Background: Crizanlizumab is a novel inhibitor of P-selectin, a key player in multicellular adhesion and inflammatory signaling, that leads to vaso-occlusion in sickle cell disease (SCD). Objectives: The SOLACE-adults study evaluated the pharmacokinetics, pharmacodynamics (P-selectin inhibition), safety, and efficacy of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in patients with SCD. Design: Phase II, single-arm, multicenter study. Methods: Patients with SCD aged 16–70 years, with ⩾1 vaso-occlusive crisis (VOC) within 12 months before screening, received crizanlizumab 5.0 or 7.5 mg/kg intravenous infusion every 4 weeks; dose groups were enrolled sequentially. Results: Of 57 patients enrolled, 45 received crizanlizumab 5.0 mg/kg and 12 received 7.5 mg/kg for a median duration of 206 and 170 weeks, respectively. Crizanlizumab concentrations reached maximum levels after a 30-min infusion and remained steady for 6 h, without significant accumulation. P-selectin inhibition was nearly complete for both doses. The median (interquartile range) absolute change in the annualized rate of VOCs leading to healthcare visit from baseline was −0.79 (−3.04, 2.01) in the 5.0 mg/kg group and −0.98 (−1.11, −0.41) in the 7.5 mg/kg group. All patients experienced at least one adverse event (AE), with no apparent differences between the two doses in the frequency and severity of AEs. Grade ⩾3 AEs occurred in 60% of the 5.0 mg/kg group and 58% of the 7.5 mg/kg group. Two patients in the 5.0 mg/kg group and one in the 7.5 mg/kg group had severe crizanlizumab-related infusion-related reactions, which resolved with treatment. No patients developed antibodies against crizanlizumab. Conclusion: Crizanlizumab 5.0 and 7.5 mg/kg demonstrated a dose-proportional increase in exposure, sustained P-selectin inhibition, a tolerable safety profile, and a sustained reduction in VOCs leading to healthcare visit. This suggests that crizanlizumab is a useful treatment option for patients with SCD who have experienced VOCs. Trial Registration: NCT03264989

Background: Acute painful vaso-occlusive crises (VOCs), the hallmark of sickle cell disease (SCD), are associated with chronic and potentially life-threatening complications. The SOLACE-adults study (NCT03264989) interim analysis (cutoff date: August 1, 2020) demonstrated the long-term pharmacokinetic (PK) and pharmacodynamic (PD) properties, potential sustained efficacy (VOC reduction), and long-term safety of crizanlizumab 5 mg/kg and 7.5 mg/kg during ≥12 months' (mo) treatment in >80% of patients (pts) with SCD [Kanter J et al . Blood advances 2023]. Here we report the updated PK/PD, including ex vivo P-selectin inhibition, safety, and efficacy results from the final interim analysis of this study (cutoff date: June 1, 2022) for all pts who received crizanlizumab 5 mg/kg (~3.5 years [y]) and 7.5 mg/kg (~3 y). Methods: This is a phase 2, multicenter, open-label study in pts with SCD, aged 16 to 70 y, who had experienced ≥1 VOC (defined as pain crises and complicated SCD crises such as acute chest syndrome, priapism and hepatic or splenic sequestration) in the 12 mo prior to screening. Pts were enrolled into 5 mg/kg and then 7.5 mg/kg groups sequentially and received crizanlizumab by intravenous infusion over 30 minutes on day 1, day 15, and every 4 weeks (wk) thereafter. Pts receiving hydroxyurea/hydroxycarbamide (HU/HC) and/or erythropoietin-stimulating agents for at least 6 mo prior to screening were allowed to continue the same dose and schedule during the study. Results: Overall, 57 pts were enrolled: 45 received crizanlizumab 5 mg/kg (median age, 29 [IQR 22, 39] y) for a median of 191 (IQR 98, 210) wk, and 12 received 7.5 mg/kg (median age, 21 [IQR 18, 41] y) for a median of 167 (IQR 120,182) wk. At cutoff, 22 pts (49%) in 5 mg/kg group and 6 pts (50%) in 7.5 mg/kg group discontinued the treatment, primarily because of physicians' (5 mg/kg, n=6; 7.5 mg/kg, n=4) and pts' decisions (5 mg/kg, n=9). For both doses, serum crizanlizumab concentrations increased to nearly maximum levels (C max) at the end of the 30-minute infusion and remained steady for 6 hours after infusion. For each dose, C max at wk 1 and 15 was similar ( Table), indicating no significant accumulation. Crizanlizumab exposure increased almost dose proportionally from 5 mg/kg to 7.5 mg/kg. P-selectin inhibition was nearly complete throughout the dosing interval for both doses at steady state (5 mg/kg, 90% to 98%; 7.5 mg/kg, 86% to 96%), with consistent and stable pre-dose inhibition throughout the study ( Figure). All pts reported ≥1 adverse events (AEs) in both dose groups. The most common AEs were pyrexia (5 mg/kg, 14 [31%]; 7.5 mg/kg, 3 [25%]), headache and hypokalemia (5 mg/kg, 12 [27%]; 7.5 mg/kg, 2 [17%], each). Grade ≥3 AEs occurred in 27 pts (60%) in the 5 mg/kg group and in 6 pts (50%) in the 7.5 mg/kg group. At least one serious AE was reported in 22 pts (49%) in the 5 mg/kg group and 5 pts (42%) in the 7.5 mg/kg group; 1 was drug related in 5 mg/kg group (none in the 7.5mg/kg group). One pt in each of the 5 mg/kg (2%) and 7.5 mg/kg (8%) groups discontinued treatment because of drug-related AEs. One pt in each group died while on treatment, but the death was not considered related to crizanlizumab. Two pts in the 5 mg/kg group had severe crizanlizumab-related infusion-related reactions (IRR) (grade 2 pain [n=1], grade 3 IRR [n=1]), which resolved with treatment. No grade ≥3 treatment-related infections or bleeding events were reported. No pts developed antibodies against crizanlizumab. The median (IQR) annualized rate of VOCs leading to a healthcare visit in the 5 mg/kg group was 4 (1, 7) at baseline and 2.75 (1.03, 5.32) on treatment; absolute change from baseline, -0.76 (-2.94, 2.01). In the 7.5 mg/kg group, the corresponding rates were 2 (1, 4.5) and 1.09 (0.30, 3.36), -0.91 (-1.06, -0.50). Eight pts (18%) in the 5 mg/kg group and 2 pts (17%) in the 7.5 mg/kg group were VOC free during the entire treatment period. Conclusions: These long-term results for ~3.5 y in 5 mg/kg and ~3 y in 7.5 mg/kg groups demonstrate that serum crizanlizumab concentrations rose to a near maximum level shortly after infusion and remained steady 6 hours after infusion for both doses. Crizanlizumab with or without HU/HC was safe with no new/unexpected safety concerns and no apparent differences between the two doses in the frequency and severity of AEs. Consistent with previously reported results from SUSTAIN study, crizanlizumab reduced the annualized rate of VOCs leading to a healthcare visit from baseline.

Background: Vaso-occlusive crises (VOCs) are a key characteristic of sickle cell disease (SCD). Safety and efficacy of crizanlizumab from 26-week analysis of SOLACE-kids study in 50 children with SCD aged 12 to <18 years were reported at ASH 2021. Safety and tolerability of the confirmed dose (5 mg/kg) of crizanlizumab in these children were consistent with the established profile in adults from the SUSTAIN study. Crizanlizumab also showed a reduction in the median annualized rate of VOCs compared to baseline. Aims: To confirm and establish appropriate dosing for different pediatric age groups (Part A), and to evaluate the safety and efficacy of the confirmed dose of crizanlizumab (Part B), in additional pediatric patients with SCD (ClinicalTrials.gov: NCT03474965; EudraCT: 2017-001747-12). Methods: SOLACE-kids is an ongoing Phase 2 study conducted in children with SCD (any genotype) and a history of ≥1 VOC leading to a healthcare visit within 12 months prior to screening. Eligible patients are grouped by age: Group 1 (12 to <18 years), Group 2 (6 to <12 years), and Group 3 (6 months to <6 years). Patients received crizanlizumab on Day 1, Day 15, then every 4 weeks (up to 2 years), with or without hydroxyurea (HU)/Hydroxycarbamide (HC). This analysis reports updated pharmacokinetics (PK)/pharmacodynamics (PD; ex vivo P-selectin inhibition), safety, and efficacy results for patients in Group 1 who received crizanlizumab 5 mg/kg IV for 2 years. Results: As of 05 May 2022, of 50 patients enrolled in Group 1 (median [range] age 14.9 [12.0–17.9] years; 58% female; 88% HbSS genotype; 64% Black/African American; 84% receiving HU), 33 (66%) completed treatment with crizanlizumab. Median (Q1-Q3) duration of crizanlizumab exposure was 106.1 (94.9–107) weeks; 86% and 56% of patients received treatment for ≥54 and ≥106 weeks, respectively. Eleven patients’ data were evaluated for PK/PD analysis. The mean area under the curve from time zero to the last measurable concentration after the first infusion (AUCd15) and after multiple doses at steady state (AUCtau) was 10500 and 15800 hr*μg/mL, respectively. The mean maximum serum concentrations (Cmax) after the first infusion (80.5 μg/ml) and at steady state (95.6 μg/mL), indicated no significant accumulation of crizanlizumab. At steady state, the mean apparent elimination half-life (T1/2) was 10.3 days. The mean P-selectin inhibition ranged from 98.7% to 100% at a first dose and from 88.6% to 97.6% at the steady-state dose. Overall, 47 (94%) patients reported ≥1 adverse event (AEs), most commonly with headache (38%). Treatment-related AEs occurred in 15 (30%) patients, of which infusion-related reaction (10%) and nausea (6%) were most common. Grade ≥3 AEs occurred in 24 (48%), of which back pain and pain in extremity in 1 patient and increased bilirubin in 1 patient were related to crizanlizumab. None of the serious AEs or AEs leading to discontinuation (including one death due to bacterial meningitis), dose change, and/or interruption were deemed related to crizanlizumab per the investigator. None of these patients developed antibodies against crizanlizumab. The impact of crizanlizumab on annualized rate of VOCs is summarized in Table. Summary/Conclusion: In this 2-year analysis, crizanlizumab 5 mg/kg with or without concomitant HU/HC has shown a reduction in VOCs resulting in decreased healthcare visits per year, consistent with the established profile of crizanlizumab in adults. Crizanlizumab was safe and well tolerated with no new/unexpected safety concerns. These results confirm 5 mg/kg as an adequate dose in pediatrics with SCD aged 12 to <18 years.Keywords: Sickle cell disease, Vasoocclusive crisis, P-selectin, Pediatric

Purpose:To evaluate the pharmacology and toxicology of SAF312, a transient receptor potential vanilloid 1 (TRPV1) antagonist.Methods:TRPV1 expression in human ocular tissues was evaluated with immunohistochemistry. Inhibition of calcium influx in Chinese hamster ovary (CHO) cells expressing human TRPV1 (hTRPV1) and selectivity of SAF312 were assessed by a fluorescent imaging plate reader assay. Ocular tissue and plasma pharmacokinetics (PK) were assessed following a single topical ocular dose of SAF312 (0.5%, 1.0%, 1.5%, 2.5%) in rabbits. Safety and tolerability of SAF312 were evaluated in rabbits and dogs. Effects of SAF312 on corneal wound healing after photorefractive keratectomy (PRK) surgery were assessed in rabbits.Results:TRPV1 expression was noted in human cornea and conjunctiva. SAF312 inhibited calcium influx in CHO-hTRPV1 cells induced by pH 5.5 (2-[N-morpholino] ethanesulfonic acid), N-arachidonoylethanolamine, capsaicin, and N-arachidonoyl dopamine, with IC50 values of 5, 10, 12, and 27 nM, respectively, and inhibition appeared noncompetitive. SAF312 demonstrated high selectivity for TRPV1 (>149-fold) over other TRP channels. PK analysis showed highest concentrations of SAF312 in cornea and conjunctiva. SAF312 was found to be safe and well tolerated in rabbits and dogs up to the highest feasible concentration of 2.5%. No delay in wound healing after PRK was observed.Conclusions:SAF312 is a potent, selective, and noncompetitive antagonist of hTRPV1 with an acceptable preclinical safety profile for use in future clinical trials.Translational Relevance:SAF312, which was safe and well tolerated without causing delay in wound healing after PRK in rabbits, may be a potential therapeutic agent for ocular surface pain.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium–glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo ( n = 21), licogliflozin 30 mg ( n = 43) or 150 mg ( n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21–43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7–32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150.

Abstract Absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported. Oral absorption of licogliflozin was rapid (t max < 1 h) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively. Excretion of licogliflozin-related radioactivity was rapid and nearly complete following oral administration with total radioactivity recovery ranging from 73% in dogs, 92.5% in humans, to 100% in rats. Dose-related radioactivity was excreted in both urine and faeces with urinary excretion playing a slightly more important role in humans (∼56%) than in animal species (∼19–41%). Elimination of licogliflozin was predominantly via metabolism with the majority of the radioactivity dose (∼54–74%) excreted as metabolites across species. The principal biotransformation pathways involved direct glucuronidation and oxidation across all species. In humans, direct glucuronidation to M17 and M27 was the major pathway observed, accounting for ∼38% of the dose in excreta while oxidative metabolism also contributed to >29% of the dose in excreta. Oxidative pathways were predominant in animal species.

To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium‐glucose co‐transporter‐1 and sodium‐glucose co‐transporter‐2 inhibitor, in patients with chronic kidney disease (CKD).

Treatment with licogliflozin, a dual sodium‐glucose co‐transporter (SGLT)1/2‐inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin‐induced stools, a randomized, open‐label, two‐part (N = 24/part), three‐period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3‐day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well‐tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

BACKGROUNDThere is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium‐glucose co‐transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity.METHODSPatients with obesity (BMI, 35‐50 kg/m2) were enrolled into a 12‐week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two‐part study, comprising a single‐dose cross‐over study (N = 12; 2.5 − 300 mg) and a 14‐day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP‐1, PYY3‐36, and GIP), insulin and glucagon.RESULTSTreatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC0‐4h) and suppressed insulin by 90% (P < 0.01; incremental AUC0‐4h). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24‐hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP‐1 by 54% (P < 0.001) and PYY3‐36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12‐week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%‐43% with licogliflozin vs 9%‐11% with placebo in the 12‐week study) were among the other gastrointestinal events reported.CONCLUSIONLicogliflozin treatment (1‐84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.

Background: Patients with resistant hypertension have a higher risk of cardiovascular morbidity and mortality. The current treatment options for patients with resistant hypertension are limited by ...

Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SGLT2). We studied mechanistic effects of dual SGLT1/2 inhibition of SGLT1 in the gut and SGLT1/2 in the kidneys. Methods: Effects of LIK066 on weight, glucose and a variety of incretin hormones (GLP-1, PYY, GIP, glucagon, insulin) were investigated in: 1) a single dose cross-over study in T2DM, 2) a 14 day randomized, double-masked study in T2DM, 3) a 12-week randomized, double-masked, placebo-controlled study in obese subjects with normoglycemia (NG) or dysglycemia (DG; HbA1c: ≥5.7% and <10%). Results: LIK066 (2.5, 30, 300 mg single dose) significantly reduced glucose excursion and insulin secretion (p<0.01 at 30 and 300 mg) following oral glucose tolerance test (OGTT) in patients with T2DM (n=12), with the 300 mg dose completely suppressing glucose and insulin excursions. In patients with T2DM (n=30), LIK066 15 mg qd for 14 days reduced blood glucose (41 mg/dL by continuous glucose monitoring) and increased 24-hour urinary glucose excretion (100 g/d on day 14). Furthermore total GLP-1 and PYY increased (AUC0-3hrs >1.5-fold; p<0.05) post-OGTT, while GIP levels were reduced (>50%; p<0.05). In obese subjects (n=88), LIK066 150 mg qd for 12 weeks reduced weight by 5.70% (p<0.001) compared to placebo, with higher effects in DG (6.85%) vs. NG (4.55%). Additionally multiple metabolic parameters improved (reduced waist circumference, postprandial glucose and insulin, and increased postprandial glucagon). LIK066 was generally safe and well tolerated. The most common AEs were headache, flatulence and diarrhea. Conclusions: LIK066 treatment leads to favorable changes in a variety of metabolic hormones (increased GLP-1, PYY and glucagon, reduced GIP, glucose and insulin), all contributing to WL effects of LIK066. The dual inhibition of SGLT1/2 in both the gut and kidneys is an attractive strategy for obesity or diabetes treatment. Disclosure Y. He: None. W.G. Haynes: Employee; Self; AstraZeneca. C.D. Meyers: Employee; Self; Janssen Research & Development. A. Amer: Employee; Self; Novartis Pharmaceuticals Corporation. Stock/Shareholder; Self; Novartis AG. Y. Zhang: Employee; Self; Novartis Pharmaceuticals Corporation. P.C. Mahling: None. A.E. Mendonza: None. S. Ma: None. W. Chutkow: Employee; Self; Novartis Pharmaceuticals Corporation. E.S. Bachman: None.

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug‐drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co‐administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel‐ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open‐label, single‐sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel‐ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co‐administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co‐administration of LCZ696 with levonorgestrel‐ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co‐administration of LCZ696 with omeprazole, metformin, or levonorgestrel‐ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.

Pradigastat, a novel diacylglycerol acyltransferase‐1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'‐diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, ‐1A3, and ‐2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and ‐1A3 indicated that these enzymes contribute ∼55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, ‐1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUCτ,ss of pradigastat were within 0.80–1.25 when administered in combination with probenecid. However, the Cmax,ss and AUCτ,ss of pradigastat decreased by 31% (90%CI: 0.62–0.78) and 26% (0.67–0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady‐state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid.

BMS-820836, a novel triple monoamine reuptake inhibitor, is an experimental monotherapy for sufferers of major depressive disorder who have had an inadequate response to an existing antidepressant treatment.

Objective: LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for the treatment of cardiovascular diseases including hypertension and heart failure. Ingestion of LCZ696 results in systemic exposure to AHU377 (an inactive prodrug converted to LBQ657, a neprilysin inhibitor) and valsartan (angiotensin receptor inhibitor). Digoxin, a narrow therapeutic index drug, is a commonly administered medication to heart failure patients. Since LCZ696 and digoxin may be co-administered in this patient population, this study was conducted to evaluate the pharmacokinetic drug-drug interaction potential between LCZ696 and digoxin. Methods: This study employed an open label, two-period, single sequence study design in 24 healthy subjects. In period 1, subjects received 200 mg LCZ696 b.i.d for 3 days and a single dose of 200 mg LCZ696 on Day 4 morning. Following a 4-7 day washout, in period 2, all subjects received 0.25 mg digoxin q.d. for 14 days and 200 mg LCZ696 b.i.d co-administered from Day 11 to Day 14. Serial PK samples were collected in both treatment periods and analyzed using validated LC/MS/MS bioanalytical methods. The PK parameters including Cmaxss and AUCtau of LCZ696 analytes (LBQ657, valsartan) and digoxin were determined using non-compartmental analysis and the results were statistically evaluated. Results: The 90% confidence intervals of the geometric mean ratios (test/reference) for Cmaxss and AUCtau of digoxin were within the 0.8-1.25 range indicating that LCZ696 did not affect the PK of digoxin. Similarly, the 90% confidence intervals of the geometric mean ratios for Cmaxss and AUCtau for both LBQ657 and valsartan were within the 0.8-1.25 range indicating that digoxin did not affect the PK of LCZ696 analytes. Conclusion: After co-administration of LCZ696 200 mg b.i.d with digoxin 0.25 mg q.d., exposures of digoxin and the LCZ696 analytes (LBQ657 and valsartan) remained unchanged. LCZ696 200 mg b.i.d was safe and well tolerated in healthy subjects when administered alone and in combination with digoxin 0.25 mg qd.

Background: Diabetes mellitus is prevalent among kidney transplant recipients. The activity of drug metabolizing enzymes or transporters may be altered by diabetes leading to changes in the concentration of parent drug or metabolites. This study was aimed to characterize the effect of diabetes on the concentration of cyclosporine (CsA) and metabolites. Methods: Concentration–time profiles of CsA and metabolites (AM1, AM9, AM4N, AM1c, AM19, and AM1c9) were characterized over a 12-hour dosing interval in 10 nondiabetic and 7 diabetic stable kidney transplant recipients. All patients were male, had nonfunctional CYP3A5*3 genotype, and were on combination therapy with ketoconazole. Results: The average daily dose (±SD) of CsA was 65 ± 21 and 68 ± 35 mg in nondiabetic and diabetic subjects, respectively (P = 0.550). Cyclosporine metabolites that involved amino acid 1 (AM1, AM19, AM1c) exhibited significantly lower dose-normalized values of area under the concentration–time curve in patients with diabetes. Moreover, during the postabsorption phase (≥3 hours after dose), metabolite–parent concentration ratios for all metabolites, except AM4N, was significantly lower in diabetic patients. The pharmacokinetic parameters of ketoconazole were similar between the 2 groups thus excluding inconsistent ketoconazole exposure as a source of altered CsA metabolism. Conclusions: This study indicates that diabetes mellitus significantly affects the concentration of CsA metabolites. Because CsA is eliminated as metabolites via the biliary route, the decrease in the blood concentration of CsA metabolites during postabsorption phase would probably reflect lower hepatic cytochrome P450 3A4 enzyme activity. However, other mechanisms including altered expression of transporters may also play a role. Results of cyclosporine therapeutic drug monitoring in diabetic patients must be interpreted with caution when nonspecific assays are used.

The oral bioavailability of valsartan from extemporaneous suspension and solution formulations were evaluated relative to tablet formulation in two separate open-label, randomized crossover studies in healthy adults. In both studies, the plasma concentrations of valsartan after oral administration were analyzed using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, and the corresponding pharmacokinetic parameters were estimated using noncompartmental analysis. The peak plasma concentration (C-max) and area under the concentration time-curves (AUC((0-infinity))) of valsartan from the extemporaneous suspension were higher by 1.93- and 1.56-fold, respectively, relative to the tablet formulation (P<.001). The C-max and AUC((0-infinity)) of valsartan from the oral solution were higher by 2.21- and 1.74-fold, respectively, relative to the tablet formulation (P<.001). These results indicate that both rate and extent of absorption of valsartan are higher in the two liquid dosage forms (extemporaneous suspension and solution formulations) relative to the solid oral dosage form (tablet formulation).