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 Table of Contents  
ORIGINAL ARTICLES
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 7-14

Serum and sebum pharmacokinetics evaluation of a novel formulation of itraconazole in healthy volunteers


1 Department of Global Medical Affairs (India Formulations), Glenmark Pharmaceuticals Ltd, Mumbai, India
2 Department of Pharmaceutics, Delhi Pharmaceutical Science and Research University, New Delhi, India
3 Department of Global Medical Affairs (India Formulations, Middle East & Africa, Asia Pacific), Glenmark Pharmaceuticals Ltd, Mumbai, India

Date of Submission10-Jun-2021
Date of Decision21-Oct-2021
Date of Acceptance16-Nov-2021
Date of Web Publication11-Jun-2022

Correspondence Address:
Dhiraj Dhoot
Department of Global Medical Affairs (India Formulations), Glenmark Pharmaceuticals Ltd, Glenmark Enclave, B D Sawant road, Andheri (East), Mumbai 400099,
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_23_21

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  Abstract 

Background and Objective: Super bioavailable itraconazole is a newer formulation of itraconazole, which overcomes challenges encountered with the use of conventional itraconazole like interpatient variability, limited absorption, reduction in its absorption with co-administered gastric acid lowering agents, etc. The present study was done to evaluate the plasma pharmacokinetics, sebum concentrations of super bioavailable itraconazole in comparison with conventional itraconazole. Materials and Methods: Twelve healthy Asian Indian male healthy volunteers were enrolled in single-center, open-labeled, two treatments, multi-dose, parallel pharmacokinetic study. Test drug (T), i.e. super bioavailable itraconazole 50 mg, was given to six volunteers twice daily after meals for 7 continuous days. Reference drug (R), i.e. conventional itraconazole 100 mg, was given in similar way to the remaining six volunteers. Concentration of the itraconazole in plasma in both the groups was quantified by using high performance liquid chromatography. Concentration of the itraconazole in sebum was measured by paper absorption method. Results: The plasma concentration of itraconazole in both the groups was comparable at all-time points. The maximum concentration (Cmax) and area under curve in test group was higher as compared to reference group. The relative bioavailability of test drug was 107% as compared to the reference drug. The intersubject variability was less in test group (8.37%) as compared to reference drug (19.82%). At day 7, the mean sebum concentration of itraconazole in test drug group was 11.6% higher as compared to reference drug (P = 0.01). Conclusion: It is apparent from the study outcomes that super bioavailable itraconazole (50 mg) is bioequivalent to the conventional itraconazole (100 mg) along with less intersubject variability, and most importantly higher sebum concentration as compared to conventional itraconazole.

Keywords: Bioavailability, pharmacokinetics, super bioavailable itraconazole, variability


How to cite this article:
Mahajan H, Jain GK, Dhoot D, Deshmukh GA, Barkate HV. Serum and sebum pharmacokinetics evaluation of a novel formulation of itraconazole in healthy volunteers. Indian J Drugs Dermatol 2022;8:7-14

How to cite this URL:
Mahajan H, Jain GK, Dhoot D, Deshmukh GA, Barkate HV. Serum and sebum pharmacokinetics evaluation of a novel formulation of itraconazole in healthy volunteers. Indian J Drugs Dermatol [serial online] 2022 [cited 2022 Aug 8];8:7-14. Available from: https://www.ijdd.in/text.asp?2022/8/1/7/347286




  Key points: Top


The relative bioavailability of super bioavailable itraconazole was calculated to be 107% as compared to conventional itraconazole. The coefficient of variation at steady state i.e. intersubject variability of test product (8.37%) was found to be less than reference product (19.82%). At day 7, test product exhibited 11.6% higher sebum concentration as compared to reference and the difference was statistically significant (P = 0.01).


  Introduction Top


Dermatophytosis in India has risen to epidemic levels with a prodigious prevalence rate of 37–74%.[1] In current scenario, dermatophytosis is treated with systemic antifungal drugs in combination with topical antifungal drugs, and that too at increased dose and duration. Itraconazole is the most commonly used systemic antifungal.[2]

Numerous factors have been cited for such changes in the management of dermatophytosis in India such as rise of Trichophyton mentagrophytes as commonest cause of dermatophytosis, abuse of topical antifungal therapies, quality of antifungal drugs, steroid abuse, etc.[2] In case of itraconazole, one critical factor that is not given much importance in clinical practice is its inherent pharmacokinetic shortcomings.

Itraconazole is a weak base (pKa 3.7) and a lipophilic compound, with poor water solubility being the rate-limiting step in its absorption from the gastrointestinal tract (GIT).[3],[4],[5],[6] Itraconazole is coated onto hydroxypropyl methylcellulose matrix (HPMC), which is dependent on gastric acid secretion for its dissolution and it releases itraconazole in the stomach. The gastric acid dependency contributes to erratic absorption of itraconazole. Administration of itraconazole with food especially a fatty meal and acidic drinks, such as cola, are the strategies used to augments its dissolution and release.[7],[8],[9] Another issue with itraconazole is that it recrystallizes on exposure to neutral/alkaline pH of the small intestine and this limits its absorption. Thus various methods have been tried to overcome these problems in the pursuit of increasing its intestinal absorption.[10] The absolute bioavailability of itraconazole in fed state is found to be 55%.[6]

Similarly, concomitant administration with gastric acid lowering agents like proton pump inhibitors (PPI) and H2 receptor blockers reduces the serum concentration of itraconazole by as much as 66%.[11] As per one Indian study, improper use of proton pump inhibitors was seen in 60% of the cases.[12] Since itraconazole is the most commonly used systemic antifungal, such misuse of PPI may hamper it absorption.

As mentioned earlier, itraconazole shows erratic absorption patterns across individuals, which is termed as intersubject variability. This has been confirmed in various studies of itraconazole, wherein intersubject variability was found to be as high as 50–60%.[13],[14],[15],[16],[17] All of these pharmacokinetic challenges with itraconazole play an important role in its bioavailability and thus might affect the clinical outcomes.

Availability of itraconazole at the site of absorption is one of the major factors determining its therapeutic efficacy in dermatophytosis. After getting absorbed from GIT, itraconazole enters the blood and reaches the skin via passive diffusion and its route of distribution in the skin is dependent on sebum production.[18] It has been found in a clinical study that the concentration of itraconazole in the skin is higher in areas with higher sebum secretion, therefore its concentration in sebum becomes more important when it is used for treatment of dermatophytosis.[19] Since, itraconazole shows erratic absorption pattern, its concentration in sebum might reflect similar fluctuations. But, there is no published Indian data on sebum concentration of conventional itraconazole.

A newer itraconazole formulation, i.e., super bioavailable itraconazole has been launched in European countries and Australia in 2019, and recently in India, which is approved by the Central Drug Standard Control Organization (central licensing authority). It is claimed to overcome all the pharmacokinetic challenges faced with conventional itraconazole. Super bioavailable itraconazole is available in 50 mg powder-based capsule formulation, in which itraconazole is known to be released majorly in the small intestine, i.e. the main site of its absorption. Super bioavailable itraconazole is claimed to have the benefits of increased bioavailability, no food interaction, less intersubject variability, no reduction in absorption with concomitant use of PPI or other gastric acid lowering agents, etc.[3],[20],[21] All these benefits can be anticipated to improve the clinical outcomes as well as the patient compliance. Given the importance of sebum concentration of itraconazole in the treatment of dermatophytosis as mentioned earlier, evaluating the same for super bioavailable itraconazole also becomes critical. There is paucity of such data for super bioavailable itraconazole.

Therefore, the objective of the present study was to evaluate the plasma pharmacokinetics, sebum concentrations of the super bioavailable itraconazole 50 mg test formulation (T), and to compare it with that of the conventional itraconazole 100 mg (R) under fed states.


  Materials and Methods Top


The study was carried out at Gamma Scan C/O Must and More, New Delhi, India from May 15 to June 20, 2020.

Study Subjects

Twelve healthy male subjects, nonsmokers, between 18 and 35 years of age were included in the study. Pre-enrollment screening of the subjects were done in the form of taking medical history, physical examination, measuring vital signs (blood pressure, pulse rate, body temperature), blood analysis (complete blood cell count, liver enzymes, kidney function tests), urine analysis, and vital signs. Subjects with abnormal clinical laboratory results, or a history of hypersensitivity to azole compounds, or inability to swallow capsules were excluded from the study. Subjects who had participated in an investigational study or received any other investigational drug within the previous month were not included.

Study Design

This was a single-center, open-labeled, two treatments, multi-dose, parallel study. The subjects were divided into two groups (n = 6). Group ‘T’ received test capsules [50 mg Super bioavailable itraconazole (ITZ), Glenmark] and group ‘R’ received reference capsule (conventional 100 mg ITZ) every 12 h, for 6 days. The products were administered orally with 240 mL of water in fed conditions. Food was consumed by the subjects 30 min before drug administration and subjects were not permitted to drink until 2 h after dosing or to eat until 4 h post-dosing. The plasma pharmacokinetics, sebum concentration evaluations of itraconazole and super bioavailable itraconazole were conducted.

Materials

Pure ITZ and test product (super bioavailable itraconazole) were supplied by Glenmark Pharmaceuticals Limited, India. All the reagents used were of analytical grade and purchased from Central Drug House Ltd (New Delhi, India).

Study Products

The test product was prepared by validated and optimized method. Briefly, hydroxypropyl methylcellulose phthalate (HPMCP) was dispersed in methylene chloride followed by addition of ITZ with stirring until a pale brown solution was formed. The solution was then spray-dried using a dual-fluid nozzle sprayer at 70°C and air inlet temperature at 15–20°C to form the solid dispersion as a spray dried powder. Spray dried powder was blended with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and sodium stearyl fumarate, until uniform. The powder was filled into size 0 hard gelatin capsules in an amount sufficient to provide 50 mg of Super bioavailable ITZ per capsule. The clinical supply (B.No 05200709; Dated 04, 2020) of the test product was provided by Glenmark Pharmaceuticals Limited, India. The sample passed all the quality control tests for capsules in accordance with British Pharmacopeia. Conventional itraconazole 100 mg was used as reference formulation for comparison.

Plasma Pharmacokinetics

Blood sample (5 mL) from each volunteer was collected for plasma pharmacokinetic analysis at 0 h (before dosing) and after dosing at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 144 h. All blood samples were drawn by using an IV catheter inserted into a forearm vein, except samples collected at 24, 48, 72, and 144 h, which were drawn by direct venipuncture. All the samples were collected into heparinized tubes and plasma was separated by centrifugation at 4000 rpm for 15 min. The plasma was transferred into polypropylene tubes and kept frozen at ≤ −20°C until analysis. Only the parent analyte was measured in the plasma.

High Performance Liquid Chromatography Analysis

The reported method[7] was modified and validated as per the FDA guidelines for the determination of ITZ in human plasma.[17] The concentration of ITZ in plasma were determined using high performance liquid chromatography (HPLC) (LC-10 AT VP, Shimadzu Corp., Kyoto, Japan) coupled with UV-Vis Detector (SPD-10A VP, Shimadzu Corp., Kyoto, Japan). Mobile Phase consisted of acetonitrile and 0.05% diethylamine in the ratio of 60:40 (v/v). Chromatographic separation was performed using a C18 column (Phenomenex C-18, 4.6 × 250 mm, 5 μm) at flow rate of 1 mL/min with a detection wavelength of 258 nm. An aliquot of 1.0 mL from each plasma sample or sebum sample was mixed with 2.0 mL of acetonitrile followed by vortex mixing for 5 min. The mixture was then subjected to centrifugation at 10,000 rpm for 10 min. The organic layer was separated and dried under a gentle stream of nitrogen and reconstituted with 200 µL mobile phase. Hundred microliter of the reconstituted sample was injected onto the HPLC column. The limit of quantification of the developed HPLC method was 2.0 ng/mL for ITZ.

Calculation of Relative Bioavailability

The relative bioavailability of super bioavailable itraconazole was calculated by the formula:[22]

Frel = Area under curve (AUC)0-t (test drug) × 100

AUC0-t (Reference drug)

Calculation of Intersubject Variability

The interpatient variability was calculated on the basis of coefficient of variation for serum values at steady state, per published literature.[15] Coefficient of variation was calculated by using the following formula:[23]

CV = Standard deviation (SD) × 100

Mean

Sebum Concentration

It is well reported that ITZ get localized in sebum and underneath skin but not before 3 days post dosing[24]. Thus sebum concentration for both test and reference were determined at day 5 and day 7. The sebum of the subjects was collected from the center of the forehead according to the previously reported paper absorption method.[25] Briefly, area measuring 1.0 square inch is defined on the forehead and previously weighed, rolling flax paper (OCB, France) is held over the demarcated area for 3 h. At the termination of the test, the paper is weighed to determine the quantity of the sebum. The papers are subsequently washed with three aliquots (1.0 mL) of acetonitrile to extract the ITZ. The samples were kept frozen at ≤ −20°C until analysis.

Pharmacokinetic and Statistical Analysis

Pharmacokinetics parameters such as Cmax, AUC0-t, AUC0-∞, T1/2, and Tmax were calculated using WinNonlin version 7.0 (Certara Corporation, Princeton, NJ, USA). The data are presented as mean of six values ± SD in both groups. Intergroup comparison between test and reference drug was done by using unpaired-t test. P-value of <0.05 was taken as statistically significant.

Safety Analysis

Safety was assessed from the screening period to the end of the study. A clinical examination, including the recording of vital signs (i.e., sitting blood pressure, radial pulse rate, and oral body temperature), was performed at the time of pre-enrollment screening and the end of the study. Laboratory tests included liver function test consisting of serum glutamic oxaloacetic transaminase (SGOT) and glutamic pyruvic transaminase (SGPT), kidney function tests and urine analysis were performed at screening and end of the study (at the time of check-out) for post-study safety assessment.

Ethical Considerations

The study was approved by Independent ethics committee of Good Society for Ethical Research, Delhi, India (Approval no. GSER/2020/NR-AP/013; dated May 27, 2020). The study was carried out per approved protocol by the ethics committee, recommendations under Schedule Y laid down by Central Drugs Standard Control Organization, Indian Council of Medical Research, Declaration of Helsinki (Brazil, October 2013), and Good Clinical Practices E6-R2, i.e. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. All subjects were informed in writing by the investigator about the consequences of the study and signed consent forms were collected before the study.


  Results Top


Baseline demographic and anthropometric parameters are depicted in [Table 1]. These characteristics were comparable in both the groups.
Table 1: Baseline demographic and anthropometric parameters in study and reference drug groups

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Serum Pharmacokinetic Findings

The mean plasma concentrations at different time points following multiple doses of test product Super bioavailable Itraconazole 50 mg (T) and the reference product Itraconazole 100 mg (R) in a fed state is shown in [Table 2] and [Figure 1].
Table 2: Mean ITZ plasma concentrations following 6 day BID oral dose of reference (ITZ, 100 mg) and test (Super bioavailable ITZ, 50 mg) product

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Figure 1: Plasma concentration vs. time profile following 6 day BID oral dose of reference [itraconazole (ITZ), 100 mg] and test (Super bioavailable ITZ, 50 mg) product

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Relative bioavailability

The plasma pharmacokinetic parameters are presented in [Table 3]. The mean ± SD values of Cmax of the test product under fed conditions was 57.53 ± 0.011 ng/mL, while the mean Cmax value of reference product was 52.73 ± 0.031 ng/mL. The mean values of AUC0-t and AUC0-∞ for test product was 2884.56 ng.h/mL and 10167.05 ng.h/mL, respectively. Similarly, the mean values AUC0-t and AUC0-∞ for reference product was 2696.54 ng.h/mL and 9876.95 ng.h/mL, respectively. The relative bioavailability of super bioavailable itraconazole was calculated to be 107% as compared to conventional itraconazole. The Tmax of both test and reference was found to be 5 h.
Table 3: Pharmacokinetic parameters following 6 day BID oral dose of reference (ITZ, 100 mg) and test (Super bioavailable ITZ, 50 mg) product

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Intersubject variability

At each time point, plasma concentrations of test product were almost similar to reference product. Steady-state concentration was achieved at 144 h in both the groups. The coefficient of variation at steady state, i.e. intersubject variability of test product (8.37%) was found to be less than the reference product (19.82%).

Sebum Concentration

As shown in [Figure 2], at day 5, sebum concentrations for reference was 4.3% higher than that of test and the difference was not statistically significant (P = 0.31). However at day 7, test product exhibited 11.6% higher sebum concentration as compared to reference and the difference was statistically significant (P = 0.01).
Figure 2: Sebum concentration of reference [Itraconazole (ITZ), 100 mg] and test (super bioavailable ITZ, 50 mg) product following 6 day BID dosing

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Safety Assessment

The laboratory investigations were within normal limits at the screening and at the end of the study. Liver function tests and kidney function test results are depicted in [Table 4]. There was no significant difference in laboratory investigation findings in both the groups. No adverse event was found in both the groups during the study period. The treatment compliance was 100% in both the groups and no clinically relevant abnormalities.
Table 4: Laboratory investigations in both the study groups of present study

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  Discussion Top


Itraconazole is a lipophilic molecule, which is a weak base, and its main site of absorption is small intestine.[10] It is characterized by plethora of pharmacokinetic limitations leading to erratic absorption, dependency on gastric acid for its release, recrystallization in small intestine, dependency on food for better absorption, reduction in absorption on concomitant use of gastric acid lowering agents like PPI, wide intersubject/patient variability, etc.[21] Conventional itraconazole is available commercially as pellets, which are filled in capsule. Despite recommendations for optimal size and number of pellets in each capsule, there are wide variations in these parameters in commercial brands in India. These factors affect the quality and therefore absorption of itraconazole is hampered.[26] Pharmacokinetic especially absorption issues of antifungal drugs have been implicated in emergence of recalcitrant dermatophytosis.[27] These problems are often overlooked in clinical practice. Super bioavailable itraconazole is recently launched new formulation of itraconazole, which overcomes all these problems encountered with conventional ITZ. The present study was the first of its kind to measure and compare the serum and sebum kinetics of super bioavailable itraconazole and conventional itraconazole.

In the present study, it was found that the serum concentration of itraconazole in super bioavailable itraconazole group (50 mg) was almost same as that of conventional itraconazole (100 mg) till the achievement of Cmax, and after this point the concentration achieved was in fact more in super bioavailable itraconazole group. This might be related to the release pattern of super bioavailable itraconazole, wherein it is consistently released and available for absorption throughout small intestine, which is the main site of absorption of itraconazole.[3],[4]

The relative bioavailability of super bioavailable itraconazole in the present study was found to be 107% as compared to conventional itraconazole. The relative bioavailability in a pharmacokinetic population modeling study by Abuhelwa et al. was found to be 173% for super bioavailable itracomazole.[3] This difference might be attributed to double duration of super bioavailable itraconazole and conventional itraconazole administration in their study and large sample size.

Steady-state concentration in the present study was achieved at day 6. In a clinico-pharmacokinetic study done by Lindsay J et al., patients who had undergone hematopoietic stem cell transplant received prophylaxis against invasive fungal infections in the form of either super bioavailable itraconazole or itraconazole solution. Time taken to reach steady-state plasma concentration was 17 days in super bioavailable itraconazole group, while it was achieved in 42 days in itraconazole solution group. Treatment failure and adverse events were less in patients who received super bioavailable itraconazole as compared to itraconazole solution.[15] Thus, super bioavailable itraconazole was found to better than itraconazole solution.

Interpatient variability is defined as fluctuations in serum concentration achieved with the drug across the individuals taking same type of formulation in same dose and duration. This may lead to failure to achieve the therapeutic serum concentration, which may result in treatment failure and selection of resistant strain of microorganism.[28] In the present study, intersubject variability was less in super bioavailable itraconazole group as compared to conventional itraconazole. Although Abuhelwa et al.[3] reported slightly more difference of intersubject variability between super bioavailable itraconazole and conventional itraconazole, the sample size was large (n = 150) and therefore chances of detecting variability are more. Wide interpatient variability is known pharmacokinetic issue with conventional itraconazole.[3] It is an important factor, as fluctuations in concentration of drug in bound to affect the optimal clinical outcome.[29] It has also been linked to development of resistance by some researchers.[30] Interpatient variability means that same dose might result in subtherapeutic effect in some patients while unacceptable adverse effects in other patients.[31] Thus, super bioavailable itraconazole can be anticipated to give consistent results owing to its uniform absorption. This is achieved due to the use of HPMC phthalate (HPMCP) matrix, which undergoes dissolution in neutral/alkaline pH, i.e. small intestine instead of stomach.

In case of systemic antifungals, concentration attained at the site of infection is one of the most critical factors governing their efficacy. Itraconazole is a lipophilic drug, therefore its excretion in sebum and concentration achieved in stratum corneum is also important in patients with recalcitrant dermatophytosis.[19] Concentration of itraconazole in sebum is crucial as its distribution in the skin, especially stratum corneum is extensively dependent on sebum production.[18] This is corroborated by the fact that itraconazole concentration is highest in skin areas where sebum secretion is higher, like face and vice versa. In usual kinetic studies, only serum kinetics and drug susceptibility are evaluated and the kinetics at the target site, i.e. skin (in case of dermatophytosis), are not taken into consideration. This is the reason why susceptibility parameters of systemic antifungals do not consistently correlate with in vivo efficacy in the treatment of dermatophytosis. Such sebum evaluation studies of oral antifungals are very scarce.[19],[24]

In the present study, sebum concentration of super bioavailable itraconazole was 11.6% higher as compared two conventional itraconazole at the end of study period, and the difference was statistically significant (P = 0.01), while the difference between two groups was nonsignificant at day 5. Only one study was available for sebum assay of itraconazole till the time of the article submission to the journal. In this study, three healthy individuals were given itraconazole 100 or 200 mg daily for 7 days and the concentration of itraconazole in stratum corneum, sebum, hairs, and nails was measured. It was found that concentration of itraconazole in skin area with more sebum secretion had highest concentration of itraconazole, i.e., beard are as compared to skin where sebum secretion is less i.e. palm. Sebum concentration of itraconazole was found to be 10 times higher as compared to its peak plasma concentration at day 7 of drug administration. Authors of this study concluded that itraconazole is majorly excreted via sebum and incorporated into the stratum corneum and this is responsible for constant delivery of itraconazole into the skin.[24] Thus, the higher sebum concentration achieved in super bioavailable itraconazole in the present study as compared to conventional itraconazole might result in more consistent delivery of drug at target site, i.e. the skin, and leads to extensive fungal eradication.

Due to all these pharmacokinetic advantages, it can be anticipated that outcomes will be more consistent and better with super bioavailable itraconazole as compared to conventional itraconazole, as was seen in a randomized clinical trial done on 174 patients diagnosed with toenail onychomycosis.[32]

In the above-mentioned clinical trial, 75 patients received super bioavailable itraconazole in the dose of 50 mg 2 capsules once daily, while remaining 75 patients received conventional itraconazole in the dose of 100 mg 2 capsules once daily and 24 patients received placebo. Duration of administration was 12 weeks. It was found that at 24 weeks, the clinical cure rate, mycological cure rate, and therapeutic cure rate (percentage of patients achieving both clinical and mycological cure rate) were higher in super bioavailable itraconazole group as compared to placebo and this difference was highly statistically significant (P = 0.001), whereas in conventional itraconazole, barring mycological cure rate, there was no statistically significant difference as compared to placebo (P = 0.08).[32] Thus, clinical outcomes with super bioavailable itraconazole were better as compared to conventional itraconazole. The lower relapse rates in super bioavailable itraconazole is also an important advantage, as dermatophytosis in India is largely presenting itself with recurrence and relapse.[33]

Such large multicentric studies are required so that the findings of the present study can be compared and generalized.


  Conclusion Top


It is apparent from the study outcome that super bioavailable itraconazole (50 mg) is bioequivalent to the conventional itraconazole (100 mg). The relative bioavailability of super bioavailable itraconazole was 107%, with less intersubject variability, and most importantly higher sebum concentration as compared to conventional itraconazole. Both the treatments were well tolerated. All these pharmacokinetic advantages of super bioavailable itraconazole over the conventional formulation will help to improve clinical outcomes.

Limitations of the study: The present study was carried in small number of subjects; therefore, such studies should be done with more number of subjects so that intersubject variability can be better judged. One of the limitations of the present study was that concentration of super bioavailable itraconazole and conventional itraconazole could not be measured in skin and nails, although serum and sebum concentration provides fair estimate of comparative pharmacokinetics of both types of itraconazole.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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