The interaction between statins and omega-3 fatty acids remains controversial. The aim of this phase 1 trial was to evaluate the pharmacokinetics of drug-drug interaction between atorvastatin and omega-3 fatty acids. Treatments were once-daily oral administrations of omega-3 (4 g), atorvastatin (40 mg), and both for 14 days, 7 days, and 14 days, respectively, with washout periods. The concentrations of atorvastatin, 2-OH-atorvastatin, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were determined with LC-MS/MS. Parameters of DHA and EPA were analyzed after baseline correction. A total of 37 subjects completed the study without any major violations. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the co-administration of a single drug for the area under the concentration–time curve during the dosing interval at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.042 (0.971–1.118), 1.185 (1.113–1.262), 0.157 (0.091–0.271), and 0.557 (0.396–0.784), respectively. The GMRs (90% Cis) for the co-administration at steady state of atorvastatin, 2-OH-atorvastatin, DHA, and EPA were 1.150 (0.990–1.335), 1.301 (1.2707–1.1401), 0.320 (0.243–0.422), and 0.589 (0.487–0.712), respectively. The 90% CIs for most primary endpoints were outside the range of typical bioequivalence, indicating a pharmacokinetic interaction between atorvastatin and omega-3.

Introduction Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. Methods A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (C_max) and area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration (AUC_last) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CV_wr) of C_max was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. Results The GMRs (90% CIs) for the AUC_last for candesartan and amlodipine were 0.9612 (0.9158–1.0089)/0.9965 (0.9550–1.0397) and 1.0033 (0.9800–1.0271)/1.0067 (0.9798–1.0344), and the GMRs (90% CIs) for C_max were 0.9600 (0.8953–1.0294)/0.9851 (0.9368–1.0359) and 1.0198 (0.9950–1.0453)/1.0003 (0.9694–1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CV_wr of the C_max of atorvastatin were 0.7814–1.2797 and 0.7415–1.3485, respectively. The GMRs (90% CIs) for the AUC_last of atorvastatin were 1.0532 (1.0082–1.1003)/1.0252 (0.9841–1.0680), and the GMRs (90% CIs) for C_max were 1.0630 (0.9418–1.1997)/0.9888 (0.8792–1.1120) in studies 1 and 2, respectively. Conclusion The C_max and AUC_last values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. Trial Registration ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.

Seo YB, et al. Transl Clin Pharmacol. 2023 Jun;31(2):95-104. https://doi.org/10.12793/tcp.2023.31.e7

Kim JH, et al. Transl Clin Pharmacol. 2021 Mar;29(1):65-72. https://doi.org/10.12793/tcp.2021.29.e6

CT‐P13, a biosimilar of infliximab, is used to treat inflammatory diseases that arise from immune system complications, resulting in excessive and persistent inflammation. The subcutaneous (SC) formulation of CT‐P13 overcomes the drawback of prolonged administration associated with the intravenous (IV) infliximab biosimilar, necessitating autoinjector (AI) administration. This randomized, open‐label, two‐arm, parallel‐group, single‐dose clinical pharmacology study aimed to evaluate the pharmacokinetics (PK) and safety of CT‐P13 SC administration via AI compared with the existing pre‐filled syringe (PFS) method. A total of 147 healthy participants were randomized into two groups, of which 139 completed the study. Blood samples were collected from before CT‐P13 SC administration to 2016 h after the start of the administration. Serum concentrations were analyzed using the Meso Scale Discovery electrochemiluminescence method. Geometric mean ratios (90% confidence interval) of the AUC_inf (areas under the concentration–time curve from zero to infinity) and C_max (The maximum serum concentration) for CT‐P13 SC AI versus CT‐P13 SC PFS groups, were 94.15% (85.02%–104.26%), 92.48% (84.66%–101.01%), respectively. CT‐P13 SC AI and CT‐P13 SC PFS achieved comparable PK because the 90% CI was within the predefined equivalence margin. At the end of the study, immunogenicity results revealed that 70 (97.22%) and 73 (98.65%) participants tested positive for anti‐drug antibody (ADA) in the CT‐P13 SC AI and CT‐P13 SC PFS groups, respectively. They were tested positive for neutralizing antibodies. No other significant safety differences were observed between the treatment groups. In conclusion, both administrations demonstrated PK equivalence and were both safe and well‐tolerated.