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Purpose Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. Methods Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. Results Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51–130 %) and 55 % (26–91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25–88 %) and 69 % (37–108 %) higher for atorvastatin, 23 % (0–52 %) and 12 % (−0.9–39 %) higher for simvastatin and 28 % (5–56 %) and 34 % (10–64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2 , area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. Conclusion Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

This study aimed to compare the pharmacokinetic (PK) profiles of a fixed-dose combination (FDC) tablet of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg and a loose-dose combination (LDC) of two FDC tablets, ezetimibe/rosuvastatin 10/20 mg and telmisartan/amlodipine 80/5 mg, in healthy Korean male subjects. This study was conducted as a randomized, open-label, two-sequence, four-period crossover study. The subjects received the FDC or the LDC of telmisartan, rosuvastatin, ezetimibe, and amlodipine twice, with a 21-day washout in each period. Each sequence was composed of either FDC/LDC/FDC/LDC or LDC/FDC/LDC/FDC in that order. Serial blood samples for PK analysis were collected up to 48 h after rosuvastatin dosing and 72 h after telmisartan, ezetimibe, and amlodipine dosing. The PK parameters were calculated by a noncompartmental method, and safety profiles were evaluated throughout the study. Fifty-four healthy Korean male subjects were enrolled, and 42 subjects completed the study. The concentration‒time profiles of telmisartan, rosuvastatin, ezetimibe, and amlodipine were similar between the FDC and LDC groups. For each compound, the geometric mean ratios (90% confidence intervals) of the peak concentration and area under the plasma concentration‒time curve of FDC to LDC were within the conventional bioequivalence criteria of 0.8–1.25. Both the FDC and LDC treatments were well tolerated and determined to be safe. The FDC and LDC treatments with telmisartan, rosuvastatin, ezetimibe, and amlodipine showed pharmacokinetic bioequivalence, indicating that the FDC of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg can be used as an alternative to the LDC treatment.

Purpose Systemic exposure to rosuvastatin in Asian subjects living in Japan or Singapore is approximately twice that observed in Caucasian subjects in Western countries or in Singapore. This study was conducted to determine whether pharmacokinetic differences exist among the most populous Asian subgroups and Caucasian subjects in the USA. Method Rosuvastatin pharmacokinetics was studied in Chinese, Filipino, Asian-Indian, Korean, Vietnamese, Japanese and Caucasian subjects residing in California. Plasma concentrations of rosuvastatin and metabolites after a single 20-mg dose were determined by mass spectrometric detection. The influence of polymorphisms in SLCO1B1 (T521>C [Val174Ala] and A388>G [Asn130Asp]) and in ABCG2 (C421>A [Gln141Lys]) on exposure to rosuvastatin was also assessed. Results The average rosuvastatin area under the curve from time zero to time of last quantifiable concentration was between 64 and 84 % higher, and maximum drug concentration was between 70 and 98 % higher in East Asian subgroups compared with Caucasians. Data for Asian-Indians was intermediate to these two ethnic groups at 26 and 29 %, respectively. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin lactone were observed. Rosuvastatin exposure was higher in subjects carrying the SLCO1B1 521C allele compared with that in non-carriers of this allele. Similarly, exposure was higher in subjects carrying the ABCG2 421A allele compared with that in non-carriers. Conclusion Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.

Combination therapy with rosuvastatin and ezetimibe is generally administered to patients with high cardiovascular risk. The objective of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the interaction between rosuvastatin and ezetimibe that incorporates enterohepatic recirculation (EHC). Concentration-time data were obtained from a two-part, open-label, multiple-dose crossover, drug interaction study. In total, 50 healthy male subjects received both monotherapy and co-therapy (Part A: rosuvastatin and co-therapy; Part B: ezetimibe and co-therapy). Rosuvastatin (20 mg) or ezetimibe (10 mg) were administered once daily for 7 days as monotherapy or co-therapy. Plasma concentrations were measured for PK analysis until 72 h post-dose at steady state. The changes in low-density lipoprotein cholesterol (LDL-C) levels from baseline to steady state at 24 h after the last administration were measured. A population PK/PD model incorporating EHC was developed using Monolix 2024R1. Covariate effects were explored, and the final model was evaluated through goodness-of-fit diagnostics and visual predictive checks. Model-based simulations were conducted to compare the LDL-C lowering effects of monotherapy and co-therapy. A population PK/PD model was established using a two-compartment model for rosuvastatin and a four-compartment model for ezetimibe incorporating EHC via intermittent gallbladder emptying. No significant PK interaction was observed. An indirect response PD model reflected the independent LDL-C lowering effects of both drugs. Simulations showed LDL-C reductions of -51.0% (rosuvastatin), -25.3% (ezetimibe), and -60.7% (co-therapy), supporting the additive efficacy of co-therapy. EHC increased the exposure of total ezetimibe with limited LDL-C lowering effects. The overall PK interaction between rosuvastatin and total ezetimibe was not significant. The developed PK/PD model incorporating EHC successfully described the independent LDL-C lowering effects. These findings support the additive benefit of co-therapy of rosuvastatin and ezetimibe and may guide future research toward personalized lipid-lowering strategies.

Background and Objective This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets. Methods A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared. Results The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration ( C max ) and area under the curve (AUC) of FDCP to individual tablets were within 0.8–1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported. Conclusion This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated. Clinical Trial Registration This trial (NCT04322266) was retrospectively registered on 9 September 2019.

PurposeCefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters.MethodsDDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates.ResultsRatios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71–1.42) and 0.92 (0.73–1.16) for furosemide, 1.09 (0.92–1.28) and 1.03 (0.93–1.15) for metformin, and 1.28 (1.12–1.46) and 1.21 (1.08–1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated.ConclusionsCefiderocol has no clinically significant DDI potential via drug transporters.

Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.

A fixed-dose combination (FDC) of candesartan cilexetil, hydrochlorothiazide and rosuvastatin (CC/HCTZ/RSV) has been developed to enhance patient compliance in the primary prevention of cardiovascular diseases. To evaluate if the combination of the product components in the new FDC capsule formulation affects their respective pharmacokinetic and in vitro dissolution patterns. In vitro dissolution profiles were compared in USP-43 and in biorelevant dissolution media. In vivo comparisons were obtained in a randomized, open-label, single-dose, two-treatment, two-way crossover study in 24 healthy subjects. During each treatment period, subjects received the test formulation (FDC hard capsule containing CC/HCTZ/RSV) or the reference formulation (co-administration of a FDC CC/HCTZ tablet and a RSV tablet). Plasma samples were collected periodically over 48 hours post-dose. Safety and tolerability were assessed. Dissolution profiles of all active drugs in the Test (capsule) and Reference Products (as tablets) were within the tolerance dissolution criteria of USP-43 conditions. HCTZ dissolution profiles were closely similar whereas those for RSV and CC did not match at specific pHs. In the pharmacokinetic study, the 90% confidence intervals (CIs) for the geometric least-square mean ratios of C , AUC , and AUC were 0.95 - 1.18, 0.95 - 1.15 and 0.95 - 1.13 (CC); 0.91 - 1.10, 0.96 - 1.08, and 0.96 - 1.09 (HCTZ) and 0.82 - 1.23, 0.81 - 1.13, and 0.82 - 1.12 (RSV), respectively. All adverse events were mild. The new FDC product (Sinlip Prevent), a stable FDC hard capsule, was bioequivalent (similar pharmacokinetics) when compared to the co-administration of the components and may be considered as a suitable and simplified medication for cardiovascular disease management.

Background Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours. Methods This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day ×2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated. Results All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin. Conclusions The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.