Pharmacokinetics Of Rosuvastatin Research Articles

Clinical Assessment of Breast Cancer Resistance Protein (BCRP)-Mediated Drug-Drug Interactions of Sepiapterin with Curcumin and Rosuvastatin in Healthy Volunteers.

Sepiapterin, also known as PTC923 and CNSA-001, is a synthetic form of endogenous sepiapterin being developed as a novel oral treatment for phenylketonuria. Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4) and, when orally administered, is converted to BH4 via the pterin salvage pathway. In vitro studies have demonstrated that both sepiapterin and BH4 are both substrates and inhibitors of the breast cancer resistance protein (BCRP) transporter. This phase I study investigated BCRP-mediated drug-drug interactions of sepiapterin as a victim and as a perpetrator. An open-label, fixed-sequence, four-period, crossover, single-dose study was conducted in adult male and female healthy volunteers (18-55 years of age). In a given treatment period, subjects received a single oral dose of sepiapterin (20 mg/kg), sepiapterin (20 mg/kg) plus curcumin (2 g), rosuvastatin (10 mg), or rosuvastatin (10 mg) plus sepiapterin (60 mg/kg). The pharmacokinetics of sepiapterin, its metabolite BH4, and rosuvastatin were studied, and geometric mean ratios of exposures in the presence and absence of the BCRP inhibitor curcumin or sepiapterin were estimated. The presence of the BCRP c.421C>A polymorphism was evaluated in all subjects. A total of 29 subjects were enrolled and included in the safety analysis. Among them, 26 subjects were included in the pharmacokinetic and drug-drug interaction analyses. Following oral administration20 mg/kg sepiapterin, sepiapterin was rapidly and extensively converted to BH4, and BH4 maximum observed concentration (415.0 ng/mL) was observed 4.95 h (time to maximum observed concentration) post-dose. Sepiapterin maximum observed concentration and area under the concentration-time curve from time 0 to time of the last quantifiable measurement or the last sample collection time (AUClast) were <1% of BH4 values. Coadministration of the BCRP inhibitor curcumin (2 g) increased BH4 maximum observed concentration, AUClast, and area under the concentration-time curve from time 0 extrapolated to infinity by 24%, 21%, and 20%, respectively. When sepiapterin was coadministered with the BCRP substrate rosuvastatin, there was no effect on the pharmacokinetics of rosuvastatin. BCRP c.421C/A carriers (n = 4) had higher plasma exposures of BH4 (1.39 × for AUClast) and rosuvastatin (1.61 × for AUClast) than c.421C/C carriers (n = 22). Greater increases in BH4 exposures (1.33 vs 1.18 for AUClast) were observed in c.421C/A carriers compared with c.421C/C carriers when sepiapterin was coadministered with curcumin. All treatments were well tolerated during the study. Oral coadministration of the BCRP inhibitor curcumin slightly increased the plasma exposure of sepiapterin and its metabolite BH4 in healthy volunteers. This modest increase was deemed not clinically meaningful. Sepiapterin did not alter the pharmacokinetics of the BCRP substrate rosuvastatin.

Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin.

Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population. We assessed exposure changes (area under the concentration-time curve (AUC∞) and maximum concentration (Cmax)) of a single dose of 10 mg atorvastatin and 10 mg rosuvastatin before and on the fifth day of ritonavir treatment (2 × 100 mg/day) in healthy volunteers and developed a semi-mechanistic pharmacokinetic model to estimate dose adjustment of atorvastatin during ritonavir treatment. By the fifth day of ritonavir treatment, the AUC∞ of atorvastatin increased 4.76-fold and Cmax 3.78-fold, and concurrently, the concentration of atorvastatin metabolites decreased to values below the lower limit of quantification. Pharmacokinetic modelling indicated that a stepwise reduction in atorvastatin dose during ritonavir treatment with a stepwise increase up to 4 days after ritonavir discontinuation can keep atorvastatin exposure within safe and effective margins. Rosuvastatin pharmacokinetics were only mildly modified; ritonavir significantly increased the Cmax 1.94-fold, while AUC∞ was unchanged. Atorvastatin doses should likely be adjusted during nirmatrelvir/ritonavir treatment. For patients on a 20-mg dose, we recommend half of the original dose. In patients taking 40 mg or more, a quarter of the dose should be taken until 2 days after discontinuation of nirmatrelvir/ritonavir. Patients receiving rosuvastatin do not need to change their treatment regimen. EudraCT number: 2021-006634-39. DRKS00027838.

Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects.

The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. NCT05480475; date of registration: 29 July, 2022.

Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity

PurposeRitlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers.MethodsIn vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively.ResultsIn vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration.ConclusionRitlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

Two curcumin analogs inhibited the function and protein expression of breast cancer resistance protein: in vitro and in vivo studies

1. Two curcumin analogs, (1E,6E)-1,7-bis(3,5-diethyl-4-hydroxyphenyl)hepta-1,6-diene-3,5- dione (N17) and its prodrug ((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2,6-diethyl-4,1- phenylene)bis(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate) (N17′), were evaluated as breast cancer resistance protein (BCRP) inhibitors. 2. MDCKII-BCRP and MDCKII-WT were used to evaluate the modulation effects of N17 and N17′ on BCRP and to explore the relevant mechanism. Sprague-Dawley rats were orally administered rosuvastatin (ROS), a probe substrate of BCRP, without and with N17′ (100 mg/kg) to investigate the effect of N17′ on ROS pharmacokinetics. 3. In cell studies, N17 and N17′ were substrates of BCRP, and they decreased the activity and protein expression of BCRP. In rat study, N17′ increased the systemic exposure of ROS by 218% (p = 0.058). 4. N17 and N17′ are potential BCRP inhibitors and will be promising candidates for overcoming the BCRP-mediated multidrug resistance.

Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance.

Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

Clinical Drug-Drug Interaction Between Vatiquinone, a 15-Lipoxygenase Inhibitor, and Rosuvastatin, a Breast Cancer Resistance Protein Substrate.

Vatiquinone is a small-molecule inhibitor of 15-lipoxygenase in phase 3 development for patients with mitochondrial disease and Friedreich ataxia. The objective of this analysis was to determine the effect of vatiquinone on the pharmacokinetic profile of rosuvastatin, a breast cancer resistance protein substrate. In vitro investigations demonstrated potential inhibition of BCRP by vatiquinone (half maximal inhibitory concentration, 3.8 µM). An open-label, fixed-sequence drug-drug interaction study in healthy volunteers was conducted to determine the clinical relevance of this finding. Subjects received a single dose of 20-mg rosuvastatin followed by a 7-day washout. On days 8 through 14, subjects received 400mg of vatiquinone 3 times daily. On day12, subjects concomitantly received a single dose of 20-mg rosuvastatin. The geometric mean ratio for maximum plasma concentration was 77.8%; however, the rosuvastatin disposition phase appeared unaffected. The geometric mean ratios for the area under the plasma concentration-time curve from time 0 to time t and from time 0 to infinity were 103.2% and 99.9%, respectively. Mean rosuvastatin apparent elimination half-life was similar between treatment groups. These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin.

A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics.

The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n =159) and a cohort of previously published studies (n =88). In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P= 1.8×10-12 and P= 3.2×10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P= .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P= .0041 and P= .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P =4.69×10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P= .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P =2.6×10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P =.01). These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

Functional in vitro characterization of SLCO1B1 variants and simulation of the clinical pharmacokinetic impact of impaired OATP1B1 function.

Organic Anion Transporting Polypeptide 1B1 is important to the hepatic elimination and distribution of many drugs. If OATP1B1 function is decreased, it can increase plasma exposure of e.g. several statins leading to increased risk of muscle toxicity. First, we examined the impact of three naturally occurring rare variants and the frequent SLCO1B1 c.388A>G variant on in vitro transport activity with cellular uptake assay using two substrates: 2′, 7′-dichlorofluorescein (DCF) and rosuvastatin. Secondly, LC–MS/MS based quantitative targeted absolute proteomics measured the OATP1B1 protein abundance in crude membrane fractions of HEK293 cells over-expressing these single nucleotide variants. Additionally, we simulated the effect of impaired OATP1B1 function on rosuvastatin pharmacokinetics to estimate the need for genotype-guided dosing. R57Q impaired DCF and rosuvastatin transport significantly yet did not change protein expression considerably, while N130D and N151S did not alter activity but increased protein expression. R253Q did not change protein expression but reduced DCF uptake and increased rosuvastatin Km. Based on pharmacokinetic simulations, doses of 30 mg (with 50% OATP1B1 function) and 20 mg (with 0% OATP1B1 function) result in plasma exposure similar to 40 mg dose (with 100% OATP1B1 function). Therefore dose reductions might be considered to avoid increased plasma exposure caused by function-impairing OATP1B1 genetic variants, such as R57Q.

Effects of Ethanolic Extract of Schisandra sphenanthera on the Pharmacokinetics of Rosuvastatin in Rats

PurposeWuzhi capsule (WZ) is a proprietary Chinese medicine prepared from the ethanolic extract of Schisandra sphenanthera that is commonly used to treat liver injury. Statins are widely used in patients with hyperlipidemia, coronary heart disease, metabolic syndrome, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Co-administration of statins with WZ is possible in clinical practice. WZ has obvious inhibitory effects on the bioavailability of atorvastatin and simvastatin; however, the drug–herb interactions between WZ and rosuvastatin have not been addressed. We explored the effects of WZ on the pharmacokinetics of rosuvastatin in Sprague-Dawley rats to promote a rational use of statins.MethodsEighteen male rats were randomly and evenly divided into three groups: control group (gavage feeding of rosuvastatin 10 mg·kg−1), single dose group (gavage feeding of a single dose of WZ 150 mg·kg−1 followed by rosuvastatin 10 mg·kg−1) and multiple doses group (gavage feeding of WZ 150 mg·kg−1 for 7 days followed by rosuvastatin 10 mg·kg−1 on the seventh day). Plasma samples were collected at different times before and after rosuvastatin administration. The other 18 female rats were tested the same way as the male rats. All samples were analyzed by a validated LC-MS/MS method, and the pharmacokinetic parameters were calculated using a non-compartmental model.ResultsIn both male and female rats, there were no statistically significant differences in rosuvastatin pharmacokinetic parameters between the control group, the single dose group, and the multi-dose group.ConclusionAcute or long-term intake of WZ had no obvious effect on the pharmacokinetics of rosuvastatin, and therefore rosuvastatin could be used as an alternative to atorvastatin and simvastatin when WZ is clinically required in conjunction with statins. An appropriate pharmacodynamic study is needed to encourage the safe use of this combination.

Effect of Green Tea Extract and Soy Isoflavones on the Pharmacokinetics of Rosuvastatin in Healthy Volunteers.

Background and AimGreen tea and soy products are extensively consumed in daily life. Research has shown that green tea catechins and soy isoflavones may influence the activity of drug metabolizing enzymes and drug transporters. We examined whether regular consumption of green tea extract or soy isoflavones affected the pharmacokinetics of a single dose of rosuvastatin in healthy subjects and whether any interactions were influenced by the polymorphism in the drug transporter ABCG2.Study DesignThis was an open-label, three-phase randomized crossover study with single doses of rosuvastatin.MethodsHealthy Chinese male subjects were given a single dose of rosuvastatin 10 mg on 3 occasions: 1. without herbs; 2. with green tea extract; 3. with soy isoflavone extract. The green tea and soy isoflavone extract were given at a dose containing EGCG 800 mg once daily or soy isoflavones−80 mg once daily for 14 days before statin dosing and at the same time as the statin dosing with at least 4-weeks washout period between phases.ResultsTwenty healthy male subjects completed the study and the intake of green tea extract significantly reduced the systemic exposure to rosuvastatin by about 20% reducing AUC0−24h from [geometric mean (% coefficient of variation)] 108.7 (28.9) h·μg/L to 74.1 (35.3) h·μg/L and Cmax from 13.1 (32.2) μg/L to 7.9 (38.3) μg/L (P < 0.001 for both), without affecting the elimination half-life. The ABCG2 421C>A polymorphism had a significant effect on rosuvastatin exposure but no impact on the interaction with green tea. Soy isoflavones had no significant effect on rosuvastatin pharmacokinetics.ConclusionThis study showed that repeated administration of green tea extract significantly reduced the systemic exposure of rosuvastatin in healthy volunteers. These effects might be predicted to either reduce or increase the lipid-lowering effect of rosuvastatin depending on the mechanism of the effect.

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞ (lnGM = 0.43; 95% CI = 0.35–0.50; p < 0.00001) and Cmax (lnGM = 0.42; 95% CI = 0.33–0.51; p < 0.00001) than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.

Changes in Rosuvastatin Pharmacokinetics During Postnatal Ontogenesis in Rats.

Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in ratsin vivoas a basis for clinical development of formulations for patients < 6 years. Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.

Physiologically Based Pharmacokinetic Modeling of Rosuvastatin to Predict Transporter-Mediated Drug-Drug Interactions

PurposeTo build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs).MethodsThe Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002–80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model.ResultsThe carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values.ConclusionsA whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach

Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25mg, rosuvastatin 10mg, and metformin 1000mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600mg 1h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. Clinicaltrials.gov NCT04231435 on January 18, 2020.

Assessment of the Effect of Filgotinib on the Pharmacokinetics of Atorvastatin, Pravastatin, and Rosuvastatin in Healthy Adult Participants.

Filgotinib, an oral Janus kinase‐1 preferential inhibitor, is approved in Europe and Japan for adults with rheumatoid arthritis. Patients with rheumatoid arthritis are at higher risk of cardiovascular morbidity/mortality; thus, it is important to understand potential drug‐drug interactions of filgotinib with lipid‐lowering agents. This open‐label, randomized, 2‐way crossover study evaluated the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin with and without filgotinib coadministration. Healthy participants (N = 27) received single doses of atorvastatin (40 mg) and of a pravastatin (40 mg)/rosuvastatin (10 mg) cocktail—alone or with filgotinib (200 mg once daily for 11 days)—on 2 different occasions with washout in between. Serial pharmacokinetic blood samples were collected, and safety was assessed. Pharmacokinetic parameters were evaluated using 90% confidence intervals (CI) of the geometric least‐squares mean (GLSM) ratio of the test treatment (statin coadministration with filgotinib) vs statin alone, with prespecified lack‐of‐interaction bounds of 0.70 to 1.43. Coadministration of filgotinib did not affect atorvastatin area under the plasma concentration–time curve extrapolated to infinity (AUCinf; [GLSM ratios (90% CI): 0.91 (0.84‐0.99)]), but maximum concentration [Cmax] was slightly lower [0.82 (0.69‐0.99)]. The exposure of 2‐hydroxy‐atorvastatin was unaffected (GLSM ratios [90% CI], 0.98 [0.81‐1.19] for Cmax; 1.11 [1.02‐1.22] for AUCinf). Pravastatin AUCinf was also unaffected (GLSM ratios, 1.22 [1.05‐1.41], but Cmax was slightly higher 1.25 [1.01‐1.54]). Rosuvastatin exposure was moderately higher with filgotinib coadministration—GLSM ratios (90% CI), 1.68 (1.43‐1.97) for Cmax; 1.42 (1.30‐1.57) for AUCinf—but this was not considered clinically relevant. These results indicate that filgotinib has no clinically meaningful effect on exposure of atorvastatin, pravastatin, or rosuvastatin.

In vitro and in vivo evaluation of organic anion-transporting polypeptide 2B1-mediated pharmacokinetic interactions by apple polyphenols

Organic anion-transporting polypeptide (OATP) 2B1 plays a critical role in the intestinal absorption of substrate drugs. Apple juice reportedly interacts with OATP2B1 substrate drugs. The purpose of this study was to investigate the effect of two apple polyphenols, phloretin and phloridzin, on OATP2B1-mediated substrate transport in vitro and to evaluate the effect of phloretin on rosuvastatin pharmacokinetics in rats. In vitro studies revealed that both polyphenols inhibited OATP2B1-mediated uptake of estrone-3-sulfate. Despite preincubation with phloretin and subsequent washing, the inhibitory effect was retained. Phloretin markedly decreased OATP2B1-mediated rosuvastatin uptake, with an IC50 value of 3.6 μM. On coadministering rosuvastatin and phloretin in rats, the plasma concentration of rosuvastatin 10 min after oral administration was significantly lower than that in the vehicle group. The area under the plasma concentration-time curve of rosuvastatin was not significant, showing a tendency to decrease in the phloretin group when compared with the vehicle group. The in-situ rat intestinal loop study revealed the inhibitory effect of phloretin on rosuvastatin absorption. Phloretin has potent and long-lasting inhibitory effects on OATP2B1 in vitro. Phloretin may inhibit OATP2B1-mediated intestinal absorption of rosuvastatin; however, it failed to significantly impact the systemic exposure of rosuvastatin in rats.

A phase 1, open-label, drug\u2013drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors

PurposeThis study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives.MethodsPatients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis.ResultsThirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug–drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration–time curve from time zero to last quantifiable measurement (AUC0–last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment.ConclusionRucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib.ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation.

OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI). OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured in vivo. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases. Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin in vivo, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations. A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.

Scutellarin is Highly Likely to be Responsible for Drug-Drug Interactions Mediated by Hepatic Organic Anion-Transporting Polypeptide1B3

PurposeScutellarin, a flavonoid derived from the plant Erigeron breviscapus, is currently widely used to treat cerebrovascular diseases, liver-related diseases, and hyperlipidemia in china and other East Asian countries. This study was to investigate the effect of scutellarin on the uptake of rosuvastatin in HEK293T cells expressing human organic anion transporting polypeptide 1B3 (hOATP1B3) and rat OATP1B2 (rOATP1B2), respectively, and the effect of scutellarin on the pharmacokinetics of rosuvastatin in rats.MethodsThe newly established HEK293T cells expressing hOATP1B3 and rOATP1B2 were used to examine the effects of scutellarin and positive controls on in vitro rosuvastatin transport. After co-feeding with scutellarin, the rosuvastatin area under the plasma concentration-time curve (AUC0–24h), the peak plasma drug concentration (Cmax), elimination half-life (t1/2), time to reach Cmax (tmax), clearance (CL) and apparent clearance (CL/F) of rosuvastatin were determined in rats.ResultsScutellarin inhibited hOATP1B3- and rOATP1B2-mediated rosuvastatin uptake (IC50: 45.54 ± 6.67 μM and 27.58 ± 3.97 μM) in vitro in a concentration-dependent manner. After co-feeding with scutellarin, the AUC0–24h and Cmax of rosuvastatin in rats increased to 27.4% and 37.7%, respectively. The t1/2 and tmax of rosuvastatin showed no significant change. Moreover, scutellarin caused 29.2% and 28.1% decrease in the CL and CL/F of rosuvastatin.ConclusionScutellarin may inhibit the hOATP1B3- and rOATP1B2-mediated transport of rosuvastatin in vitro, and exerts a moderate inhibitory effect on the pharmacokinetics of rosuvastatin in rats. Scutellarin is highly likely to participate in drug-drug interactions, as mediated by OATP1B3 in humans.