Journal of the American Academy of Dermatology, November, 2013
Guy F. Webster, MD, PhD
Background
A high-fat meal is needed for optimal absorption of isotretinoin. A new formulation of isotretinoin, which enhances absorption of isotretinoin in the absence of dietary fat, has recently been approved by the Food and Drug Administration (FDA).Objective
We sought to compare the pharmacokinetic profiles of a new formulation of isotretinoin (isotretinoin-Lidose) with the innovator isotretinoin formulation.Methods
This study was an open-label, single-dose, randomized, 4-treatment, crossover comparative trial between a new and innovator formulation of isotretinoin in the fasting and fed states.Results
Both formulations were bioequivalent under fed conditions. As expected in a fasting state, absorption of both formulations was reduced. A considerable difference between the 2 drugs occurred under fasted conditions–there was a marked improvement in overall bioavailability of the isotretinoin-Lidose formulation. Mean plasma levels of the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with a fatty meal, and those of the isotretinoin formulation only reached 39.6% of that observed with a fatty meal.Limitations
Only the FDA-stipulated standard high-fat, high-calorie meal of 50-g fat was studied in the fed state.Conclusion
Isotretinoin-Lidose formulation is bioequivalent to the innovator formulation under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast.
Key words: acne, area under the curve, bioavailability, fasting, fed, isotretinoin, maximum measured plasma concentration over sampling time period, systemic exposure, time of maximum measured plasma concentration
Abbreviations used: AUCt, area
under plasma concentration versus time curve from time zero (0 hour) to
time of last measurable plasma concentration, calculated by linear
trapezoidal method, AUCi, area
under plasma concentration verus time curve from time zero (0 hour) to
infinity (AUCi calculated as sum of AUCt + measured plasma concentration
at time of last measurable plasma concentration/apparent first order
elimination rate constant), BA, bioavailability, BE, bioequivalent, Cmax, maximum measured plasma concentration over sampling time period, FDA, Food and Drug Administration, Tmax, time of maximum measured plasma concentration
Capsule Summary
Absorption of an orally administered drug is influenced by its solubility and intestinal permeability.∗
Food is a well-known agent that can have an impact in drug absorption.
For some drugs, food will have no effect and for other drugs, it can
either increase or decrease the amount of absorption. Isotretinoin is a
molecule with good permeability and poor solubility in the aqueous
environment of the intestine, and its absorption is greatly enhanced by
fatty foods. When taken without food, absorption (permeability) is low.
Fasted plasma levels of current isotretinoin formulations are nearly 60%
lower than levels in the fed state.1
To ensure optimal and consistent absorption and maintenance of
therapeutic blood concentrations, isotretinoin must be taken with food,1 preferably with a high-fat meal (50% caloric intake from fat) as defined by the Food and Drug Administration (FDA).2A technology (Lidose) now exists that enhances the intestinal absorption of poorly soluble agents, such as isotretinoin. Lidose is a novel formulation that uses lipid agents to encase lipophilic drugs and create an optimal environment for absorption.3 The FDA has recently approved isotretinoin-Lidose, a new formulation of isotretinoin, which can be taken without regard to meals.
In this study, we describe the pharmacokinetic profiles of this new agent and compare it with the innovator formulation of isotretinoin.
Methods
This trial was an open-label, single-dose, randomized, 4-treatment, crossover comparative bioavailability (BA) study. The ethics review board at Optimum Clinical Research Inc approved the study protocol, its amendments, and informed consent form. Full trial protocol was submitted to the FDA during the approval process for isotretinoin-Lidose.Subjects
All 60 individuals who were selected for the study met the inclusion and exclusion criteria, and were judged by the investigator to be healthy.Inclusion criteria included:
•Healthy, nonsmoking, men and nonpregnant, nonlactating women, 18 to 55 years of age, inclusive.
•Body weight within ±15% of the appropriate weight for the individual's height and frame.
•Women
were either unable to have children, willing to remain abstinent, used
an effective method of double-barrier birth control, or used a hormonal
contraceptive agent.
Exclusion criteria included:
•Known history or presence of any clinically significant disease.
•Known or suspected carcinoma.
Study drugs and administration
Study drugs were administered in a clinical facility over 4 periods/intervals with a 21-day washout period between successive administrations:Isotretinoin-Lidose (Absorica) capsules manufactured for Cipher Pharmaceuticals Inc, Barbados, by Galephar PR Inc, lot 28A02.
Isotretinoin (Accutane) capsules manufactured by Roche Laboratories Inc, Nutley, NJ, lot U0622.
A predetermined computer-generated randomization scheme for the 4 treatment periods (assigned to participants in 1 of 12 different sequences):
Treatment A: Isotretinoin-Lidose (2 × 20 mg) administered after an overnight fast of at least 10 hours.
Treatment B: Isotretinoin-Lidose (2 × 20 mg) 30 minutes after consumption of a modified∗ high-fat, high-calorie breakfast with a reduced vitamin-A content.
Treatment C: Isotretinoin (1 × 40 mg) administered after an overnight fast of at least 10 hours.
Treatment D: Isotretinoin (1 × 40 mg) administered 30 minutes after consumption of a modified∗ high-fat, high-calorie breakfast with a reduced vitamin-A content.
Blood sample collection and handling
Blood samples were collected within 1 minute of their scheduled time at regular intervals from 10 hours before to 72 hours after each drug administration.Analyses for isotretinoin, 4-oxo-isotretinoin, tretinoin, and 4-oxo-tretinoin in human plasma were performed using a validated analytical method with a calibration range of 1.00 to 750 ng/mL (isotretinoin and 4-oxo-isotretinoin) and 1.00 to 250 ng/mL (tretinoin and 4-oxo-tretinoin). All laboratory personnel were blinded regarding the randomization scheme and treatment plan.
Clinical evaluations
Laboratory tests included those for hematology, serum chemistry, urinalysis, HIV, hepatitis B antigen, and hepatitis C for all individuals, and human chorionic gonadotropin pregnancy tests on women who were not postmenopausal and who did not have a hysterectomy. Blood pressure, pulse rate, temperature, and respiration were also measured.A physical examination was performed on all individuals upon study completion or upon removal from the study.
Data analysis
Pharmacokinetic analysis was conducted using a noncompartmental approach.4 The following parameters were estimated: area under plasma concentration versus time curve from time zero (0 hour) to time of last measurable plasma concentration, calculated by linear trapezoidal method (AUCt); area under plasma concentration versus time curve from time zero (0 hour) to infinity (AUCi) (AUCi calculated as sum of AUCt + measured plasma concentration at time of last measurable plasma concentration/apparent first order elimination rate constant); maximum measured plasma concentration over sampling time period (Cmax); and time of maximum measured plasma concentration (Tmax).Statistical analysis was performed to compare the BE of the isotretinoin-Lidose formulation and the isotretinoin formulation under fasting and fed conditions. The pharmacokinetic parameters were statistically analyzed according to current FDA guidance.5
Arithmetic means, SD, and coefficients of variation were calculated. Analyses of variance were performed on the log-transformed AUCt, AUCi, and Cmax and on the untransformed Tmax. A 5% level of significance was used for within-subject comparisons (ie, period, treatment). Each analysis of variance included a calculation of least-squares means, adjusted differences between treatment means, and the SE associated with these differences.
The 90% confidence intervals for the ratio of drug treatment least-squares means were calculated for the AUCt, AUCi, and Cmax parameters using log-transformed data. The confidence intervals are expressed as a percentage relative to the least-squares mean of the isotretinoin formulation.
Results
Patient demographics
A total of 60 healthy individuals (40 male and 20 female) were dosed in period 1. Three individuals did not complete period 2 of the study: 1 withdrew after period 2 check-in for personal reasons, and 2 were dismissed because of nonadherence. The remaining individuals, 57, were dosed in periods 3 and 4 and completed the study. They had a mean ± SD (range) age of 36 ± 9 (21-55) years, height of 169.7 ± 8.7 (150.0-188.0) cm, and weight of 71.5 ± 9.1 (49.8-86.4) kg.Pharmacokinetic analyses
The average of the measured predose concentration levels of isotretinoin, 4-oxo-istoretinoin, tretinoin, and 4-oxo-tretinoin at −10, −2, and 0 hours was used as baseline for each individual, within each period. The subject- and period-specific baseline values were subtracted from the subsequent postdose measured levels. The 0-hour levels of isotretinoin and its metabolites and the negative levels for the baseline-adjusted concentrations were set to 0. The pharmacokinetic analysis was performed on the baseline-adjusted analyte levels.Arithmetic means and geometric means for AUCt, AUCi, Cmax, and Tmax in the 4 dosing periods were calculated for isotretinoin, 4-oxo-isotretinoin, tretinoin, and 4-oxo-isotretinoin, respectively.
Effect of food
The high-fat, high-caloric meal produced the highest observed plasma concentrations of isotretinoin and metabolites for both formulations when compared with the fasting state. Food increased the systemic exposure to isotretinoin to 6695.87 ng•h/mL with the isotretinoin-Lidose formulation and to 6315.15 ng•h/mL with the innovative isotretinoin formulation. The peak exposure to isotretinoin (Cmax) was 434.33 ng/mL for the isotretinoin-Lidose formulation and 431.88 ng/mL for the isotretinoin formulation. Food triggered a similar delay between the 2 formulations in the time to reach Cmax. Time of maximum plasma concentrations reached with food was 6.85 hours for the isotretinoin-Lidose formulation and 6.75 hours for the isotretinoin formulation.Table I. Menu for modified, high-fat, high-calorie breakfast
| Calories | Carbohydrates | Protein | Fat | |
|---|---|---|---|---|
| 1 Regular bagel | 300 | 67 g | 12 g | 3 g |
| 2 T peanut butter | 250 | 9 g | 12 g | 22 g |
| 5 Slices bacon | 125 | 0.2 g | 10 g | 10 g |
| 6 Fluid oz apple juice | 80 | 22 g | 0.1 g | 0.1 g |
| 1 Dutchie donut (square donut containing raisins and coated with sugary glaze from Canadian Tim Hortons chain) | 250 | 33 g | 3 g | 15 g |
| Total | 1005 | 131.2 g | 37.1 g | 50.1 g |
Pharmacokinetic data from the 2 formulations were BE under fed conditions. The 90% confidence interval of the ratios of geometric means of the 2 formulations conducted under fed conditions for AUCt, AUCi, and Cmax were within the 80% to 125% range for isotretinoin, 4-oxoisotretinoin, tretinoin, and 4-oxo-tretinoin. Given these results, isotretinoin-Lidose exhibited equivalent rate and extent of exposure to isotretinoin under high-fat fed conditions in human beings after a single dose.
Effect of fasting
AUCt, AUCi, and Cmax for both formulations were reduced in the absence of food. Significant differences were observed between the 2 formulations in the fasting state. After an overnight fast, the isotretinoin-Lidose formulation delivered approximately twice as much isotretinoin (4470.45 vs 2500.01 ng•h/mL) and 4-oxo-isotretinoin (11,865.08 vs 6049.60 ng•h/mL) as did the isotretinoin formulation. Similar findings were observed for tretinoin and 4-oxo-tretinoin (data not shown), respectively. Mean AUCi plasma levels of isotretinoin from the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with food, and those of the isotretinoin formulation only reached 39.6% of that observed with food.Cmax for isotretinoin was also twice as high with the isotretinoin-Lidose formulation when compared with the isotretinoin formulation: 323.18 versus 161.43 ng•h, respectively. Similar to that observed with AUCi, Cmax for isotretinoin with the isotretinoin-Lidose formulation during fasting represented 74% of the Cmax achieved after a meal and with the isotretinoin formulation, it only represented 37% of the Cmax achieved after a meal. For 4-oxo-isotretinoin, Cmax was 163.73 ng•h after fasting for the isotretinoin-Lidose formulation (46.5% of the Cmax after a meal) and 70.55 ng•h for the isotretinoin formulation (22.7% of the Cmax after a meal).
Mean plasma concentrations of isotretinoin over time
Although both formulations share a similar Tmax for isotretinoin in the fasting state (about half of the Tmax under fed conditions), mean peak plasma concentration of isotretinoin is clearly higher with the isotretinoin-Lidose formulation, reaching 289.49 ng/mL at 3 hours after ingestion versus the isotretinoin formulation, which reached 133.75 ng/mL at 3.5 hours (Fig 1). After reaching peak concentrations, plasma concentrations of isotretinoin declined at approximately the same rate for both formulations; however, overall, isotretinoin levels from the Lidose formulation always remained higher during the clearance phase.
Fig 1.
Mean baseline-adjusted plasma isotretinoin concentration (conc) versus time curves (N = 57).
Mean measured plasma concentrations of 4-oxo-isotretinoin, tretinoin, and 4-oxo-tretinoin over time followed similar kinetics as mean plasma concentrations of isotretinoin (data not shown).
Adverse events
There were 55 adverse events involving 25 individuals during the course of the 4 periods of the study. Headache was the most commonly reported adverse event for all 4 periods. There were no serious adverse events recorded, and none of the adverse events had a significant impact on the safety of the participants or on the integrity of the study results.Discussion
Results from this crossover comparative study demonstrate a BE of the isotretinoin-Lidose formulation and the isotretinoin formulation under fed conditions: AUCt, AUCi, Cmax, and Tmax for the 4 analytes were comparable. As anticipated, a high-fat, high-calorie meal increased the relative BA of both formulations compared with the fasting state and is in agreement with results reported by Colburn et al.1In contrast, striking differences in the BA of isotretinoin were observed between the 2 formulations in the fasting state. Systemic exposure of isotretinoin was 1.8-fold higher with isotretinoin-Lidose than with the isotretinoin formulation. In addition, mean Cmax of isotretinoin in the fasting state was 66.8% of the mean Cmax observed in the fed state with the isotretinoin-Lidose formulation versus 39.6% with the isotretinoin formulation.
More than 75% of individuals in this study absorbed less than 50% isotretinoin when it was taken in a fasting state compared with a high-fat meal (Fig 2). In the case of isotretinoin-Lidose, 75% of individuals absorbed 60% or more isotretinoin in the fasting state compared with taking it with a fatty meal. The box plot analysis (Fig 2) shows the variability of absorption of these formulations. Only 1 individual had a higher ratio of fasting to fed area under the curve (AUC) for isotretinoin and only in a handful of individuals was the isotretinoin-Lidose not more effective than isotretinoin alone.
Fig 2.
Effect of food on absorption. Top and bottom of the box are the 75th and 25th percentiles, respectively, dash line is the median, solid line is the mean, bars are the highest and lowest values of not more than 1.5 times the length of the box, circles are outliers, and x is an extreme outlier (greater than 3 times the intrabox distance). More than 75% of individuals in the fasting state achieved plasma levels less than 50% of that when isotretinoin was taken with food (mean difference 39.6%). In the same individuals, plasma levels with the new formulation reached 66.8% of that found with food. AUC, Area under the curve.
In summary, isotretinoin-Lidose is a novel formulation of isotretinoin that is BE to innovator isotretinoin under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast. The clinical consequences of the decreased variability in absorption between the fed and fasted states with isotretinoin-Lidose will need to be established in future studies.
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