The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis.

Aspergillus spp. infections remain a global concern, with ∼30% attributable mortality of invasive aspergillosis (IA). VT-1598 is a novel fungal CYP51 inhibitor designed for exquisite selectivity versus human CYP enzymes to achieve a maximal therapeutic index and therefore maximal antifungal efficacy. Previously, its broad-spectrum in vitro antifungal activity was reported. We report here the pharmacokinetics (PK) and pharmacodynamics (PD) of VT-1598 in neutropenic mouse models of IA. The plasma area-under-the-curve (AUC) of VT-1598 increased nearly linearly between 5 and 40 mg/kg after 5 days of QD administration (155 and 1033 µg*h/ml, respectively), with a further increase with 40 mg/kg BID dosing (1354 µg*h/ml). When A. fumigatus isolates with in vitro susceptibilities of 0.25 and 1.0 µg/ml were used in a disseminated IA model, VT-1598 treatment produced no decrease in kidney fungal burden at QD 10 mg/kg, intermediate decreases at QD 20 mg/kg and maximum or near maximum decreases at 40 mg/kg QD and BID. The PK/PD relationships of AUCfree/MIC for 1-log killing for the two strains were 5.1 and 1.6 h, respectively, similar to values reported for approved CYP51 inhibitors. In a survival study where animals were observed for 12 days after the last treatment, survival was 100% at the doses tested (20 and 40 mg/kg QD), and fungal burden remained suppressed even though drug wash-out was complete. Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection.

A validated RP-HPLC method for the evaluation of the influence of grapefruit juice on liver S9 activation of sacubitril.

Grapefruit juice inhibits esterase enzyme. Therefore, a possible interaction with ester prodrugs should be taken into consideration. In this study, the influence of grapefruit juice on sacubitril (SAC) rat liver S9 activation by esterase enzyme was evaluated. An RP-HPLC method was developed and validated for estimation of SAC in rat liver S9 fraction using a C18 Cyano column as stationary phase and acetonitrile-sodium di-hydrogen phosphate buffer (0.02 m, pH 4 adjusted by o-phosphoric acid, 40:60, v/v), as mobile phase at a flow rate of 1 mL/min and UV detection at 254 nm. The method was successfully applied to an in vitro study in which SAC was incubated with rat liver S9 fraction prepared from rats that had previously ingested grapefruit juice for a week. The calculated SAC concentration after incubation was compared with that of SAC incubated with rat liver S9 fraction from the rat control group. The statistical significance between the results of test and control incubation sets was assessed. In conclusion, the current study demonstrated that grapefruit juice decreased SAC hydrolysis, hence delaying its activation to sacubitrilat (active form) in gut lumen. Based on this food-drug interaction, it may be required that grapefruit juice should be consumed with caution in patients receiving SAC.

Multiparameter Responses to Tedizolid Monotherapy and Moxifloxacin Combination Therapy Models of Children With Intracellular Tuberculosis.

Background: Children are often neglected during early development of antituberculosis agents, and most receive treatment after it is first tested in adults. However, very young children have tuberculosis that differs in many respects from adult cavitary pneumonia and could have different toxicity profiles to drugs. Linezolid is effective against intracellular tuberculosis, a common manifestation in young children. However, linezolid has considerable toxicity due to inhibition of mitochondrial enzymes. Tedizolid could be a replacement if it shows equal efficacy and reduced toxicity. Methods: We performed tedizolid dose-effect studies in the hollow fiber system model of intracellular tuberculosis. We measured linezolid concentrations, colony-forming units (CFU), time-to-positivity, and monocyte viability and performed RNA sequencing on infected cells collected from repetitive sampling of each system. We also compared efficacy of tedizolid vs linezolid and vs tedizolid-moxifloxacin combination. Results: There was no downregulation of mitochondrial enzyme genes, with a tedizolid 0-24 hour area under the concentration-time curve (AUC0-24) of up to 90 mg*h/L. Instead, high exposures led to increased mitochondrial gene expression and monocyte survival. The AUC0-24 to minimum inhibitory concentration ratio associated with 80% of maximal bacterial kill (EC80) was 184 by CFU/mL (r2 = 0.96) and 189 by time-to-positivity (r2 = 0.99). Tedizolid EC80 killed 4.0 log10 CFU/mL higher than linezolid EC80. The tedizolid-moxifloxacin combination had a bacterial burden elimination rate constant of 0.27 ± 0.05 per day. Conclusions: Tedizolid demonstrated better efficacy than linezolid, without the mitochondrial toxicity gene or cytotoxicity signatures encountered with linezolid. Tedizolid-moxifloxacin combination had a high bacterial elimination rate.

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.

Complex formation equilibria of Cu2+ and Zn2+ with Irbesartan and Losartan.

We conducted a thorough study of Cu2+ complex formation equilibria with Irbesartan and Losartan, the two primary drugs for the cure of cardiovascular diseases, with the aim of recognising if these drugs could exert a chelating action towards Cu2+. We used different complementary techniques to gain a clear picture of the involved protonation and complexation equilibria. The low solubility in water of the ligands and of the formed metal complexes prevented the use of water as solvent, so we had to perform the measurements in mixed methanol-water solvents. Further, we studied the related equilibria with Zn2+ for evaluating a potential interference of this essential metal ion, largely present in biological fluids. Our study provided a strong evaluation of the formed complexes and of the relative stability constants. The binding of both metal ions takes place through the tetrazole moiety except for the Zn2+-Irbesartan system. In this last case, NMR measurements gave evidence of a tautomeric equilibrium involving the imidazole ring and the aliphatic chain. The estimated complexation model, and the related stability constants, allowed a speciation study in human plasma, based on a number of simplifying assumptions, which remarked that both drugs, Losartan and Irbesartan, could exert a chelating action, scavenging non-negligible amounts of Cu2+ from the organism.

Fimasartan: A New Angiotensin Receptor Blocker.

Fimasartan is the ninth, and most recent, angiotensin II receptor antagonist approved as an antihypertensive agent. Fimasartan, a pyrimidin-4(3H)-one derivative of losartan with the imidazole ring replaced, which enables higher potency and longer duration than losartan. Fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan and the urinary excretion was found to be less than 3 % 24 h after administration. Fimasartan is primarily catabolized by cytochrome P450 isoform 3A and no significant drug interaction was observed when used in combination with hydrochlorothiazide, amlodipine, warfarin, or digoxin. Fimasartan at a dosage range of 60-120 mg once daily showed an antihypertensive effect over 24 h. In a large, population-based observational study, fimasartan showed an excellent safety profile. Anti-inflammatory and organ-protecting effects of fimasartan have been shown in various preclinical studies, including aortic balloon injury, myocardial infarct ischemia/reperfusion, doxorubicin cardiotoxicity, and ischemic stroke models.

Negligible Pharmacokinetic Interaction of Red Ginseng and Losartan, an Antihypertensive Agent, in Sprague-Dawley Rats.

Red ginseng (RG) is one of the top selling herbal medicines in Korea, but is not recommended in hypertensive patients. In this study, the pharmacokinetic (PK) interaction between RG and losartan, an antihypertensive drug, was examined. RG was orally administered for 2 wk to male Sprague-Dawley (S-D) rats at either control (0), 0.5, 1, or 2 g/kg/d for 2 wk. After the last administration of RG and 30 min later, all animals were treated with 10 mg/kg losartan by oral route. In addition, some S-D rats were administered RG orally for 21 d at 2 g/kg followed by losartan intravenously (iv) at 10 mg/kg/d. Post losartan administration, plasma samples were collected at 5, 15, and 30 min and 1, 1.5, 2, 3, 6, 12, and 24 h. Plasma concentrations of losartan and E-3174, the active metabolite of losartan, were analyzed by a high-pressure liquid chromatography-tandem mass spectrometer system (LC-MS/MS). Oral losartan administration showed dose-dependent pharmacokinetics (PK) increase with time to maximum plasma, but this was not significant between different groups. There was no significant change in tmax with E-3174 PK. With iv losartan, pharmacokinetics showed elevation of area under the plasma concentration-time curve from time zero extrapolated to infinitity. There was not a significant change in AUCinf with E-3174 PK. Therefore, RG appeared to interfere with biotransformation of losartan, as RG exerted no marked effect on E-3174 PK in S-D rats. Data demonstrated that oral or iv treatment with losartan in rats pretreated with RG for 2 wk showed that losartan PK was affected but E-3174 PK remained unchanged among different dose groups. These results suggested that RG induces negligible influence on losartan and E-3174 PK in rats.

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models.

Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 µg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.

VT-1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a guinea pig model.

Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 µg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 µg/ml (or µg/g), at or above the MIC against the isolate used in the model (0.5 µg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function.

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 µM versus 6.4 ± 1.2 µM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects.

AIMS: The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol. METHODS: A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol) were measured using liquid chromatography-tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment. RESULTS: The geometric mean ratios of area under the concentration-time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89-1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90-1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93-1.03; P = 0.47) for 4'-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments. CONCLUSIONS: Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.

Influence of compound danshen tablet on the pharmacokinetics of losartan and its metabolite EXP3174 by liquid chromatography coupled with mass spectrometry.

Losartan is an effective anti-hypotension drug frequently used in clinic. Compound danshen tablet (CDST) is an important traditional Chinese multiherbal formula composed of Danshen, Sanqi and Bingpian, which is widely used for the treatment of cardiovascular and cerebrovascular diseases in China. More often, losartan and CDST are simultaneously used for the treatment of anti-hypertension in the clinic. The aim of this study was to compare the pharmacokinetics of losartan and EXP3174 after oral administration of single losartan and both losartan and CDST, and to investigate the influence of CDST on the pharmacokinetics of losartan and its metabolite EXP3174. Male Sprague-Dawley rats were randomly assigned to two groups: a losartan-only group and a losartan and CDST group. Plasma concentrations of losartan and EXP3174 were determined by LC-MS at designated points after drug administration, and the main pharmacokinetic parameters were estimated. It was found that there were significant differences (p < 0.05) between the pharmacokinetic parameters of losartan and EXP3174, which showed that CDST influenced the metabolism and excretion of losartan in vivo. The result could be used for clinical medication guidance of losartan and CDST to avoid the occurrence of adverse reactions.

Comparative efficacies of human simulated exposures of tedizolid and linezolid against Staphylococcus aureus in the murine thigh infection model.

Tedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhanced in vitro potency against Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The efficacies of human simulated exposures of tedizolid and linezolid against S. aureus in an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 µg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P ≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similar in vivo efficacies against the S. aureus isolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused by S. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.

Impact of granulocytes on the antimicrobial effect of tedizolid in a mouse thigh infection model.

Tedizolid (TR-700, formerly torezolid) is the active component of the new oxazolidinone prodrug tedizolid phosphate (TR-701). We had previously demonstrated that tedizolid possessed potent antistaphylococcal activity superior to that of linezolid in a neutropenic mouse thigh infection model (A. Louie, W. Liu, R. Kulawy, and G. L. Drusano, Antimicrob. Agents Chemother. 55:3453-3460, 2011). In the current investigation, we used a mouse thigh infection model to delineate the effect of an interaction of TR-700 and granulocytes on staphylococcal cell killing. We compared the antistaphylococcal killing effect of doses of TR-701 equivalent to human exposures ranging from 200 to 3,200 mg/day in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 h after therapy initiation. In granulocytopenic mice, a clear exposure response in which, depending on the time point of evaluation, stasis was achieved at "human-equivalent" doses of slightly below 2,300 mg/day (at 24 h) to slightly below 2,000 mg/day (at 72 h) was observed. In immune-normal animals, stasis was achieved at human-equivalent doses of slightly greater than 100 mg/day or less. The variance in bacterial cell killing results was attributable to the presence of granulocytes (without drug), the direct effect of TR-700 on Staphylococcus aureus, and the effect of the drug on Staphylococcus aureus mediated through granulocytes. The majority of the bacterial cell killing in normal animals was attributable to the effect of TR-700 mediated through granulocytes. Additional studies need to be undertaken to elucidate the mechanism underlying this observation.

Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan.

Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C(max) and AUC(last) parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.

Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea.

To evaluate the pharmacological properties of cilostazol (CLZ), we examined its intraocular pressure (IOP) -lowering effect. CLZ is an inhibitor of Type III phosphodiesterase that increases intracellular cyclic AMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water solubility. We attempted to enhance CLZ solubility using 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). The solubility of CLZ increased with increasing HPbetaCD concentrations, and 0.05% CLZ was dissolved in 10% HPbetaCD. Moreover, fine particle suspension of 0.5% CLZ in 5% HPbetaCD (soluble CLZ: ca. 0.027%) were prepared using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration experiment through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solutions and suspensions. When a 0.05% CLZ ophthalmic solution was instilled into a rabbit eye, the absorption rate constant for CLZ into an aqueous humor was 0.0059+/-0.001 min(-1), and the elimination rate constant was 0.048+/-0.024 min(-1). Also CLZ ophthalmic solutions and fine particle suspension were examined to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solutions and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solutions and fine particle suspensions may represent an effective anti-glaucoma formulation.

Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi).

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Single-pill combination of amlodipine and valsartan in the management of hypertension.

Combination therapy is increasingly recommended for selected patients with hypertension to facilitate prompt attainment and maintenance of goal blood pressure (BP). Single-pill combination therapy simplifies treatment and optimizes long-term compliance. Amlodipine, a dihydropyridine calcium antagonist, and valsartan, an angiotensin receptor blocker, are well-established antihypertensive agents with complementary mechanisms of action. This combination lowers BP significantly more than either of its components, and valsartan reduces the incidence of dose-related amlodipine-induced edema. Rigorous clinical trial data have proven the BP-lowering efficacy and high tolerability of the amlodipine/valsartan combination in patients with moderate to severe hypertension as well as other difficult-to-treat populations. Amlodipine/valsartan is indicated as initial therapy in patients who are unlikely to be controlled with a single drug and as second-line therapy in patients not responding adequately to monotherapy.

Effect of soy extract administration on losartan pharmacokinetics in healthy female volunteers.

BACKGROUND: osartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E-3174, which has greater antihypertensive activity than the parent compound. Soy extract has been shown to be an activator of CYP2C9 and CYP3A4 in vitro. Coadministration of soy extract and losartan may therefore alter the pharmacokinetics of losartan and E-3174. OBJECTIVE: To determine whether, when losartan was used in combination with soy extract, a significant pharmacokinetic interaction would be observed in healthy female volunteers. METHODS: Eighteen healthy Chinese female volunteers were recruited. In an open-label, 2-phase study, losartan 50 mg was given to each subject, with and without soy extract. Plasma concentrations of losartan and E-3174 were determined by liquid chromatography-tandem mass spectrometry for 12 and 24 hours, respectively. On day 8 through day 21 of the study, following a 7-day washout period, each subject consumed two 1000-mg Genistein Soy Complex tablets orally after meals, twice daily, for 14 days. On day 22, all volunteers received losartan 50 mg and blood samples were collected again. RESULTS: All subjects completed the study, without adverse drug effects. Over the 14-day pretreatment period, soy extract did not significantly influence the pharmacokinetics of losartan or E-3174. The ratio of the area under the curve of the drug and metabolite after losartan administration, with and without soy extract ingestion, was 0.21 +/- 0.05 and 0.23 +/- 0.05 (mean +/- SD), respectively. The difference was not statistically significant (p = 0.22). CONCLUSIONS: Our data indicate that a significant interaction between soy extract and losartan is unlikely to occur in females.

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.