Identification and characterization of critical values in therapeutic drug monitoring: a retrospective analysis.

Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.

Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail.

PURPOSE: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail. METHODS: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination. RESULTS: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h-1 vs. 5.18 h-1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min. CONCLUSION: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used.

Visual monitoring and optical recognition of digoxin by functionalized AuNPs and triangular AgNPs as efficient optical nano-probes.

In this study, we presented elective, sensitive, and rapid UV-Vis spectrophotometry and calorimetric assay for the recognition of digoxin. Therefore, cysteamine-gold nanoparticles (Cys A-AuNPs) in the presence of cysteine acid amine and Silver nanoparticles in the presence of tetramethyl benzidine and hydrogen peroxide (AgNPs-TMB [3,3',5,5'-tetramethylbenzidine]-H2 O2 ) were synthesized and utilized as the desired probe. Finally, color variation of probes was observed in the absence and presence of digoxin. Obtained results indicate that the color of Cys A-AuNPs changed from dark pink to light in the absence and the presence of digoxin, respectively. Also, the color of AgNPs-TMB-H2 O2 changed from dark blue to light blue, in the absence and the presence of digoxin, respectively. Moreover, UV-Vis spectroscopies results indicate digoxin with a low limit of quantification of 0.125 ppm in human plasma samples which linear range was 0.125 to 11 ppm.

Influence of OATP1B1 and OATP1B3 mutations and glomerular filtration rate on trough serum digoxin concentration in the Chinese population: A prospective cohort study.

Polymorphisms of organic anion transporting polypeptides (OATPs) have been reported to affect trough serum digoxin concentration (SDC). However, the association of these polymorphisms with trough SDC in Chinese heart failure patients has not been studied. We aim to explore whether OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A influence trough SDC in Chinese heart failure patients and to make clinical recommendations.Chinese patients (n = 104) diagnosed with heart failure under long-term digoxin therapy (0.125 mg daily) were enrolled in this study. Blood samples were collected for the analysis of trough SDC (immunofluorescence) and the polymorphisms of OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A (PCR-RFLP and Sanger sequencing).Patients with glomerular filtration rate (GFR) under 30 mL/min had significantly higher trough SDC (1.20 ±â€Š0.50 ng/mL) than recommended trough SDC for heart failure patients. Trough SDC was not significantly influenced by mutations of OATP1B1 388A>G (P = .890), 521T>C (P = .054), and OATP1B3 699G>A (P = .854). Patients with OATP1B1 521T>C mutant-type carrier had slightly higher trough SDC (0.98 ±â€Š0.53 ng/mL) than those with wild-type carrier (0.74 ±â€Š0.40 ng/mL) when they have repaired renal function.Heart failure patients with severe renal dysfunction (GFR<60 mL/min) and/or OATP1B1 521T>C mutant-type carriers are recommended a smaller dosage of digoxin and strict therapeutic drug monitoring.

Taking Advantage of Assay Harmonization, Biotin Interference in the LOCI Digoxin Assay Could Be Eliminated by Using the ADVIA Centaur Digoxin Assay.

Biotin at elevated concentration interferes with immunoassays that utilize biotin in assay design. We earlier reported interference of biotin in the luminescent oxygen channeling assay (LOCI) digoxin assay which utilizes biotinylated antibody against digoxin. However, the ADVIA Centaur digoxin assay, also manufactured by Siemens Diagnostics, does not utilize biotin in assay design. We hypothesized that if the LOCI and the ADVIA Centaur digoxin assay are harmonized, then interference of biotin in the LOCI digoxin assay could be eliminated by using the ADVIA Centaur digoxin assay. We analyzed 25 specimens from patients receiving digoxin using both assays to investigate harmonization between these two assays. Then aliquots of drug-free serum pool were supplemented with various biotin concentrations (range: 10 ng/mL to 2000 ng/mL) followed by measuring apparent digoxin levels using the ADVIA Centaur digoxin assay. In another set of experiments, aliquots of a serum digoxin pool were supplemented with biotin (10-2000 ng/mL) and digoxin concentrations were measured by the ADVIA Centaur digoxin assay. We observed an excellent correlation between digoxin values obtained by the LOCI digoxin assay (reference method) and the ADVIA Centaur digoxin assay (y= 1.0514 x+0.1083, r=0.99) indicating that both assays are harmonized. We did not observe any interference of biotin even at a highly elevated concentration of 2000 ng/mL with the ADVIA Centaur digoxin assay. We conclude that taking advantage of assay harmonization, interference of biotin in the LOCI digoxin assay can be eliminated by using the ADVIA Centaur digoxin assay.

High doses of digoxin increase the myocardial nuclear factor-kB and CaV1.2 channels in healthy mice. A possible mechanism of digitalis toxicity.

BACKGROUND: Toxic effects of digoxin may occur with normal therapeutic serum level. However, the underlying mechanisms are not fully understood. Nuclear factor kappa-B (NF-kB) is an important transcription factor in most organ systems and is often implicated in the harmful effects of cardiac injury. NF-kB promotes inflammatory responses, mediates adverse cardiac remodeling and has a function correlation with calcium. The voltage-gated L-type calcium channel CaV1.2 mediates the influx of Ca+2 into the cell in response to membrane depolarization. Our aim was to characterize the role of NF-kB during digoxin toxicity and to assess its correlation with Cav 1.2 in healthy mice in vivo. METHODS: To address these questions, digoxin was administered in doses of 0.1, 1 or 5 mg/kg orally daily for seven days to the animals. Serum digoxin, serum calcium, atrial and ventricular calcium levels were measured. We, also, looked for NF-kB and CaV1.2 channel expression in cardiac muscle of mice. RESULTS: Digoxin at a dose of 0.1 mg/kg did not enhance serum, atrial, and ventricular Ca+2 levels, but were increased when digoxin dose of 1 and 5 mg/kg were administered. Histologically, myocardial necrosis and cellular infiltration on day 7 were significantly more severe in the 5 mg/kg/day digoxin group. Immunohistochemical studies showed more expression of both NF-kB and CaV1.2 in 1 and 5 mg/kg/day digoxin groups. CONCLUSIONS: These data suggest that NF-kB may be responsible for digoxin toxicity, at least partially via modulation of CaV1.2 and intracellular calcium homeostasis in the myocardium.

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin.

BACKGROUND: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. METHODS: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. RESULTS: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). CONCLUSIONS: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. METHODS: Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). RESULTS: Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. CONCLUSIONS: No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. METHODS: In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. RESULTS: Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed. CONCLUSIONS: Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen® are recommended when coadministered with dulaglutide. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

ABCB1 and SLCO1B3 Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population.

BACKGROUND: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. METHODS: ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. RESULTS: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. CONCLUSION: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.

Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a P-Glycoprotein Substrate): Results From in Vitro and Phase I Clinical Studies.

PURPOSE: Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of fostamatinib on the pharmacokinetic parameters of digoxin to understand drug-drug interaction (DDI) potential in the clinic. METHODS: Inhibition of P-gp-mediated digoxin transport by fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC50) and theoretical gastrointestinal concentration [I2] (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration-time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral fostamatinib 100 mg BID on days 9 to 15. FINDINGS: Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC50 = 3.2 µM). On the basis of a theoretical gastrointestinal concentration (I2)/IC50 ratio of 216 ([I2] = 691 µM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70-fold increase in digoxin maximum plasma concentration at steady state (Cmax,ss) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of Cmax was earlier when digoxin was co-administered with fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported. IMPLICATIONS: Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354.

Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects.

AIM: Interindividual epigenetic variation is likely to be an important mechanism contributing to the interindividual variability in the expression and function of ATP-binding cassette, sub-family B, member 1 (ABCB1). The aim of the present study was to explore the effect of interindividual epigenetic variability in the ABCB1 promoter on ABCB1 expression and function in healthy Chinese subjects. METHODS: Using bisulfite sequencing polymerase chain reaction (PCR) and chromatin immunoprecipitation assays, the DNA methylation and histone acetylation status of the ABCB1 promoter in stool DNA and exfoliated colonic epithelial cells of 157 healthy Chinese male volunteers was analysed. ABCB1 mRNA levels in colonic epithelial cells were detected by real-time PCR. The digoxin pharmacokinetics in subjects with different epigenetic profiles was investigated after a single oral administration of digoxin (0.5 mg). RESULTS: The methylation levels of ABCB1 promoter in stool DNA showed a significant interindividual variation, from 0.84% to 18.05%. A high methylation level of the ABCB1 promoter was closely related to the low levels of acetylated histone H3 and ABCB1 mRNA expression. In the high methylation group, the area under the concentration-time curves (AUC(0-4 h) and AUC(0-10 h) ) of digoxin was increased by 19% [95% confidence interval (CI) 10%, 31%; P = 0.024] and 13% (95% CI 8%, 26%; P = 0.026), respectively, and the peak concentration (Cmax ) of digoxin was increased by 30% (95% CI 12%, 41%; P = 0.021) compared with the low methylation group. CONCLUSIONS: The epigenetic modifications of the ABCB1 promoter show high interindividual variability in healthy Chinese subjects, and are closely related to the interindividual variation in ABCB1 mRNA expression and digoxin 0-4 h plasma concentrations in vivo.

Clinical drug interaction profile of idelalisib in healthy subjects.

Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ], respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.

Effect of lapatinib on oral digoxin absorption in patients.

The potential for an interaction between lapatinib and absorption of the P-glycoprotein (ABCB1) substrate digoxin at a therapeutic dose in breast cancer patients was characterized. Seventeen women with HER2-positive metastatic breast cancer received a single oral 0.5-mg dose of digoxin on days 1 and 9 and oral lapatinib 1500 mg once daily on days 2 through 9. Digoxin pharmacokinetic parameters were determined on day 1 (digoxin administration alone) and on day 9 (coadministration of lapatinib and digoxin), and parameters were compared to determine the effects of lapatinib on digoxin absorption. Concomitant medications that could affect ABCB1 were accounted for. Lapatinib 1500 mg/day increased digoxin absorption approximately 80%, implicating lapatinib inhibition of intestinal ABCB1-mediated efflux. In summary, coadministration of lapatinib with narrow therapeutic index drugs that are substrates of ABCB1 should be undertaken with caution and dose adjustment should be considered.

[Study of pharmacokinetics of digoxin in ovariectomized rats model].

This study aims to investigate the change of plasma concentration of digoxin (DIG) in rats with ovariectomy. Twelve female SD rats were randomly assigned into ovariectomized group and sham group (n = 6). All rats plasma was collected after a single dose of 2 mg x kg(-1) DIG administrated orally, serum DIG concentration was determined by LC-MS/MS. The level of P-gp in the intestinal was analyzed by Western blotting. Pharmacokinetic calculations were performed on each individual using DAS 2.0 practical pharmacokinetic software. Compared with the sham group, C(max) of ovariectomized group decreased significantly (P < 0.01). There was no significant difference of AUC(0-t), and the level of P-gp was elevated in ovariectomized group. It was found that C(max) of DIG was significantly reduced after ovariectomy, and the change was associated with the decreased level of estrogen, which contributes to the increased level of P-gp.

Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.

OBJECTIVE: Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. METHODS: All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 µg) + ethinyl estradiol (30 µg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). RESULTS: Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin'€™s PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. CONCLUSION: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.

Pharmacokinetic evaluations of the co-administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or ranitidine.

BACKGROUND AND OBJECTIVE: Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655). METHODS: Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. RESULTS: Vandetanib + metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. CONCLUSION: Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.