Intraamniotic digoxin administration versus intracardiac or funic potassium chloride administration to induce foetal demise before termination of pregnancy: a prospective study.

Different foeticide techniques and pharmacological agents have been used to achieve foetal asystole. This study aimed to compare the success of intraamniotic digoxin, intracardiac potassium chloride (KCl), and funic KCl in achieving foetal asystole and discuss procedural difficulties for physicians and clinical outcomes. This prospective observational study included 124 patients who received foeticide at 22-31 weeks of gestation. All procedures were performed transabdominally, and 1 mg of intraamniotic digoxin, funic KCl, or intracardiac KCl was administered. Procedure times, procedural difficulty scores, patient pain scores, decrease in haematocrit levels, induction and hospitalisation times, and the presence of chorioamnionitis were recorded. The foeticide success rates were 93.0, 95.1, and 97.5% for intraamniotic digoxin, intracardiac KCl, and funic KCl, respectively. Intraamniotic digoxin was associated with shorter procedure times, lower procedural difficulty scores, and lower patient pain scores (p < 0.001). Decreases in haematocrit, induction times, and chorioamnionitis were similar in all three procedures. Success rates and clinical results were similar for all three procedures. Foeticide with intra-amniotic digoxin has a high success rate, the procedure is easier to perform, and patients experience less procedural pain.IMPACT STATEMENTWhat is already known on this subject? Different foeticide techniques and pharmacological agents have been used to achieve foetal asystole. Pharmacological agents used in the foeticide procedure can be injected as intracardiac, funic, intrafetal, or intraamniotic, and the most commonly used are potassium chloride (KCl), digoxin, and lidocaine.What do the results of this study add? The success rates and clinical outcomes in achieving foetal asystole are similar for intracardiac KCl, funic KCl, and intra-amniotic digoxin procedures. Foeticide with intra-amniotic digoxin is less difficult to perform, and patients experience less pain associated with the procedure. All three techniques appear to be safe and have similar short-term obstetric outcomes.What are the implications of these findings for clinical practice and/or further research? Physicians may prefer foeticide with intra-amniotic digoxin as the procedure is technically simpler and has similar success rates to intracardiac or funic KCl administration. A prospective randomised study could better compare the advantages and limitations of the foeticide techniques.

Digoxina: alternativas a la pauta de descanso / Digoxin: alternatives to the rest regimen

Introducción: La digoxina se caracteriza por estrecho margen terapéutico que hace dificultosa su dosificación y sea necesaria una monitorización de sus niveles séricos. Esto se hace más complejo en pacientes con nefropatía crónica que precisan de un mayor ajuste de dosis.Desarrollo de la experiencia:Presentamos el caso de una mujer de 88 años admitida en nuestra unidad en tratamiento con digoxina oral por insuficiencia cardiaca crónica con pauta de 1 comprimido diario con descanso los fines de semana, que presenta mal control de síntomas y niveles séricos de digoxina infraterapéuticos en controles. Al cambiar la formulación a jarabe oral pediátrico (Lanacordin® 0,05mg/mL) se consiguió un mejor nivel de los niveles del fármaco y del control de síntomas.Conclusiones:La utilización de la digoxina en jarabe oral puede ser una alternativa a la formulación con comprimidos, sobre todo en pacientes en los que el control de los niveles del fármaco puede resultar complejo por sus comorbilidades. (AU)

Introduction: Digoxin is characterized by narrow therapeutic margin which makes its dosing difficult and monitoring of its serum levels necessary. This becomes more complex in patients with chronic nephropathy who require a greater dose adjustment.Development of the experience:We present the case of an 88-year-old woman admitted to our unit under treatment with oral digoxin for chronic heart failure with a regimen of 1 tablet daily with rest at weekends, who presented poor symptom control and subtherapeutic serum digoxin levels in controls. Changing the formulation to pediatric oral syrup (Lanacordin® 0.05mg/mL) resulted in better drug levels and symptom control.Conclusions:The use of digoxin in oral syrup may be an alternative to tablet formulation, especially in patients in whom drug level control may be complex due to their comorbidities. (AU)

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.

A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin.

Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.

Benefits of prescribing low-dose digoxin in atrial fibrillation.

INTRODUCTION: The role of digoxin (cardiac glycoside) in controlling the heart rate (HR) for the treatment of atrial fibrillation (AF) patients has not been explored in depth. METHODS: To contribute to the limited data, our team conducted retrospective analysis of the clinical records of 1444 AF patients. We divided the AF patients into two groups, wherein group 1 patients were treated with beta-blockers (BB), low-dose digoxin, and an anticoagulant (vitamin K antagonist/factor-IIa inhibitor/factor-Xa inhibitor), and group 2 patients were treated with just BB and an anticoagulant. Our objectives were to compare the impact of combination therapy of BB and digoxin on the resting HR in patients with permanent AF and the patients' quality of life (QOL) at periodic intervals. RESULTS: The findings of our study showed a better control of the resting HR rate (<110bpm) and an improved QOL among the group 1 patients when compared with group 2 patients. CONCLUSION: Our findings are indicative of the favorable clinical outcomes that resulted from the addition of a low-dose of digoxin to the AF treatment regimen. However, larger studies/trials elucidating the outcomes of AF patients treated with the dual rate control therapy are required, to clarify the role of digoxin, guide the choice of agents, and standardize the AF treatment protocol.

Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

To evaluate the ocular safety of intravitreal carboplatin and digoxin injections as a new intravitreal chemotherapy option for retinoblastoma tumor vitreous seeds. Eighteen rabbits were divided randomly into three groups to receive intravitreal injection of Digoxin (6 rabbits), Carboplatin (7 rabbits), or Saline (5 rabbits). In every group, one eye randomly treated with 10 µg Digoxin in 0.1 cc or 1 µg Carboplatin or Saline, and the contralateral eye was considered as the control. All groups underwent three consecutive injections of the drugs with 1-week intervals. Baseline electroretinography (ERG) was recorded from both eyes of all the animals prior to injection and was repeated 1st day, 1st week, and 1st month after the last injection. All rabbits were sacrificed 1 month after the last injection, and histological studies were done. Mean a and b wave amplitudes decreased significantly at 1st day, 1st week, and 1st month after the last intravitreal injection of 10 µg Digoxin in comparison with other groups (p-value: .02). Contradictory, 1 µg Carboplatin injected eyes had minimal ERG changes. There were some nonspecific ERG changes with unclear clinical significance in non-injected contralateral control eyes of Digoxin and Carboplatin groups in comparison with the control eyes of the Saline group. Histological studies revealed considerable neural retinal atrophy in injected eyes of the Digoxin group. Intravitreal 10 µg Digoxin might have more local ocular toxicity in comparison with intravitreal Carboplatin in albino rabbit eyes. Future studies should assess the induced toxicity of intravitreal injection of these drugs on the non-injected contralateral eye.

Supine Parasympathetic Withdrawal and Upright Sympathetic Activation Underly Abnormalities of the Baroreflex in Postural Tachycardia Syndrome: Effects of Pyridostigmine and Digoxin.

[Figure: see text].

Association of digoxin with mortality in patients with advanced chronic kidney disease: A population-based cohort study.

Digoxin is commonly prescribed for heart failure and atrial fibrillation, but there is limited data on its safety in patients with chronic kidney disease (CKD). We conducted a population-based cohort study using the pre-end stage renal disease (ESRD) care program registry and the National Health Insurance Research Database in Taiwan. Of advanced CKD patient cohort (N = 31,933), we identified the digoxin user group (N = 400) matched with age and sex non-user group (N = 2,220). Multivariable Cox proportional hazards and sub-distribution hazards models were used to evaluate the association between digoxin use and the risk of death, cardiovascular events (acute coronary syndrome, ischemic stroke, or hemorrhagic stroke) and renal outcomes (ESRD, rapid decline in estimated glomerular filtration rate-eGFR, or acute kidney injury). Results showed that all-cause mortality was higher in the digoxin user group than in the non-user group, after adjusting for covariates (adjusted hazard ratio, aHR 1.63; 95% CI 1.23-2.17). The risk for acute coronary syndrome (sub-distribution hazard ratio, sHR 1.18; 95% CI 0.75-1.86), ischemic stroke (sHR 1.42; 95% CI 0.85-2.37), and rapid eGFR decline (sHR 1.00 95% CI 0.78-1.27) was not significantly different between two groups. In conclusion, our study demonstrated that digoxin use was associated with increased mortality, but not cardiovascular events or renal function decline in advanced CKD patients. This finding warns the safety of prescribing digoxin in this population. Future prospective studies are needed to overcome the limitations of cohort study design.

Digoxin Combined with Aerobic Interval Training Improved Cardiomyocyte Contractility.

Digoxin is a cardiotonic that increases the cardiac output without causing deleterious effects on heart, as well as improves the left ventricular performance during physical exercise. We tested whether the association between chronic digoxin administration and aerobic interval training (AIT) promotes beneficial cardiovascular adaptations by improving the myocardial contractility and calcium (Ca2+) handling. Male Wistar rats were randomly assigned to sedentary control (C), interval training (T), sedentary digoxin (DIGO) and T associated to digoxin (TDIGO). AIT was performed on a treadmill (1h/day, 5 days/week) for 60 days, consisting of successive 8-min periods at 80% and 20% of VO2máx for 2 min. Digoxin was administered by orogastric gavage for 60 days. Left ventricle samples were collected to analysis of Ca2+ handling proteins; contractility and Ca2+ handling were performed on isolated cardiomyocytes. TDIGO group had a greater elevation in fractional shortening (44%) than DIGO, suggesting a cardiomyocyte contractile improvement. In addition, T or TDIGO groups showed no change in cardiomyocytes properties after Fura2-acetoxymethyl ester, as well as in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), phospholamban and calcineurin expressions. The main findings indicate that association of digoxin and aerobic interval training improved the cardiomyocyte contractile function, but these effects seem to be unrelated to Ca2+ handling.

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.

Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma.

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.

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.

PBPK modeling of CYP3A and P-gp substrates to predict drug-drug interactions in patients undergoing Roux-en-Y gastric bypass surgery.

Roux-en-Y gastric bypass surgery (RYGBS) is an effective surgical intervention to reduce mortality in morbidly obese patients. Following RYGBS, the disposition of drugs may be affected by anatomical alterations and changes in intestinal and hepatic drug metabolizing enzyme activity. The aim of this study was to better understand the drug-drug interaction (DDI) potential of CYP3A and P-gp inhibitors. The impacts of RYGBS on the absorption and metabolism of midazolam, acetaminophen, digoxin, and their major metabolites were simulated using physiologically-based pharmacokinetic (PBPK) modeling. PBPK models for verapamil and posaconazole were built to evaluate CYP3A- and P-gp-mediated DDIs pre- and post-RYGBS. The simulations suggest that for highly soluble drugs, such as verapamil, the predicted bioavailability was comparable pre- and post-RYGBS. For verapamil inhibition, RYGBS did not affect the fold-change of the predicted inhibited-to-control plasma AUC ratio or predicted inhibited-to-control peak plasma concentration ratio for either midazolam or digoxin. In contrast, the predicted bioavailability of posaconazole, a poorly soluble drug, decreased from 12% pre-RYGBS to 5% post-RYGBS. Compared to control, the predicted posaconazole-inhibited midazolam plasma AUC increased by 2.0-fold pre-RYGBS, but only increased by 1.6-fold post-RYGBS. A similar trend was predicted for pre- and post-RYGBS inhibited-to-control midazolam peak plasma concentration ratios (2.0- and 1.6-fold, respectively) following posaconazole inhibition. Absorption of highly soluble drugs was more rapid post-RYGBS, resulting in higher predicted midazolam peak plasma concentrations, which was further increased following inhibition by verapamil or posaconazole. To reduce the risk of a drug-drug interaction in patients post-RYGBS, the dose or frequency of object drugs may need to be decreased when administered with highly soluble inhibitor drugs, especially if toxicities are associated with plasma peak concentrations.

Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin.

Effects of different genotypes on the pharmacokinetics of probe substrates may support their use as phenotyping agents for the activity of the respective enzyme or transporter. Digoxin is recommended as a probe substrate to assess the activity of the transporter P-glycoprotein (P-gp) in humans. Current studies on the individual effects of three commonly investigated single nucleotide polymorphisms (SNPs) of the ABCB1 gene encoding P-gp (C1236T, G2677T/A, and C3435T) on digoxin pharmacokinetics are inconclusive. Since SNPs are in incomplete linkage disequilibrium, considering combinations of these SNPs might be necessary to assess the role of polymorphisms in digoxin pharmacokinetics accurately. In this study, the relationship between SNP combinations and digoxin pharmacokinetics was explored via a population pharmacokinetic approach in 40 volunteers who received oral doses of 0.5 mg digoxin. Concerning the SNPs 1236/2677/3435, the following combinations were evaluated: CGC, CGT, and TTT. Carriers of CGC/CGT and TTT/TTT had 35% higher apparent bioavailability compared to the reference group CGC/CGC, while no difference was seen in CGC/TTT carriers. No significant effect on renal clearance was observed. The population pharmacokinetic model supports the use of oral digoxin as a phenotyping substrate of intestinal P-gp, but not to assess renal P-gp activity.

Symptomatic digoxin toxicity in a patient on haemodialysis.

We present a man undergoing regular haemodialysis sessions, who presented with non-specific symptoms of nausea, vomiting and light-headedness. He was found to have significantly raised serum digoxin concentrations, as well as a heart rate of 30 beats per minutes. An ECG showed complete heart block. He has a history of non-ischaemic dilated cardiomyopathy with resistant supraventricular and ventricular tachycardias and was on concomitant beta-blockade and digoxin. On questioning, he reported a gradual decline in his residual urine output over the past 6 months. He was reviewed by the cardiology team and required both pharmacological therapy for reversal of digoxin toxicity and temporary pacing in view of significant bradyarrhythmias. The beta-blockade and digoxin were discontinued. He was kept on continuous monitoring at the Cardiac Critical Care Unit. His symptoms resolved spontaneously once digoxin-specific antibody fragments were administered and temporary pacing successfully performed.

Feasibility of intra-amniotic digoxin administration by obstetrics and gynecology trainees to induce fetal demise prior to medical abortion beyond 20 weeks.

BACKGROUND: Transient fetal survival is one issue that providers may face while managing late second-trimester abortion. Induction of fetal demise using digoxin and other means has been widely performed by maternal-fetal medicine and family planning subspecialists worldwide. However, there are no data available in Ethiopia as regards preventing transient fetal survival in late second-trimester medical termination of pregnancy. OBJECTIVE: The objective of the study was to document the feasibility of intra-amniotic digoxin administration for inducing fetal demise prior to medical abortion beyond 20 weeks of gestational age. Additionally, we aimed to demonstrate that this skill could be transferred to obstetrics and gynaecology residents at St Paul's Hospital Millennium Medical College in Addis Ababa, Ethiopia. METHODS: A retrospective cross-sectional study design was conducted to document the feasibility, safety and effectiveness of intra-amniotic digoxin. A structured questionnaire was used to collect selected sociodemographic data and clinical characteristics. Data were entered and analysed using SPSS statistical package version 20. RESULTS: During the study period, 49 women received intra-amniotic digoxin. The success rate of intra-amniotic digoxin in this study was 95.9%. Thirty-seven (75.5%) procedures were performed by obstetrics and gynaecology residents and 12 (24.5%) were performed by family planning faculties. There were two out of hospital expulsions with no signs of life, and no other serious maternal complications were observed. CONCLUSION: It is feasible for obstetrics and gynaecology trainees in Ethiopia to learn how to safely administer intra-amniotic digoxin to induce fetal demise for induced medical terminations.

Effect of eliglustat on the pharmacokinetics of digoxin, metoprolol, and oral contraceptives and absorption of eliglustat when coadministered with acid-reducing agents.

Eliglustat is an oral substrate reduction therapy indicated for patients with Gaucher disease type 1. Based on in vitro data, clinical trials were conducted to assess the potential for drug-drug interactions between eliglustat and digoxin (P-glycoprotein substrate), metoprolol (sensitive CYP2D6 substrate), a combined oral contraceptive (CYP3A substrate), and acid-reducing agents. Healthy subjects were enrolled in four Phase 1 clinical studies to evaluate the effect of eliglustat on the pharmacokinetics, safety, and tolerability of digoxin (N = 28), metoprolol (N = 14), and a combined oral contraceptive (N = 30) and the effect of acid-reducing agents on eliglustat pharmacokinetics, safety, and tolerability (N = 24). Coadministration resulted in increased exposure to digoxin (1.49-fold) and metoprolol (2-fold) with eliglustat, negligible effects on oral contraceptive pharmacokinetics with eliglustat, and a negligible effect of acid-reducing agents on eliglustat pharmacokinetics. Across all studies, eliglustat was well-tolerated. One serious adverse event (spontaneous abortion) and one discontinuation due to an adverse event (urinary tract infection) were reported, both during the acid-reducing agents study. When eliglustat is coadministered with medications that are P-glycoprotein or CYP2D6 substrates, lower doses of these concomitant medications may be required. Eliglustat may be coadministered with oral contraceptives and acid-reducing agents without dose modifications for either drug.

Semimechanistic Modeling to Guide Venetoclax Coadministration with Ritonavir and Digoxin.

Venetoclax is a cytochrome P450, family 3, subfamily A (CYP3A) substrate and was shown to inhibit P-gp efflux transporters in vitro. To quantify the impact of CYP3A inhibition by ritonavir on venetoclax disposition and P-gp inhibition by venetoclax on digoxin pharmacokinetics, two semimechanistic drug-drug interaction (DDI) models of venetoclax were developed using clinical data from healthy volunteers who received subtherapeutic doses of venetoclax with ritonavir 50-100 mg or digoxin 0.5 mg. These models were then used to assess the magnitude of interaction at therapeutic venetoclax doses and to explore various clinical dosing strategies that maintain venetoclax and digoxin concentrations within their respective therapeutic windows. Simulations demonstrated that venetoclax dose reductions of at least 75% are needed when venetoclax is coadministered with ritonavir and administering digoxin at least 2 hours before venetoclax would minimize DDI. Semimechanistic modeling leveraging clinical data is a plausible approach to predict DDI and propose dose adjustments, and administration time of interacting drugs.

Effects of Maribavir on P-Glycoprotein and CYP2D6 in Healthy Volunteers.

Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin Cmax , AUClast , and AUC0-∞ with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the "no-effect" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUClast and AUClast ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.