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Fixed-dose combination of ibuprofen acid 400 mg and caffeine 100 mg film-coated tablet 1 of 10 2. SYNOPSIS Title of Trial: Principal/Coordinating Investigator: Trial Sites: Publications: Clinical Phase: Objectives: Methodology: A single center, single dose, open label, randomized, two period, two sequence Crossover Study to evaluate the relative Bioavailability of Ibuprofen from a Fixed Dose Combination Tablet containing Ibuprofen 400 mg and Caffeine 100 mg, and a tablet of Ibuprofen 400 mg in at least 30 healthy males and females under fed conditions Dr (South Africa) Phase I (Relative Bioavailability Study) The objective of this study was to evaluate the relative bioavailability of a fixed dose combination (FDC) of 400 mg ibuprofen acid and 100 mg caffeine tablets, and the reference product Dolormin Extra 400 mg film coated tablets, following oral administration in a clinical phase I study. For this purpose the rate and extent of absorption of S-ibuprofen, R-ibuprofen and ibuprofen (the sum of the enantiomers) were evaluated after administration of a single dose FDC of 400 mg ibuprofen acid and 100 mg caffeine, and 684 mg ibuprofen lysinate (equivalent to 400 mg ibuprofen), under fed conditions. The effect of the caffeine on the S- and R-ibuprofen was explored. For this purpose, the caffeine levels in the FDC were measured. Furthermore, the effect of caffeine on the changes of endogenous epinephrine and norepinephrine plasma levels was investigated. The study comprised: Screening period of maximum 21 days; Two treatment periods (each of which included a profile period of 24 hours) separated by a wash-out period of at least 6 calendar days between consecutive administrations of the investigational medicinal product (IMP), and A follow-up visit 72 hours after completion of the last treatment period of the study. Subjects were assigned randomly to treatment sequence, before the first
2 of 10 No. of Subjects: administration of IMP. Planned: Entered: 36 Actual: Enrolled: 36 Entered: 36 Fixed-dose combination of ibuprofen acid 400 mg and caffeine 100 mg film-coated tablet Entered: 36 Treated: 36 Analysed (for primary endpoint): 26 Dolormin Extra, 400 mg film-coated tablet Entered: 36 Treated: 36 Analysed (for primary endpoint): 26 Diagnosis: Main Criteria for Inclusion: Persons who met the inclusion criteria were considered eligible to participate in the study. Inclusion Criteria: 1. Healthy males and females, 18 to 50 years (inclusive) at time of screening. 2. Body Mass Index (BMI) between 18.5 and 29.9 kg/m 2 (inclusive). 3. Body mass not less than 50 kg. 4. Medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations had to be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests, unless the Principal Investigator (PI) considered the deviation to be irrelevant for the purpose of the study. 5. Non-smokers. 6. Females, if: Not of childbearing potential, e.g., had been surgically sterilized, undergone a hysterectomy, amenorrhea for 12 months and were considered post-menopausal. Note: In post-menopausal women, the value of the serum pregnancy test could be increased slightly. This test was to be repeated to confirm the results. If there was no increase indicative of pregnancy, the female was included in the study.
3 of 10 Of childbearing potential, the following conditions were to be met: Negative pregnancy test If this test was positive, the subject was excluded from the study. In the rare circumstance that a pregnancy was discovered after the subject received the IMP; every attempt was to be made to follow her to term. Not lactating Abstaining from sexual activity (if this was the usual lifestyle of the subject) or had to agree to use an accepted method of contraception, and had to agree to continue with the same method throughout the study. In this study the concomitant use of hormonal contraceptives was allowed. Examples of reliable methods of contraception included oral (documented that the dose had been stable for at least one month before the first intake of the IMP), injectable or implantable contraceptives, non-hormonal/hormonal intrauterine device, and barrier methods combined with an additional contraceptive method. Other methods, if considered by the PI as reliable, were accepted. 7. Written consent given for participation in the study. 8. Subjects had to be willing to consume the meal prescribed with administration of the IMP in full and within the required time. Dose: Mode of Admin.:, FDC of 400 mg ibuprofen acid and 100 mg caffeine film-coated tablets Single dose (1 tablet) of 400 mg ibuprofen acid and 100 mg caffeine under fed conditions Oral Batch No.: B151002036 / 319740
4 of 10 Comparator Product: Dose: Mode of Admin.: Batch No.: Duration of Treatment: Criteria for Evaluation: Clinical Pharmacology: Safety: Ibuprofen lysinate, Dolormin Extra (ibuprofen lysinate), film-coated tablets Single dose (1 tablet) of 400 mg ibuprofen (equivalent to 684 mg ibuprofen lysinate) under fed conditions Oral B151001647 / EJL7U00 A single dose of either the test or the reference product in each of the two treatment periods with a PK profile period of 24 hours for each treatment period. Pharmacokinetic (PK) Endpoints Primary Pharmacokinetic Endpoints for S-ibuprofen, R-ibuprofen and Ibuprofen: Maximum observed plasma concentration (C max ) obtained directly from the concentration-time data Area under the plasma concentration versus time curve, from time zero to t, where t was the time of the last quantifiable concentration (AUC 0-t ) Secondary Pharmacokinetic Endpoints for S-ibuprofen, R-ibuprofen and Ibuprofen: Area under the plasma concentration versus time curve, with extrapolation to infinity (AUC 0- ) In addition to the PK parameters mentioned above, S/R-ibuprofen ratios for AUC 0-t (i.e. AUC 0-t S-ibuprofen / AUC 0-t R-ibuprofen) were calculated for each treatment arm. Further PK endpoints could have been calculated as appropriate. Caffeine: Maximum observed plasma concentration (C max ) Area under the plasma concentration versus time curve, from time zero to t, where t was the time of the last quantifiable concentration (AUC 0-t ) Time to maximum observed plasma concentration (t max ) Further endpoints could have been calculated as appropriate. Safety variables (other endpoints) included vital signs, physical examination, 12-lead ECG, hematology, clinical chemistry, urinalysis, PFA 100 and
5 of 10 Statistical Methods: SUMMARY - CONCLUSIONS: Trial Subjects and Compliance with Trial Protocol: pregnancy test results. Adverse events (AEs) and concomitant medication were also reported. All subjects randomized to a treatment sequence formed part of the randomized population. All subjects who completed the PK sampling in both periods and with no major protocol deviations considered to impact on the analysis of the PK data were included in the statistical analysis and formed part of the pharmacokinetic population. The PD population included all subjects who received at least 1 dose of the IMP and who had at least the baseline (2 hours pre-dose) and one post-dose measurement available for endogenous plasma epinephrine and norepinephrine and with no major protocol deviations considered to impact on the analysis of the PD data. The PK and PD population were determined at a data review meeting (DRM) held prior to the database lock. Relative bioavailability was estimated by the ratios of the geometric means (test/reference [T/R]) for the primary and secondary endpoints for S-ibuprofen, R-ibuprofen and ibuprofen. Additionally, their two sided 90% confidence intervals (CIs) were provided. The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including fixed effects for sequence, subject nested within sequence, period and product. For each endpoint, the difference between the expected means for the natural log(t)-log(r) was estimated by the difference in the corresponding adjusted means (Least Squares Means). Confidence intervals were calculated based on the residual error from the ANOVA. The differences between the test and reference product and the CIs were back transformed to the original scale, resulting in point estimates of the T/R gmean ratios and 90% CIs. All subjects who received at least one dose of the IMP were included in the safety population applicable to the safety analysis for the study. All baseline data, demographic and anthropometric data were presented using the safety population. A total of 36 subjects (17 [47.22%] caucasian subjects, 2 [5.56%] colored [mixed race] subjects and 17 [47.22%] black subjects) were included in the trial.
6 of 10 The mean age was 28.0 ±7.33 years and ranged from 20 to 46 years across treatment groups. The mean body mass was 70.356 ±10.162 kg and the mean BMI was 24.10±3.109 kg/m 2. A total of 25 (69.44%) subjects were males and 11 (30.56%) subjects were females. The trial protocol was adhered to, except for the following deviations: Minor PK blood sampling time window Five (5) subjects had PK blood sampling time deviations that fell outside the pre-defined tolerance window at 6 time points. Actual blood sampling times were used in the analysis. Posture control All subjects (36) had deviations regarding posture control on Day 1 of both treatment periods. The posture control procedures were not performed as proposed in the protocol, i.e., sitting upright for 20 minutes and lying on the right side for the remainder of the first hour (40 minutes). The reason being that the schedule of assessments required that safety procedures (ECG and vital signs) be assessed in the supine position within the first hour. Change in posture was, however, the same for all subjects in both periods. Post-study visit The post-study visit for one subject was not done within 72 hours after completion of Treatment Period 2. Major Non-compliance with caffeine intake restrictions Ten (10) subjects (Subjects and ) had deviations regarding caffeine intake restrictions. The study protocol included a restriction of caffeine for 24 hours prior to dosing, but there was evidence in the pre-dose plasma samples of 27 subjects of caffeine intake suggesting non-compliance with this dietary restriction. These 10 subjects were identified as having pre-dose caffeine concentrations in the test and/or reference arm that were > 10% of the observed Cmax in the test arm. Given the aim of this study, it was agreed at the Data Review Meeting (DRM) that this was considered a major protocol deviation that could impact the PK analysis. In the opinion of the investigator, these deviations did not impact the integrity of the data
7 of 10 Clinical Pharmacology Results: Pharmacokinetic profiles were available for 36 subjects. Subjects with pre-dose caffeine levels (either in test or reference treatment) greater than 10% of the observed caffeine C max in the test treatment were excluded from the PK population. This was the case for 10 subjects (Subjects ). The PK population included analysis for 26 subjects and the safety population included analysis of all 36 subjects. The table of results for primary and secondary PK endpoints regarding plasma S-ibuprofen, R ibuprofen and Ibuprofen includes descriptive statistics and relative bioavailability ratios for single orally administered Ibuprofen + 100 mg Caffeine FDC tablet (T) as compared with single orally administered 400 mg Dolormin tablet (R) (Pharmacokinetic Population) PK Parameter (unit) S-ibuprofen C max (ng/ml) AUC 0-t (h ng/ml) AUC 0- N 26 26 26 (h ng/ml) R-ibuprofen C max (ng/ml) 26 AUC 0-t (h ng/ml) 26 AUC 0- (h ng/ml) 26 Ibuprofen C max (ng/ml) 26 gmean (gcv%) * 90% Test Reference % Ratio ** Confidence product product (Test/Reference) interval of ratio 14967.2 (34.9) 63150 (21.7) 64990 (20.6) 11454.6 (26.6) 41200 (15.9) 41960 (16.3) 26309.5 (30.3) 13268.7 (38.0) 65110 (21.9) 68900 (17.2) 10495.7 (32.7) 42480 (19.0) 43910 (17.2) 23557.9 (34.8) 113.77 97.36 96.47 110.16 97.55 97.21 112.69 98.99 ; 130.75 94.61 ; 100.19 93.74 ; 99.28 96.32 ; 125.97 92.57 ; 102.80 92.22 ; 102.46 98.49 ; 128.94 Intra CV (%) 29.9 6.0 5.9 28.8 11.1 10.8 28.9
8 of 10 AUC 0-t 105300 26 (h ng/ml) (16.9) AUC 0-107300 26 (h ng/ml) (16.4) S-ibuprofen / R-ibuprofen AUC 0-t 1.533 (h ng/ml) 26 (20.1) 108400 (18.4) 113200 (14.6) 1.534 (19.7) 97.57 96.83 99.81 94.50 ; 100.73 93.75 ; 100.01 95.17 ; 104.68 6.7 6.6 10.0 * geometric mean (geometric CV [%]) ** bioavailability ratio calculation used geometric means based on ANOVA least squares means For S-ibuprofen, the point estimates of the "test/reference" geometric mean ratios for the PK parameters C max, AUC 0-t and AUC (0-) were 113.77%, 97.36% and 96.47%, respectively. The 90% CIs for the "test/reference" geometric mean ratios for the PK parameters C max, AUC 0-t and AUC (0-) for S-ibuprofen were 98.99% to 130.75%, 94.61% to 100.19% and 93.74% to 99.28%, respectively. For R-ibuprofen, the point estimates of the "test/reference" geometric mean ratios for the PK parameters C max, AUC 0-t and AUC 0- were 110.16%, 97.55% and 97.21%, respectively. The 90% CIs for the "test/reference" geometric mean ratios for the PK parameters C max, AUC 0-t and AUC 0- for R- ibuprofen were 96.32% to 125.97%, 92.57% to 102.80% and 92.22% to 102.46%, respectively. For ibuprofen, the point estimates of the "test/reference" geometric mean ratios for the PK parameters C max, AUC 0-t and AUC 0- for ibuprofen were 112.69%, 97.57% and 96.83%, respectively. The 90% CIs for the "test/reference" geometric mean ratios for the PK parameters C max, AUC 0-t and AUC 0- for ibuprofen were 98.49% to 128.94%, 94.50% to 100.73% and 93.75% to 100.01%, respectively. The S-ibuprofen/R-ibuprofen ratio of AUC 0-t was the same for both products, with adjusted gmean values of 1.5 for both products. As such, the point estimate of the "test/reference" geometric mean ratio was 99.81% and the 90% CIs for the "test/reference" geometric mean ratio were 95.17% to 104.68%.
9 of 10 The statistical evaluation of ibuprofen PK parameters based on the safety population (i.e. including the subjects with relatively high caffeine pre-dose levels) showed very similar results as observed based on the PK population. The AUC comparisons showed almost identical point estimates of the test vs reference ratios. The small difference in C max between the FDC and ibuprofen lysinate was slightly more pronounced compared to the PK population (test vs reference ratio for S-ibuprofen of 117% based on safety population and 114% based on PK population). After administration of the FDC product, caffeine was rapidly absorbed, with a median T max of 1.13 h (range of 0.25-5.00 hours) and a peak (C max ) exposure of 2.1047 µg/ml. The geometric mean of caffeine for AUC 0-t was 17.09 μg h/ml and for AUC 0- was 18.55 μg h/ml. Individual caffeine elimination half-lives ranged between 3.3 and 12.8 h. Geometric mean values were 5.8 h (PK population) and 6.1 h (safety population). Safety Results: Results of the effect of caffeine on the changes of endogenous epinephrine and norepinephrine plasma levels after administration of the test product are not included in this clinical trial report, and will be reported separately Five TEAEs were reported by four subjects. Three subjects in the test arm reported three on treatment TEAEs (of which one event [tiredness] was considered related). Two subjects in the reference arm reported two TEAEs (both considered unrelated). All TEAEs were of mild intensity. No post treatment TEAEs were reported. No serious TEAEs were reported and no deaths occurred during the study. Most hematology, clinical chemistry, renal function and platelet function evaluations at screening were within the laboratory reference ranges. Out of range evaluations at screening were considered acceptable (not clinically significant) by the investigator. At post-study, out of range evaluations were repeated until they returned to normal or were considered acceptable (abnormal not clinically significant) by the investigator. No abnormal laboratory findings were reported as AEs. Urinalysis investigations at screening were normal/negative and considered acceptable (abnormal/positive not clinically significant). All subjects had non-reactive serology results. All urine screens for drugs of abuse were negative. All
10 of 10 Conclusions: subjects had negative alcohol breath tests during the study. Pregnancy tests were negative at all time points. For the test and reference for collagen/adenosine diphosphate (COL/ADP) and collagen/epinephrine (COL/EPI), increase in values were observed at 12 hours compared to baseline, and at 24 hours decreased counts from baseline were observed. No deviating COL/Epi values were observed in samples of slow-metabolizers. Overall, pulse and blood pressure remained essentially unchanged throughout the study, and there were no notable differences or trends observed between the test and reference arms. Seventeen (17) subjects had NCS ECG abnormalities in the test arm and 16 subjects had NCS ECG abnormalities in the reference arm. The number of subjects with post-dose abnormal NCS ECG findings were essentially the same between the test and reference arms. Under fed conditions, S-ibuprofen (the enantiomer responsible for the analgesic effect) as well as total ibuprofen (sum of S-ibuprofen and R- ibuprofen) exposure for the ibuprofen/caffeine FDC was equivalent to ibuprofen lysinate. Thus, the result from the fasted trial 1335.2, that caffeine does not influence ibuprofen exposure in the FDC, has been confirmed by chiral measurements as well. Ibuprofen C max was slightly higher for the FDC compared to ibuprofen lysinate. The absolute C max values observed in the current trial were lower compared to the values previously observed under fasted conditions. Therefore, the slightly higher C max observed for the FDC compared to ibuprofen lysinate in the current trial was not considered relevant from safety and tolerability perspective. In general, a single oral dose combination of ibuprofen acid 400 mg and caffeine 100 mg film-coated tablets was well tolerated by healthy subjects in this study. No serious TEAEs, other significant AEs or deaths occurred during the study. All AEs were of mild intensity. Of all reported AEs, 1 event (tiredness) was considered related to the test product. The PFA-100 test gave no indication, that the combination of ibuprofen and caffeine has an influence on platelet aggregation.