Dosage Optimization of Digoxin in Older Patients with Heart Failure and Chronic Kidney Disease: A Population Pharmacokinetic Analysis.

BACKGROUND: Renal function is an important index for digoxin dose adjustment, especially in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is common in older patients with cardiovascular disease. OBJECTIVE: The aim of this study was to establish a digoxin population pharmacokinetic model in older patients with heart failure and CKD and to optimize the digoxin dose strategy. METHODS: Older patients with heart failure and CKD aged > 60 years from January 2020 to January 2021 and who had an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or urine protein production were enrolled in this retrospective study. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using NONMEN software. The precision and stability of the final model were analyzed by graphical and statistical methods. RESULTS: Overall, 269 older patients with heart failure were enrolled. A total of 306 digoxin concentrations were collected, with a median value of 0.98 ng/mL (interquartile range [IQR] 0.62-1.61, range 0.04-4.24). The median age was 68 years (IQR 64-71, range 60-94) and eGFR was 53.6 mL/min/1.73 m2 (IQR 38.1-65.2, range 11.4-89.8). A one-compartment model with first-order elimination was developed to describe the digoxin pharmacokinetics. Typical values for clearance and volume of distribution were 2.67 L/h and 36.9 L, respectively. Dosage simulations were stratified by eGFR and metoprolol. Doses of 62.5 and 125 µg were recommended for older patients with eGFR < 60 mL/min/1.73 m2. CONCLUSIONS: A population pharmacokinetic model of digoxin in older patients with heart failure and CKD was established in this study. A novel digoxin dosage strategy was recommended in this vulnerable population.

Novel Explanted Human Liver Model to Assess Hepatic Extraction, Biliary Excretion and Transporter Function.

Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug-drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (Cmax ) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.

Black ginger extract and its active compound, 5,7-dimethoxyflavone, increase intestinal drug absorption via efflux drug transporter inhibitions.

Black ginger is used as an herbal medicine for self-care and health promotion. Black ginger extract has been shown to alter the function of transporters in several cell types. This study demonstrates the interaction between the extract and 5,7-dimethoxyflavone (DMF) on drug efflux mediated by breast cancer resistance proteins (BCRP) and P-glycoprotein (P-gp) in Caco-2 cells and heterologous cell systems [Madin-Darby canine kidney type II (MDCKII) stably transfected with human BCRP (MDCKII/BCRP) or human P-gp (MDCKII/P-gp)]. The transepithelial flux of 3H-Digoxin and 3H-Estrone sulfate, prototypic substrates of P-gp, and BCRP, respectively, across Caco-2 cell monolayers, MDCKII/BCRP, and MDCKII/P-gp cells were determined. The results demonstrate that black ginger extract (10 µg/ml) significantly increases 3H-Digoxin and 3H-Estrone sulfate transport from the apical to basolateral side while decreasing transport from the basolateral to apical side of Caco-2 cells and MDCKII cell overexpression of BCRP or P-gp. The effect of the extract on 3H-Digoxin and 3H-Estrone sulfate transport was related to a decrease in efflux ratio. Likewise, DMF (5 µM) significantly increased 3H-Digoxin and 3H-Estrone sulfate absorption with a decreased efflux ratio compared to the control. Interestingly, the extract also significantly increased absorption of paclitaxel, an anti-cancer drug, which has poor oral absorption. Taken together, co-administration of drugs as substrates of BCRP and P-gp, with the black ginger extract containing DMF, might alter the pharmacokinetic profiles of the medicine.

Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro Analyses and an Open-Label, Single-Sequence Phase I Study.

PURPOSE/BACKGROUND: Glycine transporter-1 inhibitors may ameliorate cognitive deficits in schizophrenia. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809. METHODS/PROCEDURES: Interactions with cytochromes P450 (CYP) and P-glycoprotein (P-gp) were assessed in in vitro assays using human hepatocytes and Caco-2 cells, respectively. Pharmacokinetic characteristics of probe drugs were subsequently assessed in a Phase I, open-label, single-sequence crossover study in healthy male participants. Participants received a probe-drug cocktail containing midazolam (CYP3A4), warfarin (CYP2C9), and omeprazole (CYP2C19) and a separate dose of digoxin (P-gp), alone and on a background of steady-state BI 425809 25 mg once daily in 2 treatment periods. Adverse events were monitored. FINDINGS/RESULTS: In vitro assays revealed concentration-dependent induction of CYP3A4 and inhibition of P-gp by BI 425809. In the clinical study, 12 of 13 participants completed both periods. With BI 425809, area under the plasma concentration curve from administration to the last measurement (AUC 0-tz ) and maximum plasma concentration ( Cmax ) for midazolam were lower than when administered alone. Adjusted geometric mean ratios (90% confidence interval) were 70.6% (63.9%-78.1%) for AUC 0-tz and 77.6% (67.3%-89.4%) for Cmax . For warfarin and digoxin, AUC 0-tz and Cmax were similar with and without BI 425809. For omeprazole, BI 425809 slightly reduced AUC 0-tz but not Cmax versus omeprazole alone. No new safety signals were identified. IMPLICATIONS/CONCLUSIONS: These findings indicate induction of CYP3A4 by once-daily BI 425809 25 mg (the assumed highest therapeutic dose) and no meaningful effects on CYP2C9, CYP2C19, or P-gp in vivo.

Assessment of Aging-Related Function Variations of P-gp Transporter in Old-Elderly Chinese CHF Patients Based on Modeling and Simulation.

BACKGROUND AND OBJECTIVES: P-glycoprotein (P-gp) is one of the most intensely studied transporters owing to its broad tissue distribution and substrate specificity. Existing research suggests that the risk of systemic exposure to dabigatran etexilate (DABE) and digoxin, two P-gp probe substrates in vivo, has significantly increased in elderly patients. We applied a model-based quantitative pharmacological approach to assess aging-related P-gp changes in the Chinese old-elderly population. METHODS: Population pharmacokinetic (PopPK) modeling was first performed using clinical pharmacokinetic data to explore the effect of age on the pharmacokinetic characteristics of dabigatran (DAB, the active principle of DABE) and digoxin in elderly Chinese patients. Corresponding physiologically based pharmacokinetic (PBPK) models were established to further explain the elevated systemic exposure to these two drugs. Eventually, standard dosing regimens of DABE and digoxin were assessed in Chinese old-elderly patients with chronic heart failure (CHF) with different stages of renal impairment. RESULTS: PopPK analysis suggested that age as a covariate had an additional effect on the apparent clearance of these two drugs after correcting for creatinine clearance. PBPK simulation results suggested that disease-specific pathophysiological changes could explain DAB exposure in the young elderly. In the elderly population, 17.1% of elevated DAB exposure remained unexplained, and 25.5% of the reduced P-gp function associated with aging was ultimately obtained using sensitivity analysis. This value was further validated using digoxin data obtained by PBPK modeling. The simulation results suggest that CHF patients with advanced age and moderate-to-severe renal impairment require heightened vigilance for elevated exposure risk during the use of DABE and digoxin. CONCLUSIONS: Aging might be a significant risk factor for elevated systemic exposure to DAB and digoxin by reducing P-gp-mediated efflux in the Chinese old elderly population.

Effect of enzalutamide on PK of P-gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters.

Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (Cmax ), area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast ), and AUC from the time of dosing extrapolated to time infinity (AUCinf ). Secondary end points were enzalutamide and N-desmethyl enzalutamide (metabolite) plasma Cmax , AUC during a dosing interval, where tau is the length of the dosing interval (AUCtau ), and concentration immediately prior to dosing at multiple dosing (Ctrough ). When administered with enzalutamide, there was a 17% increase in Cmax , 29% increase in AUClast , and 33% increase in AUCinf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a "mild" inhibitor of P-gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N-desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter-mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P-gp and BCRP does not require dose adjustment in this patient population.

Evaluation of the Effect of Isobutyl Paraben and 2-ethyl Hexyl Paraben on P-glycoprotein Functional Expression in Rats: A Pharmacokinetic Study.

BACKGROUND: Pharmaceutical excipients have been shown to influence drug disposition through modulating transport protein. OBJECTIVES: This study assessed the effect of single dose administration of parabens on the pharmacokinetics (PK) of digoxin, a probe substrate of p-glycoprotein (p-gp), in vivo. Also, the effect of multiple dosing of parabens on p-gp expression was examined. METHODS: Rats were randomized into four groups that received either the vehicle, 25 mg/ kg verapamil, 100 mg/ kg isobutyl paraben, or 100 mg/ kg 2-ethyl hexyl paraben, which was followed by giving 0.2 mg/ kg digoxin via oral gavage. Blood samples were collected at different time points, digoxin concentration was measured using LC/MS-MS, and digoxin PK parameters were estimated. Another set of rats received multiple doses of parabens for 14 days, followed by measuring intestinal and hepatic mRNA expression of p-gp using qRT-PCR. RESULTS: Single dose administration of verapamil significantly increased Cmax (by 60.4 %) and AUC0-t (by 61.7 %) of digoxin compared to the control group, while the PK parameters of digoxin in rats exposed to parabens were not significantly different from the control. Consistently, the mRNA expression of p-gp in the intestine and liver was not affected by parabens treatment. CONCLUSIONS: The lack of isobutylparaben and 2-ethylhexyl paraben effect on p-gp may suggest the insignificant interaction of parabens with p-gp drug substrates, which could be considered for safety when designing pharmaceutical formulations.

Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers.

PURPOSE: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. METHODS: MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a-/-/Mdr1b-/- or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. RESULTS: MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a-/-/Mdr1b-/- mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. CONCLUSION: Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.

Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study.

Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT: We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.

Physiologically-based pharmacokinetic modeling to evaluate in vitro-to-in vivo extrapolation for intestinal P-glycoprotein inhibition.

As one of the key components in model-informed drug discovery and development, physiologically-based pharmacokinetic (PBPK) modeling linked with in vitro-to-in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug-drug interactions (DDIs) on drug-metabolizing enzymes and transporters. This study aimed to investigate an IVIVE for intestinal P-glycoprotein (Pgp, ABCB1)-mediated DDIs among three Pgp substrates, digoxin, dabigatran etexilate, and quinidine, and two Pgp inhibitors, itraconazole and verapamil, via PBPK modeling. For Pgp substrates, assuming unbound Michaelis-Menten constant (Km ) to be intrinsic, in vitro-to-in vivo scaling factors for maximal Pgp-mediated efflux rate (Jmax ) were optimized based on the clinically observed results without co-administration of Pgp inhibitors. For Pgp inhibitors, PBPK models utilized the reported in vitro values of Pgp inhibition constants (Ki ), 1.0 µM for itraconazole and 2.0 µM for verapamil. Overall, the PBPK modeling sufficiently described Pgp-mediated DDIs between these substrates and inhibitors with the prediction errors of less than or equal to ±25% in most cases, suggesting a reasonable IVIVE for Pgp kinetics in the clinical DDI results. The modeling results also suggest that Pgp kinetic parameters of both the substrates (Km and Jmax ) and the inhibitors (Ki ) are sensitive to Pgp-mediated DDIs, thus being key for successful DDI prediction. It would also be critical to incorporate appropriate unbound inhibitor concentrations at the site of action into PBPK models. The present results support a quantitative prediction of Pgp-mediated DDIs using in vitro parameters, which will significantly increase the value of in vitro studies to design and run clinical DDI studies safely and effectively.

The Effect of Oral Letermovir Administration on the Pharmacokinetics of a Single Oral Dose of P-Glycoprotein Substrate Digoxin in Healthy Volunteers.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.

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

INTRODUCTION: 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). METHODS: In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: Clinicaltrials.gov NCT04231435 on January 18, 2020.

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs.

Drug reabsorption following biliary excretion is well-known as enterohepatic recirculation (EHR). Renal tubular reabsorption (RTR) following renal excretion is also common but not easily assessed. Intestinal excretion (IE) and enteroenteric recirculation (EER) have not been recognized as common disposition mechanisms for metabolically stable and permeable drugs. IE and intestinal reabsorption (IR:EHR/EER), as well as RTR, are governed by dug concentration gradients, passive diffusion, active transport, and metabolism, and together they markedly impact disposition and pharmacokinetics (PK) of small molecule drugs. Disruption of IE, IR, or RTR through applications of active charcoal (AC), transporter knockout (KO), and transporter inhibitors can lead to changes in PK parameters. The impacts of intestinal and renal reabsorption on PK are under-appreciated. Although IE and EER/RTR can be an intrinsic drug property, there is no apparent strategy to optimize compounds based on this property. This review seeks to improve understanding and applications of IE, IR, and RTR mechanisms.

Population Pharmacokinetic Studies of Digoxin in Adult Patients: A Systematic Review.

BACKGROUND: Digoxin is a cardiac glycoside that was introduced to cardiovascular medicine more than 200 years ago. Its use is associated with large variability, which complicates achieving the desired therapeutic outcomes. OBJECTIVES: To present a synthesis of the available literature on the population pharmacokinetics of digoxin in adults and to identify the sources of variability in its pharmacokinetics. METHODS: This is a PROSPERO registered systematic review (CRD42018105300). A literature search was conducted using the ISI Web of Science, Science Direct, PubMed, and SCOPUS databases to identify digoxin population pharmacokinetic studies of adults that utilized the nonlinear mixed-effect modeling approach. RESULTS: Sixteen articles were included in the present analysis. Only two studies were conducted in elderly subjects as a separate population. Both the pharmacokinetics and pharmacodynamics of digoxin were investigated in one study. Furthermore, the reviewed studies were mostly conducted in East Asian populations (68.8%). Digoxin's pharmacokinetics were usually described by a one-compartment model because of the nature of the collected data. Weight, age, kidney function, presence of heart failure, and co-administered medications such as calcium channel blockers were the most commonly identified predictors of digoxin clearance. The value of apparent clearance in a typical study individual ranged from 0.005 to 0.2 l/h/kg, while the value of the apparent volume of distribution ranged from 3.14 to 15.2 l/kg. The quality of model evaluation was deemed excellent only in 31.3% of the studies. CONCLUSION: This review provides information about variables that need to be considered when prescribing digoxin. The results highlight the need for prospective studies that allow two-compartment pharmacokinetic/pharmacodynamic models to be established, with a special focus on the elderly subpopulation.

Impact of interleukin-6 on drug transporters and permeability in the hCMEC/D3 blood-brain barrier model.

The blood-brain barrier (BBB) is a highly selective membrane composed predominantly of brain capillary endothelial cells expressing drug efflux transporters that prevent substrates from accessing the brain. Inflammation is associated with central nervous system diseases and can impair BBB permeability via several mechanisms, including altered transporter and cell junction expression. This can modify the brain's exposure to drugs. However, comprehensive genomic analysis of the impact of interleukin (IL)-6, which plays a key role in the inflammatory response, on the BBB is lacking. In the present study, we analyzed the effects of exposure of hCMEC/D3 cells to 20 ng/mL IL-6 for 72 h. We performed RNA sequencing and ABC transporter efflux assays. Physiologically based pharmacokinetics (PBPK) simulations were conducted to evaluate the potential impact of IL-6 on the digoxin pharmacokinetics profile and brain exposure by decreasing BBB ABCB1 efflux activity. Exposure of hCMEC/D3 cells to IL-6 triggered the deregulation of numerous genes involved in barrier permeability, such as cell junctions, focal adherens complex, and cell adhesion molecules. We observed mild modification of the mRNA expression and efflux activities of ABC transporters. PBPK simulation showed that, if we only consider the impact of IL-6 on ABCB1 transporter, the modification of the digoxin pharmacokinetics profile and brain exposure is slight. IL-6 slightly affected the gene expression levels and activities of ABC transporters on BBB cells, exhibiting a weaker effect than on hepatic cells. However, inflammation may cause other modifications, such as altered BBB permeability, that could modify drug pharmacokinetics.

The impact of serum concentration-guided digoxin therapy on mortality of heart failure patients: A long-term follow-up, propensity-matched cohort study.

BACKGROUND: Recently published studies suggested that digoxin may increase mortality in heart failure with reduced ejection fraction (HFrEF). However, in the vast majority of former trials serum digoxin concentration (SDC) was not measured and therapy was not SDC-guided. AIM: To assess the impact of SDC-guided digoxin therapy on mortality in HFrEF patients. METHODS: Data of 580 HFrEF patients were retrospectively analyzed. In patients on digoxin, SDC was measured every 3 months and digoxin dosage was SDC-guided (target SDC: 0.5-0.9 ng/mL). All-cause mortality of digoxin users and nonusers was compared after propensity score matching (PSM). RESULTS: After 7.1 ± 4.7 years follow-up period (FUP) all-cause mortality of digoxin users (n = 180) was significantly higher than nonusers (n = 297) (propensity-adjusted HR = 1.430; 95% CI = 1.134-1.804; P = .003). Patients having SDC of 0.9 to 1.1 ng/mL (n = 60) or > 1.1 ng/mL (n = 44) at any time during the FUP had an increased risk of all-cause mortality (HR = 1.750; 95% CI = 1.257-2.436, P = .001 and HR = 1.687; 95% CI = 1.153-2.466, P = .007), while patients having a maximal SDC < 0.9 ng/mL (n = 76) had similar mortality risk (HR = 1.139; 95% CI = 0.827-1.570, P = .426), compared to digoxin nonusers. CONCLUSIONS: According to our propensity-matched analysis, SDC-guided digoxin therapy was associated with increased all-cause mortality in optimally treated HFrEF patients, especially with SDC ≥0.9 ng/mL. These results reinforce the expert opinion that digoxin in HFrEF can only be used among carefully selected patients with close SDC monitoring.

Drug-Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone With Midazolam, Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers.

PURPOSE: To characterize the clinical relevance of in vitro drug-drug interaction findings with apararenone (MT-3995), the effects of apararenone on the sensitive substrates of cytochrome P450 3A4 (midazolam) and 2C9 (warfarin), and P-glycoprotein (digoxin), were assessed through a series of studies conducted in healthy volunteers. METHODS: Three studies were conducted in 56 healthy adults. Study 1 investigated the effects of the administration of apararenone with midazolam; apararenone was administered on days 2 (320 mg) and days 3-15 (20 mg/d), and midazolam 2 mg, on days 1 and 15. Study 2 investigated the effects of the administration of apararenone with warfarin; apararenone was administered on days 8-11 (40 mg/d) and days 12-27 (10 mg/d), and warfarin 25 mg, on days 1 and 21. Study 3 assessed the effects of the administration of apararenone with digoxin; apararenone was administered on days 11 (160 mg) and days 12-28 (10 mg/d), and digoxin 0.5 mg, on days 1 and 24. Pharmacokinetic parameters included Cmax, AUC0-t, and AUC0-∞. The safety profile was evaluated based on adverse events from spontaneous reports and clinical findings. FINDINGS: After the administration of midazolam together with apararenone, compared with midazolam alone, the midazolam ± apararenone treatment ratios (90% CIs) of the geometric least squares (LS) mean Cmax, AUC0-t, and AUC0-∞ values were 1.263 (1.147-1.392), 1.342 (1.220-1.477), and 1.370 (1.225-1.534), respectively. After the administration of warfarin ± apararenone, the R-warfarin ± apararenone treatment ratios (90% CIs) of the geometric LS mean Cmax, AUC0-t, and AUC0-∞ values were 1.008 (0.934-1.089), 1.078 (1.029-1.129), and 1.110 (1.056-1.166). Corresponding values for S-warfarin were 1.025 (0.941-1.117), 1.024 (0.979-1.071), and 1.031 (0.984-1.080). After the administration of digoxin ± apararenone, the digoxin ± apararenone treatment ratios (90% CIs) of the geometric LS mean Cmax, AUC0-t, and AUC0-∞ values were 0.929 (0.789-1.093), 0.894 (0.797-1.033), and 0.887 (0.805-0.977), respectively. Treatment-emergent adverse events were generally of mild to moderate intensity, and no serious adverse events of any kind were reported. IMPLICATIONS: The findings from this analysis of data from healthy volunteers suggest minimal risk for potential drug-drug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency.

PURPOSE: This study aimed to utilize a population pharmacokinetic method to obtain information about the influence of covariates on the in vivo behavior of digoxin in patients with cardiac insufficiency. METHODS: A total of 228 therapeutic drug monitoring concentrations were retrospectively collected from 176 inpatients. The patients were randomly divided into a modeling group (n = 126) and a validation group (n = 50). The first-order absorption one-compartment model was used to develop a population pharmacokinetic model from a nonlinear mixed effects modeling approach. Sixteen single nucleotide polymorphisms involved in the pharmacokinetic variables of digoxin were identified by using the MassARRAY system. Various demographic parameters, biochemical test values, concomitant medications, and genetic variants were investigated. FINDINGS: The typical population value of digoxin CL/F was 5.06 L/h, and the volume of distribution was 211.82 L. The drug CL/F was significantly related to serum creatinine, in a combination of spironolactone and SLCO4C1 genotypes of 2 variants (rs3114660 and rs3114661). Results of model evaluation and internal/external validation indicated a stable and precise performance of the final model. IMPLICATIONS: For the first time, 2 single nucleotide polymorphisms (rs3114660 and rs3114661) in SLCO4C1 were found to significantly affect the elimination of digoxin in vivo. The final population model may be useful for the individualized dosing of digoxin for patients with cardiac insufficiency.