and gelation temperature of FCZ-TSS, but increased the mucoadhesive force and gel strength. Optimised FCZ-TSS was liquid at room temperature which upon increase in temperature converted into gel at approximately 30.16 °C. The gel formation took around 1.23 min and exhibited its easy administration and quick gelation inside the body. FCZ-TSS released the drug over a time period of 24 h, displaying sustained behaviour as compared with the drug solution which take only 4 h for complete release of the drug. Moreover, the higher Cmax and AUC values of FCZ-TSS as compared to FCZ solution showed increased bioavailability of FCZ. Furthermore, in vivo safety study demonstrated safe profile of FCZ-TSS when compared with FCZ solution, after their application to rectal mucosa. These results confirmed that TSS has the potential to improve the bioavailability of FCZ with increased safety.
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Citation Excerpt :
The protolytic properties are responsible for the weak pH dependence of the FCZ solubility profile ranging between pH 2–8 [31]. Fig. 5 shows the literature values of the drug solubility in aqueous solutions of different acidity [29–31] and the solubility values obtained in the present work in pH 1.2, 2.0 and 7.4 buffers. The protolytic equilibrium of different molecular forms of fluconazole is also shown in Fig. 5.
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CommentaryBiowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fluconazole

ABSTRACT:

Section snippets

INTRODUCTION

Literature Search

Name and Structure

Therapeutic Indications and Dose

Salt and Polymorphs

Absorption and Permeability

Excipients

Solubility

CONCLUSIONS

ACKNOWLEDGMENTS

Am J Med

J Pharm Sci

J Pharm Sci

Pediatr Clin N Am

Int J Pharm

Eur J Pharm Sci

J Am Acad Dermatol

J Pharm Sci

Int J Pharm

Clin Ther

Fluconazole

An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs

Fluconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential, in superficial and systemic mycoses

Drugs

Treatment of fungal infections in patients infected with the human immunodeficiency virus

Pharmacotherapy

Safety

Safety of fluconazole in the treatment of vaginal candidiasis. A prescription-event monitoring study, with special reference to the outcome of pregnancy

Eur J Clin Pharmacol

PEM Report Number 3. Fluconazole

Pharmacoepidemiol Drug Safety

Fluconazole-related hepatotoxicity in patients with acquired immunodeficiency syndrome

Arch Intern Med

Safety and tolerability of fluconazole in children

Antimicrob Agents Chemother

Clinical pharmacokinetics of fluconazole

Clin Pharmacokinet

Guidelines for treatment of candidiasis

Clin Infect Dis

Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms

Guidances for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System

Note for guidance on the investigation of bioavailability and bioequivalence

Biopharmaceutics Classification System (BCS)

The United States Pharmacopoeia—The National Formulary

World Health Organization

Diflucan 200 mg hard capsules, Pfizer Limited

Fluconazole for the treatment of candidiasis: 15 years experience

Exp Rev Anti Infect Ther

High-dose fluconazole therapy for cryptococcal meningitis in patients with AIDS

Clin Infect Dis

Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in Southwestern Uganda

Clin Inf Dis

Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS

Antimicrob Agents Chem

A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation

N Engl J Med

Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—A prospective, randomized double-blind study

J Infect Dis

Pfizer, NY 10017

Fluconazole maintenance therapy in recurrent vulvovaginal candidiasis

Int J Gynaecol Obstet

Dandruff and seborrhoeic dermatitis: Causes and management

Clin Exp Derm

Free fluconazole for cryptococcal meningitis: Too little of a good thing?

Clin Inf Dis

Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections

J Inf Dis

High-versus low-dose fluconazole therapy for empiric treatment of suspected invasive candidiasis among high-risk patients in the intensive care unit: A cost-effectiveness analysis

Curr Med Res Opin

Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis

Med Mycol

High-dose therapy with fluconazole > 800 mg day − 1

Mycoses

High-dose fluconazole therapy in patients with severe fungal infections

Eur J Clin Microbiol Infect Dis

Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard NCCLS document M27-A

Wayne, Pennsylvania: National Committee for Clinical Laboratory Standards

Commentary
Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fluconazole