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Full-Text PDF: 605-610.pdf
Ketoconazole Associated Hepatotoxicity: A Systematic Review and Meta- analysis
 

Original Article

Ketoconazole Associated Hepatotoxicity: A Systematic Review and Meta- analysis

YAN Jiang Ying1, NIE Xiao Lu2, TAO Qing Mei2, ZHAN Si Yan2, and ZHANG Yan De1

1.National Hepatobilliary & Enteric Surgery Research Center, Central South University, Changsha 410012, Hunan, China; 2.School of Public Health, Peking University, Beijing 100871, China

 Received: April 4, 2013;             Accepted: July 8, 2013

Abstract

Objective  To evaluate the incidence of Ketoconazole associated hepatotoxicity and related factors.

Methods  Literature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies.

Results  Totally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged >60 years was 1.4% (95% CI: 0.5%-4.2%) and 3.2% (95% CI: 1.1%-8.7%) respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% (95% CI: 4.5%-7.2%).

Conclusion  Ketoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.

Key words: ketoconazole; oral treatment; hepatotoxicity; systematic review

Biomed Environ Sci, 2013; 26(7):605-610    doi: 10.3967/0895-3988.2013.07.013     ISSN:0895-3988

www.besjournal.com(full text)            CN: 11-2816/Q          Copyright ©2013 by China CDC


 


INTRODUCTION

K

etoconazole (NIZORAL, chemical name: CIS- 1-ethanoyl-4-[4-[[2-(2,4-dichlorophenyl)-2- (1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine), is an azol-based broad-spectrum antifungal drug, which operates through inhibiting the biosynthesis of ergosterol in fungal cell and cell wall, as well as the absorption of the DNA and RNA precursors to increase the cell permeability of mycetes, and further inhibit and damage mycetes[1]. It is mainly used to treat systemic infection such as candidiasis, blastomycetic dermatitidis, coccidioidomycosis, histoplasmosis and chromoblastomycosis[2-5]. Meanwhile, it was also reported that oral ketoconazole had been used to treat female hirsutism[6], polycystic ovarian syndrome[7], ovarian hyperstimulation syndrome[8], and male pattern alopecia[9], etc. Ketoconazole was developed in 1978 by Belgian pharmacologists, and was once widely used in the world. It was introduced into China in mid-1980s as an improved substitute for griseofulvin. In recent years, the data in spontaneous case reports from China National Center for Adverse Drug Reaction (ADR) showed that oral administration of Ketoconazole had serious problem of hepatotoxicity, which arounted for a large proportion among severe cases. In addition, United Kingdom and France have taken more strict measures for its risk management. This systematic review and meta-analysis aims to investigate the incidence of Kotoconazole associated hepatotoxicity and related factors and provide evidence for the rational use of Kotoconazole.

Materials and Methods

Sources of Data

Literature retrieval was conducted by using PubMed, EMBASE and The Cochrane library for English papers and Chinese Biological Medical Database(CBM), Chinese National Knowledge Infrastructure database (CNKI), Chongqing VIP, and Wanfang database for Chinese papers about Kotoconazole associated hepatotoxicity in human updated to March 31, 2013 with the key words of “ketoconazole” and “oral administration”. Completed but unpublished papers were obtained from websites: http://www.ClinicalTrials.gov and http://www.chictr.org/ with the same key words and limits.

Inclusion and Exclusion Criteria

Studies met the following criteria were included: (1) participants who used Ketoconazole; (2) oral administration of Ketoconazole was given, (3) participants with adverse events related to oral administration of Ketoconazole; (4) the study papres were published in English or Chinese; (5) the studies conducted were randomized controlled trial (RCT), quasi trial, case series analysis, case control study, cohort study, etc; (6) with complete baseline data, including the number of patients studied, sources of cases and follow-up time, etc. The eligibility of the studies for inclusion was initially assessed by two researchers (Nie XL. and Tao QM.) respectively, then by a senior researcher (Yan JY). Studies which did not meet the above criteria were excluded from the analysis.

Study Quality Assessment and Data Collection

The study quality was assessed by the relevant criteria according to the type of researches[10]. Standardized forms were used to collect the data about study information, quality assessment, treatment intervention and outcome and prognosis of adverse events related to oral administration of Ketoconazole. Data collection was done by two researchers (Nie XL. and Tao QM.) respectively, and examined by a senior researcher (Yan JY). All the data collected were entered into computer with Epidata 3.1 software (Odense, Denmark) for further analysis.

According to the diagnostic criteria developed by National Center for Adverse Drug Reaction, hepatotoxicity caused by taking normal dose of oral administration of Ketoconazole was defined as (1) an increase of alanine aminotransferase (ALT) and/or total bilirubin (TB) >1 time over upper limit of normal (ULN) in two consecutive measurements; (2) an increase of alanine aminotransferase (ALT) >2 times over ULN and/or total bilirubin (TB) >1 time over ULN in one measurement.

Data Analysis

Overall estimation of incidence for the hepatotoxicity was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies with 95% confidence intervals (CIs). Statistical heterogeneity was assessed by calculating the I2 index. Additionally, in order to investigate the factors associated with the occurrence of hepatotoxicity, subgroup analyses of the studies based on dosage, treatment duration, age and disease were performed. Non-overlapping CIs indicated significant differences among groups with a 95% probability of a true difference.

Excel version 2010 was used to classify the data. And all analyses were performed using MetaAnalyst version beta 3.13.

Results

Result of Literature Retrieval

Totally 2570 English papers and 964 Chinese papers were obtained, among which 1130 repeated papers were excluded. 2404 were used in analysis. After reading the titles and abstracts, 353 were selected for further assessment. After the full text review, 204 papers were finally included in this analysis. The process of paper selection was summarized in Figure 1 (Supplementary Materials).

General Characteristics

One of the 204 papers reported 2 studies, so 205 studies were included in the analysis. Since some randomized controlled trials (RCTs) were conducted in two more groups with different dosing regimen of Ketoconazole, all the Ketoconazole treatment groups should be included in the analysis. So there were 226 Ketoconazole treatment groups in 205 studies included in the analysis. The detail information was summarized in Table 1.

Quality Assessment

The quality of studies included in this review was generally high, but the methodology was not clearly described, such as the detailed randomization method in RCTs and the inclusion and exclusion criteria of case series studies (Table 2).

Incidence Rate of Ketoconazole Associated Hepatotoxicity

Considering that study subjects who might be lost in follow up, with ADRs or not after taking Ketoconazole orally might not be reported in some studies, intention-to-treat (ITT) and per-protocol (PP) analyses were conducted respectively. The overall incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The incidence rate was higher in PP analysis and in the transparent report than that in ITT analysis and in the opaque report. In addition, a combinational analysis was conducted according  to different study types. The high incidence rate was

Table 1. Characteristics of all 204 Papers Included

Classifications

Categories

Number of Studies

Percentage (%)

Language

Chinese

118

57.84

English

86

42.16

Location

China

111

54.41

United States

22

10.78

United Kingdom

7

3.43

Other countries

55

26.96

Unspecified

9

4.41

Single-center or multi-center study

Single-center

184

90.20

Multi-center

11

5.39

Unspecified

9

4.41

Study design

(205 studies in total)

RCT

75

36.59

Quasi RCT

35

17.07

Cohort study

1

0.49

Case series

94

45.85

Underlying disease

Skin, mucosa, or

hair infection

130

63.73

Systemic disease

10

4.88

Off-label use for

other diseases

64

31.22

found in case series analysis. In contrast, the incidence rates in controlled clinical trials and RCTs were low (Table 3).

Subgroup Analysis of Ketoconazole Associated Hepatotoxicity

Dosage and Duration    Among the 226 groups of Ketoconazole treatment, the data of 199 groups were analyzed after the exclusion of 20 groups without clear duration or total daily dose data, 5 groups in children, 1 group showing dosage in a different way and 1 group of cohort study. Intention-to-treat (ITT) and per-protocol (PP) analysis were conducted respectively too.

Total daily dosage of 50 mg, 100 mg, 200 mg, 400 mg, 450 mg, 600 mg, 800 mg, 1200 mg, and 2400 mg reported in the papers were used as the classification criteria respectively, and the treatment durations were 0-7 days, 8-30 days, 32-90 days, and over 90 days for each dose group (Table 4). Subgroup analyses did not show any significant difference among those groups.

Age    Seventeen papers reported the dosage in children according to their weight and age. Five of these studies were done only in children. One case of hepatotoxicity was reported among 218 children,

Table 2. Quality Assessment of Including Papers

Item of quality assessment

Yes

No

Unclear

RCT and Quasi RCT (N=110)

 

 

 

Clear clinical question

109

0

1

Randomization

84

16

10

Blindness

25

62

23

Baseline comparison

79

0

31

Considering lost of follow-up

57

49

4

Suitable tools to collect data

98

0

12

Case series and case reports (N =93)

 

 

 

Representative sample

81

8

4

Clear inclusion and exclusion criteria

20

70

3

Similar severity for all cases

57

19

17

Follow-up sufficiently long and

complete

72

1

20

Objective outcome criteria

89

0

4

Cohort study (N =1)

 

 

 

Detailed description for expose and

non-expose group

1

0

0

Cosidering the possible factors

1

0

0

Baseline comparison

1

0

0

Follow-up sufficiently long and

complete

1

0

0

Objective outcome criteria

1

0

0

the incidence rate was 1.4% (95% CI: 0.5%-4.2%).

Two of the trials included 117 elder patients over 60 years old, among whom 3 cases of the hepatotoxicity were reported, and the incidence rate was 3.2% (95% CI: 1.1%-8.7%).

Underlying Disease    After exclusion of one cohort study with no incidence of the hepatotoxicity and 2 study groups with no underlying disease reported in the 226 ketoconazole treatment group, the incidence of the hepatotoxicity was 3.3% for skin, mucosa or hair disease, 2.5% for systemic disease, 5.7% in off-label use group for other diseases, respectively (Table 5).

The results showed a higher incidence of liver damage in the subgroup of off-label use of Ketoconazole for other diseases not stated as the indication in its usage instruction.

Discussion

Study Findings

The overall incidence of the hepatotoxicity was 3.6%-4.2% based on different analysis (ITT and PP) and whether transparent report or not. According to

 

the suggestion by Council for International Organization of Medical Sciences (CIOMS)[11], the incidence of Ketoconazole associated hepatotoxicity is common. Therefore, it is important to take appropriate measures to reduce the incidence of adverse outcome. As all of the 204 papers included in this study did not report the diagnosis criteria, and most of them only used the increase of alanine aminotransferase (ALT) as the evidence and reporting indicator, this study did not identify the incidence or proportion of the hepatotoxicity with different severity. At present, only a few papers reported the liver enzyme levels in details, thus it is difficult to know about the severity of the hepatotoxicity. Even though, the liver function should be monitored during the oral administration of Ketoconazole.

The mechanism of Ketoconazole causing liver damage is still unknown at present. As a potent inhibitor of microsomal CYP3A4 both in the liver and the gastrointestinal tract, Ketoconazole might reduce metabolism of drug[12]. A latest research found that Ketoconazole increased the level of lipopolysaccharide-induced TNF release and implied the mechanisms of inflammatory stress[13].


Table 3. Incidence of Hepatotoxicity Associated with Oral Ketoconazole

Groups

Clear about Whether
Adverse Reactions
Happened or not

Method

Number of

Patients

Number of

Articles

Number of

Groups

I2

Combined
Rate (%)

95% CI (%)

All RCTs

No

ITT

5 028

75

92

0.219

3.0

2.4-3.8

PP

4 844

0.226

3.2

2.5-4.0

Yes

ITT

4 074

61

74

0.261

3.4

2.7-4.4

PP

3 953

0.269

3.6

2.8-4.6

Controlled clinical

trals

No

ITT

6 654

110

131

0.170

3.1

2.5-3.7

PP

6 425

0.183

3.2

2.6-3.9

Yes

ITT

5 200

101

104

0.217

3.5

2.9-4.3

PP

5 034

0.229

3.7

3.0-4.6

Case series

No

ITT

8 001

91

91

0.334

4.4

3.6-5.2

PP

7 806

0.333

4.4

3.7-5.3

Yes

ITT

6 190

69

69

0.357

4.8

4.0-5.8

PP

5 995

0.355

4.9

4.0-5.9

Cohort study

No

ITT

737

1

1

-

0.0

-

PP

737

-

0.0

-

Yes

ITT

737

1

1

-

0.0

-

PP

737

-

0.0

-

All ketoconazole

groups

No

ITT

15 429

213

224

0.275

3.6

3.2-4.2

PP

15 005

0.277

3.7

3.3-4.3

Yes

ITT

12 164

159

175

0.304

4.1

3.6-4.7

PP

11 803

0.306

4.2

3.7-4.9

Table 4. Subgroup analysis of hepatotoxicity associated with ketoconazole according to dose and duration

Total Daily
Dose (mg)

Therapy Duration
(day)

Number
of Study
Groups

Number of
Patients with Liver
Damage
Adverse
Reaction

ITT Analysis

 

PP Analysis

Total Number of
Patients

ITT Analysis

Incidence
of Liver
Damage (%)

95% CI
(%)

 

Total Number of

Patients

PP Analysis

Incidence of

Liver Damage
(%)

95% CI
(%)

 

50

8-30

1

1

40

2.5

-

 

40

2.5

-

100

0-7

4

0

152

0.0

-

 

152

0.0

-

8-30

4

0

59

0.0

-

 

59

0.0

-

200

0-7

18

11

1 017

2.9

1.8-4.6

 

982

3.2

2.0-5.2

8-30

46

56

2 605

4.5

3.4-5.6

 

2 571

4.6

3.5-5.7

31-90

16

7

724

2.7

1.6-4.7

 

711

2.8

1.6-4.9

90+

9

6

261

5.1

2.7-9.3

 

261

5.1

2.7-9.3

400

0-7

42

12

4 097

2.4

1.7-3.5

 

4 047

2.5

1.7-3.5

8-30

23

11

1 386

3.1

2.1-4.9

 

1 362

3.2

2.1-5.0

31-90

4

0

85

0.0

-

 

83

0.0

-

90+

2

0

68

0.0

-

 

68

0.0

-

450

0-7

1

0

16

0.0

-

 

16

0.0

-

600

0-7

5

0

138

0.0

-

 

138

0.0

-

8-30

5

0

199

0.0

-

 

199

0.0

-

31-90*

1

13

71

18.3

-

 

71

18.3

-

90+

1

0

6

0.0

-

 

6

0.0

-

800

0-7

2

2

63

4.9

1.4-15.6

 

63

4.9

1.4-15.6

 

8-30

2

0

125

0.0

-

 

125

0.0

-

1200

0-7

5

0

251

0.0

-

 

235

0.0

-

8-30

4

1

135

2.3

0.7-7.8

 

134

2.4

0.7-7.9

90+

2

8

64

20.4

10.0-37.1

 

62

21.9

10.6-39.9

2400

0-7

1

0

7

14.3

-

 

7

14.3

-

Total

 

199

128

11 571

3.7

3.2-4.3

 

11 393

3.8

3.2-4.3

Note. *This study aimed to assess the efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer(CRPC).

Table 5. Subgroup analysis of Ketoconazole associated hepatotoxicity according to underlying diseases

Underlying Diseases

Number of

Study
Groups

Number of

Patients with

Liver Damage

Adverse Reaction

ITT analysis

 

PP analysis

Total Number

of Patients

ITT Analysis

Incidence of

Liver Injury (%)

95% CI(%)

 

Total
Patients

PP Analysis

Incidence of

Liver Injury (%)

95% CI (%)

 

Skin, mucosa or hair disease

142

91

12 127

3.0

2.5-3.7

 

11 987

3.3

2.7-3.9

Systemic disease

 10

 6

  538

2.5

1.3-4.5

 

  538

2.5

1.3-4.5

Off-label use for other diseases

 71

49

2 240

5.7

4.5-7.2

 

2 199

5.7

4.5-7.2

 


Subgroup analyses according to dosage and duration did not show any significant difference among these groups. This might be explained by that most studies focused on the dose groups of     200 mg/d or 400 mg/d, and the number and weighting of subjects in various groups were different. The population specific analysis in this study showed the incidence of the hepatotoxicity was 1.4% in children and 3.2% in the elderly, respectively. And the incidence of the hepatotoxicity in patients with off-label use of oral administration of Ketoconazole for diseases not stated as the indication in usage instruction was 5.7%, which was relatively high. Therefore, we suggest that off-label use of Ketoconazole should be strictly controlled.

Advantages and Limitations

Systematic review has been generally believed as the best way to accurately evaluate and identify the evidence of a specific problem as well as the strong support for evidence-based decision making due to its clear method, systematic analysis and accurate assessment to conduct a comprehensive review of all related literatures. In this study, a systematic review of both Chinese papers and English papers was conducted to get a comprehensive understanding about the safety of oral administration of Ketoconazole, and papers about all types of studies were included to analyze the risk factors of Ketoconazole associated with hepatotoxicity. As many cases series study were included, ITT and PP analyses of clinical trials were conducted in this study for the first time, so it was possible to compare the incidence between in initially included participants and those who completed. The incidence of ITT analysis reflected the characteristics of the original study design, while that of the PP analysis was more close to actual situation.

This study also has some limitations. Firstly, systematic review is greatly influenced by the quality and differences of papers. The large geographical and time span of the study reports included in our analysis, the problems of data incompleteness and quality of adverse event reporting would affect the accuracy of our study’s results. Secondly, publication bias was another problem that cannot be neglected. In addition, regarding the specific data in this study, as the numbers of papers and sample sizes of the dosage subgroups except 200 mg/d and 400 mg/d were small in the dosage and treatment duration subgroup analysis, the final evaluation was relatively conservative.

In conclusion, Ketoconazole associated hepatotoxicity is common. The related factors might include the off-label use. Further well-designed large sample studies are needed to identify the other risk factors.

Supplementary Materials

http://www.besjournal.com/Articles/Archive/2013/No7/

References

1.   Yi Hei. The Concise Handbook of New Drugs. People’s Military Medical Press, 1994; 81.

2.   Sobel J. Recurrent vulvovaginal candidiasis. A prospective study of the efficacy of maintenance ketoconazole therapy. New England Journal of Medicine, 1986; 315(23), 1455-8.

3.   De Wit S, Weerts D, Goossens H, et al. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet, 1989; 1(8641), 746-8.

4.   Jones HE, Simpson JG, Artis W. Oral ketoconazole. An effective and safe treatment for dermatophytosis. Archives of Dermatology, 1981; 117(3), 129-34.

5.   Negroni R, Robles AM, Arechavala A, et al. Ketoconazole in the treatment of paracoccidioidomycosis and histoplasmosis. Reviews of Infectious Diseases, 1980; 2(4), 643-9.

6.   Isik AZ, Gokmen O, Zeyneloglu HB, et al. Low dose ketoconazole is an effective and a relatively safe alternative in the treatment of hirsutism. Aust N Z J Obstet Gynaecol, 1996; 36(4), 487-9.

7.   Vidal-Puig Aj, Munoz- Torres M, Jodar - Gimeno E, et al.Ketoconazole therapy: hormonal and clinical effects in nontumoral hyperandrogenism. Eur J Endocrinol, 1994; 130(4), 333-8.

8.   Parsanezhad ME, Alborzi S, Pakniat M, et al. A double-blind, randomized, placebo- controlled study to assess the efficacy of ketoconazole for reducing the risk of ovarian hyperstimulation syndrome. Fertil Steril, 2003; 80(5), 1151-5.

9.   Khandpur S, Suman M, Reddy BS. Comparat ive efficacy of various treatment regimens for androgenetic alopeciainmen. J Dermatol, 2002; 29( 8), 489-98.

10.Sharon E. straus, W. Scott Richardson, Paul Glasziou, et al. Evidence Based Medicine: How to Practice and Teach it, 3rd edition. England:Churchill Livingstone , 2005.

11.Report of CIOMS Working Group III, 1994. ISBN 92 9036 062 3.

12.J.L.C.M. Dorne, K. Walton, A.G. Renwick. Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment. Food Chem. 2003, Toxicol, 41, 201-24.

13.Hadi M, Westra IM, Starokozhko V, et al. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury. Chem Res Toxicol, 2013; May 20, 26(5), 710-20.

Appendix(download pdf)



 

 
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