Presented at the Fall Clinical Dermatology Conference, October 17–20, 2019, Las Vegas, NV, USA SYNOPSIS • Lidose-isotretinoin 40 mg, unlike traditional isotretinoin, does not require administration with a high-fat, high-calorie meal to optimize bioavailability and efficacy because it is presolubilized in a lipid matrix1,2 • A novel low-dose Micronized-isotretinoin 32-mg formulation has been developed by adopting an optimized micronization technology that substantially increases the surface area per unit mass of the drug in formulation OBJECTIVES • To evaluate the bioavailability of Micronized-isotretinoin 32 mg compared with Lidose-isotretinoin 40 mg under fed and fasted conditions in healthy participants • To assess the effect of food on the bioavailability of Micronized-isotretinoin 32 mg in healthy participants METHODS • This analysis includes data from 2 open-label, randomized crossover studies in healthy volunteers: the fed bioequivalence and food-effect study and the fasting study • Eligible participants were healthy men (both studies) and women (fed bioequivalence and food-effect study only) ≥18 years of age with body mass index between 18 and 30 kg/m2 – Male participants were required to use a reliable form of contraception throughout the study, and female participants were required to be of nonchildbearing potential (defined as naturally postmenopausal [no menses] for at least 2 years before initial dosing with a documented follicle-stimulating hormone level ≥40 mIU/mL at screening or surgically postmenopausal/sterile [eg, bilateral oophorectomy, tubal ligation, or hysterectomy], with the procedure performed at least 6 months before initial dosing) • Exclusion criteria for both studies included: – History of allergy or sensitivity to retinoids or vitamin A – Significant history or current evidence of chronic infectious disease system disorders or organ dysfunction – History or presence of gastrointestinal disease or inflammatory bowel disease or a history of malabsorption in the previous year – History (personal or family) of psychiatric disorders in the last 2 years requiring treatment or hospitalization – Presence of a medical condition requiring regular treatment with prescription drugs – History of excessive alcohol consumption or any drug or alcohol addiction that required treatment during the previous 12 months Treatments • Fed bioequivalence and food-effect study – Multicenter, 3-treatment, 3-period, 6-sequence crossover study in which participants were randomized to 1 of 6 possible sequences that each included 3 periods of treatment: • Fasted-state Micronized-isotretinoin 32 mg: a single dose of Micronized- isotretinoin 32 mg following an overnight fast (defined as no food or beverage intake other than water) of at least 10 hours • Fed-state Micronized-isotretinoin 32 mg: a single dose of Micronized- isotretinoin 32 mg following a standardized high-fat, high-calorie breakfast (2 fried eggs, 2 strips of bacon, 4 oz of hash browns, 2 slices of buttered toast, and 8 oz of whole milk; this Food and Drug Administration standard meal contained about 150 protein calories, 250 carbohydrate calories, and 500 fat calories) preceded by an overnight fast of at least 10 hours • Fed-state Lidose-isotretinoin 40 mg: a single dose of Lidose-isotretinoin 40 mg following a standardized high-fat, high-calorie breakfast preceded by an overnight fast of at least 10 hours • Fasting study – Single-center, 2-treatment, 2-period, 2-sequence crossover study in which participants were randomized to 1 of 2 possible sequences that each included 2 periods of treatment: • Fasted-state Micronized-isotretinoin 32 mg: a single dose of Micronized- isotretinoin 32 mg following an overnight fast of at least 10 hours • Fasted-state Lidose-isotretinoin 40 mg: a single dose of Lidose-isotretinoin 40 mg following an overnight fast of at least 10 hours • The interval between dosing was 21 days in both studies • Blood samples were collected before dosing to establish endogenous isotretinoin levels and then at intervals over the 96 hours postdosing REFERENCES 1. Colburn W, et al. J Clin Pharmacol. 1983;23:534–539. 2. Webster G, et al. J Am Acad Dermatol. 2013;69:762–767. 3. Roche Laboratories Inc. ACCUTANE® (isotretinoin capsules) PI. November 2008. 4. Sun Pharmaceutical Industries, Inc. ABSORICA® (isotretinoin capsules) PI. August 2018. ACKNOWLEDGMENTS We thank the participants for their involvement in these studies. These studies were funded by Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India. Editorial support was provided by JK Associates, Inc., part of the Fishawack Group of Companies, and was funded by Sun Pharmaceutical Industries, Inc. Statistical support was provided by Novum Pharmaceutical Research Services, Inc., and was funded by Sun Pharmaceutical Industries Ltd. DISCLOSURES SM and SK are employees of Sun Pharmaceutical Industries Ltd. JS is an employee of Sun Pharmaceutical Industries, Inc. Comparative Pharmacokinetic Profiles of a Novel Low-Dose Micronized-Isotretinoin 32-mg Formulation and Lidose-Isotretinoin 40 mg in Fed and Fasted Conditions: 2 Open-label, Randomized Crossover Studies in Healthy Adult Participants Sumit Madan,1 Sudershan Kumar,2 Jeanett Segal3 1Research and Development Centre, Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India; 2Clinical Pharmacology and Pharmacokinetics, Sun Pharmaceutical Industries Ltd, Gurgaon, Haryana, India; 3Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA Endpoints • Fed bioequivalence and food-effect study – Relative bioavailability of Micronized-isotretinoin 32 mg compared with Lidose-isotretinoin 40 mg in the fed state – Effect of food on the bioavailability of Micronized-isotretinoin 32 mg • Fasting study – Relative bioavailability of Micronized-isotretinoin 32 mg compared with Lidose- isotretinoin 40 mg in the fasted state • In both studies, safety was determined by the evaluation of adverse events (AEs) Statistical Analysis • For all treatments, bioavailability was measured using baseline-adjusted log- transformed maximum isotretinoin plasma concentration (LnCmax) and baseline-adjusted log-transformed area under the plasma concentration-time curve from time 0 to last measurable isotretinoin concentration (LnAUC0–t) and from time 0 to infinity (LnAUC0–∞) – For comparison of fed-state Micronized-isotretinoin 32 mg with fed-state Lidose- isotretinoin 40 mg, bioequivalence was determined if the 90% confidence intervals (CIs) on the least squares geometric mean (LSGM) ratios for each parameter fell within the 80.0%–125.0% range – Absorption rate in the fasted state was compared between Micronized- isotretinoin 32 mg and Lidose-isotretinoin 40 mg by post hoc partial area evaluation from dose to Cmax, after Cmax to 12 hours, and from 12 hours to 24 hours • Analysis of variance was performed for both studies, testing 2 1-sided hypotheses at the α=0.05 level of significance using SAS® (SAS Institute Inc., Cary, NC, USA), with the general linear model procedure used for the fasting study and a mixed procedure used for the fed bioequivalence and food-effect study • Data from participants with some missing data were used if pharmacokinetic parameters could be estimated using the remaining data points; otherwise, data from these participants were excluded from the final analysis RESULTS • In the fed bioequivalence and food-effect study, 71 participants enrolled and 65 were included in the analyses – Reasons for discontinuation were voluntary withdrawal (5 participants), positive substance abuse screen (2 participants), noncompliance with breakfast requirements (2 participants), and loss to follow-up (1 participant) • In the fasting study, 18 participants enrolled and all were included in the analyses • Baseline demographics for participants in both studies are presented in Table 1 • 90% CIs for the LSGM ratios for the baseline-adjusted LnAUC0–t (91.9%–98.4%), LnAUC0–∞ (91.5%–98.0%), and LnCmax (96.3%–112.6%) for fed-state Micronized- isotretinoin 32 mg vs fed-state Lidose-isotretinoin 40 mg all fell within the 80.0%–125.0% range for bioequivalence, showing that Micronized-isotretinoin 32 mg is bioequivalent to Lidose-isotretinoin 40 mg under fed conditions (Table 2, Figure 1A) • Baseline-adjusted LSGM ratios for fasted-state Micronized-isotretinoin 32 mg vs fasted-state Lidose-isotretinoin 40 mg show that Micronized-isotretinoin 32 mg had approximately 2 times higher bioavailability than Lidose-isotretinoin 40 mg under fasted conditions (Table 3, Figure 1B) – Partial area evaluation indicates that fasted-state Micronized-isotretinoin 32 mg had higher absorption than fasted-state Lidose-isotretinoin 40 mg in each segment from dose to Cmax (LnAUC0–4 LSGM ratio: 164.8%), after Cmax to 12 hours (LnAUC4–12 LSGM ratio: 206.1%), and from 12 hours to 24 hours (LnAUC12–24 LSGM ratio: 200.3%) • Administering Micronized-isotretinoin 32 mg with a high-fat meal increased LnAUC0–t and LnAUC0–∞ by 24.8% and 23.2%, respectively, compared with administration in the fasted state, but had no effect on LnCmax, indicating that food minimally affects the extent but not the rate of Micronized-isotretinoin 32 mg absorption (Table 4, Figure 1A) • Sixty-eight AEs were reported by 36 of the 71 participants in the fed bioequivalence and food-effect study: 34 occurred after administration of fasted-state Micronized- isotretinoin 32 mg, 16 after fed-state Micronized-isotretinoin 32 mg, and 18 after fed-state Lidose-isotretinoin 40 mg – Headache was the most frequently reported AE, reported by 6, 3, and 2 participants following administration of fasted-state Micronized-isotretinoin 32 mg, fed-state Micronized-isotretinoin 32 mg, and fed-state Lidose-isotretinoin 40 mg, respectively • In the fasting study, 7 AEs were reported by 4 of the 18 participants (3 for fasted-state Micronized-isotretinoin 32 mg and 4 for fasted-state Lidose-isotretinoin 40 mg) – Oropharyngeal pain was the most frequently reported AE, occurring in 1 participant following administration of fasted-state Micronized-isotretinoin 32 mg and 1 participant following administration of fasted-state Lidose-isotretinoin 40 mg • No serious AEs were reported in either study CONCLUSIONS • Micronized-isotretinoin 32 mg is bioequivalent to Lidose-isotretinoin 40 mg under fed conditions and is twice as bioavailable as Lidose-isotretinoin 40 mg under fasted conditions • Food has no effect on the rate and a marginal effect on the extent of Micronized- isotretinoin 32 mg absorption, which is less than the effect on Lidose-isotretinoin 40 mg and other marketed isotretinoin products3,4 Table 1. Baseline Demographics Fed Bioequivalence and Food-Effect Study Fasting Study Fasted-State Micronized- Isotretinoin 32 mg (N=63) Fed-State Micronized- Isotretinoin 32 mg (N=65) Fed-State Lidose- Isotretinoin 40 mg (N=63) Fasted-State Micronized- Isotretinoin 32 mg (N=18) Fasted-State Lidose- Isotretinoin 40 mg (N=18) Sex Male Female 47 (74.6) 16 (25.4) 49 (75.4) 16 (24.6) 47 (74.6) 16 (25.4) 18 (100) 0 18 (100) 0 Race Asian Black White Hispanic Other 2 (3.2) 34 (54.0) 20 (31.8) 4 (6.4) 3 (4.8) 2 (3.1) 35 (53.9) 20 (30.8) 5 (7.7) 3 (4.6) 2 (3.2) 34 (54.0) 19 (30.2) 5 (7.9) 3 (4.8) 0 7 (38.9) 8 (44.4) 2 (11.1) 1 (5.6) 0 7 (38.9) 8 (44.4) 2 (11.1) 1 (5.6) Age, y Mean±SD Median Range 44.2±14.8 38.0 21–68 44.2±14.6 38.0 21–68 44.3±14.4 38.0 21–68 44.1±11.8 43.5 22–62 44.1±11.8 43.5 22–62 Weight, lb Mean±SD Median Range 169.4±27.0 165.0 90–225 169.5±27.2 165.0 90–225 169.9±27.6 166.0 90–225 175.3±28.1 180.5 133–232 175.3±28.1 180.5 133–232 BMI, kg/m2 Mean±SD Median Range 25.5±2.9 26.1 18.2–30.0 25.4±3.0 26.1 18.2–30.0 25.5±3.0 26.1 18.2–30.0 25.5±2.9 24.9 20.4–29.8 25.5±2.9 24.9 20.4–29.8 Tobacco user Yes No 20 (31.8) 43 (68.3) 21 (32.3) 44 (67.7) 20 (31.8) 43 (68.3) 6 (33.3) 12 (66.7) 6 (33.3) 12 (66.7) Data presented as n (%) unless otherwise stated. BMI, body mass index; N, number of participants in the treatment group; n, number of participants of a particular demographic; SD, standard deviation. Table 2. Baseline-Adjusted Plasma Isotretinoin Concentrations for Fed-State Micronized-Isotretinoin 32 mg and Fed-State Lidose-Isotretinoin 40 mg (Fed Bioequivalence and Food-Effect Study) Parameter Treatment Arithmetic Mean±SD (% CV) LSGM Participants Contrasted, na LSGM Ratio (%) 90% Confidence Interval (%) P-Value Sequence AUC0–t (h·ng/mL) Fed-state Micronized-isotretinoin 32 mg 10,209.1±1967.5 (19.3) 9915 61 95.07 91.88–98.36 0.1327 Fed-state Lidose-isotretinoin 40 mg 10,693.0±2247.3 (21.0) 10,430 AUC0–∞ (h·ng/mL) Fed-state Micronized-isotretinoin 32 mg 10,921.9±2176.1 (19.9) 10,654 61 94.71 91.51–98.02 0.1940 Fed-state Lidose-isotretinoin 40 mg 11,676.6±2851.0 (24.4) 11,249 Cmax (ng/mL) Fed-state Micronized-isotretinoin 32 mg 645.7±275.2 (42.6) 596.7 63 104.09 96.27–112.55 0.4744 Fed-state Lidose-isotretinoin 40 mg 595.7±183.8 (30.9) 573.2 aNumber of participants contrasted represents the number of participants who had data for this parameter in each treatment group. AUC0–t, area under the plasma concentration-time curve from time 0 to the last measurable concentration; AUC0–∞, area under the plasma concentration- time curve from time 0 to infinity; Cmax, maximum measured plasma concentration; CV, coefficient of variation; LSGM, least squares geometric mean; SD, standard deviation. Table 3. Baseline-Adjusted Plasma Isotretinoin Concentrations for Fasted-State Micronized-Isotretinoin 32 mg and Fasted-State Lidose-Isotretinoin 40 mg (Fasting Study) Parameter Treatment Arithmetic Mean±SD (% CV) LSGM Participants Contrasted, na LSGM Ratio (%) 90% Confidence Interval (%) P-Value Sequence AUC0–t (h·ng/mL) Fasted-state Micronized-isotretinoin 32 mg 7485.1±1693.9 (22.6) 7289 18 198.62 175.19–225.17 0.9168 Fasted-state Lidose-isotretinoin 40 mg 3833.6±1160.7 (30.3) 3670 AUC0–∞ (h·ng/mL) Fasted-state Micronized-isotretinoin 32 mg 8016.3±1800.4 (22.5) 7807 18 196.33 172.86–222.98 0.7367 Fasted-state Lidose-isotretinoin 40 mg 4164.2±1294.4 (31.1) 3977 Cmax (ng/mL) Fasted-state Micronized-isotretinoin 32 mg 539.0±180.3 (33.5) 507.6 18 219.63 187.26–257.60 0.4234 Fasted-state Lidose-isotretinoin 40 mg 238.2±60.8 (25.5) 231.1 aNumber of participants contrasted represents the number of participants who had data for this parameter in each treatment group. AUC0–t, area under the plasma concentration-time curve from time 0 to the last measurable concentration; AUC0–∞, area under the plasma concentration- time curve from time 0 to infinity; Cmax, maximum measured plasma concentration; CV, coefficient of variation; LSGM, least squares geometric mean; SD, standard deviation. Table 4. Baseline-Adjusted Plasma Isotretinoin Concentrations for Fasted-State Micronized-Isotretinoin 32 mg and Fed-State Micronized-Isotretinoin 32 mg (Fed Bioequivalence and Food-Effect Study) Parameter Treatment Arithmetic Mean±SD (% CV) LSGM Participants Contrasted, na LSGM Ratio (%) 90% Confidence Interval (%) P-Value Sequence AUC0–t (h·ng/mL) Fasted-state Micronized-isotretinoin 32 mg 8466.3±2458.2 (29.0) 8042 63 124.84 117.29–132.88 0.0351 Fed-state Micronized-isotretinoin 32 mg 10,209.1±1967.5 (19.3) 10,039 AUC0–∞ (h·ng/mL) Fasted-state Micronized-isotretinoin 32 mg 9219.1±2782.1 (30.2) 8711 62 123.24 115.93–131.01 0.0600 Fed-state Micronized-isotretinoin 32 mg 10,921.9±2176.1 (19.9) 10,736 Cmax (ng/mL) Fasted-state Micronized-isotretinoin 32 mg 611.3±285.2 (46.6) 539.4 63 108.25 94.42–124.12 0.2908 Fed-state Micronized-isotretinoin 32 mg 645.7±275.2 (42.6) 583.9 aNumber of participants contrasted represents the number of participants who had data for this parameter in each treatment group. AUC0–t, area under the plasma concentration-time curve from time 0 to the last measurable concentration; AUC0–∞, area under the plasma concentration- time curve from time 0 to infinity; Cmax, maximum measured plasma concentration; CV, coefficient of variation; LSGM, least squares geometric mean; SD, standard deviation. Figure 1. Mean Baseline-Adjusted Plasma Isotretinoin Concentration vs Time Curves for (A) Fasted-State Micronized-Isotretinoin 32 mg, Fed-State Micronized-Isotretinoin 32 mg, and Fed-State Lidose-Isotretinoin 40 mg (Fed Bioequivalence and Food-Effect Study) and (B) Fasted- State Micronized-Isotretinoin 32 mg and Fasted-State Lidose-Isotretinoin 40 mg (Fasting Study) C on ce nt ra tio n (n g/ m L) 500 400 300 200 100 0 0 10 20 30 40 50 60 70 80 90 100 Hours After Dosing C on ce nt ra tio n (n g/ m L) 500 400 300 200 100 0 0 10 20 30 40 50 60 70 80 90 100 Hours After Dosing Fasted-state Micronized-isotretinoin 32 mg (N=18) Fasted-state Lidose-isotretinoin 40 mg (N=18) Fasted-state Micronized-isotretinoin 32 mg (N=63) Fed-state Micronized-isotretinoin 32 mg (N=65) Fed-state Lidose-isotretinoin 40 mg (N=63) A B