Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
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OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
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Osilodrostat (LCI699), a potent 11ß-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats.

The somatostatin analog pasireotide and the 11ß-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3mg/kg/day, subcutaneously), osilodrostat (20mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03mg/kg/day; mid-dose, 5/0.1mg/kg/day; or high dose, 20/0.3mg/kg/day), or vehicle for 13weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. Cmax and AUC0-24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy.

Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base: mechanistic investigation of food effect.

Physiologically based pharmacokinetic (PBPK) modeling has been broadly used to facilitate drug development, hereby we developed a PBPK model to systematically investigate the underlying mechanisms of the observed positive food effect of compound X (cpd X) and to strategically explore the feasible approaches to mitigate the food effect. Cpd X is a weak base with pH-dependent solubility; the compound displays significant and dose-dependent food effect in humans, leading to a nonadherence of drug administration. A GastroPlus Opt logD Model was selected for pharmacokinetic simulation under both fasted and fed conditions, where the biopharmaceutic parameters (e.g., solubility and permeability) for cpd X were determined in vitro, and human pharmacokinetic disposition properties were predicted from preclinical data and then optimized with clinical pharmacokinetic data. A parameter sensitivity analysis was performed to evaluate the effect of particle size on the cpd X absorption. A PBPK model was successfully developed for cpd X; its pharmacokinetic parameters (e.g., C max, AUCinf, and t max) predicted at different oral doses were within ±25% of the observed mean values. The in vivo solubility (in duodenum) and mean precipitation time under fed conditions were estimated to be 7.4- and 3.4-fold higher than those under fasted conditions, respectively. The PBPK modeling analysis provided a reasonable explanation for the underlying mechanism for the observed positive food effect of the cpd X in humans. Oral absorption of the cpd X can be increased by reducing the particle size (<100 nm) of an active pharmaceutical ingredient under fasted conditions and therefore, reduce the cpd X food effect correspondingly.

Utility of physiologically based modeling and preclinical in vitro/in vivo data to mitigate positive food effect in a BCS class 2 compound.

Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the performance of orally administrated drugs. Here, we described multiple in silico/in vitro/in vivo tools to support formulation development toward mitigating the positive food effect of NVS123, a weak base with a pH-dependent and limited solubility. Administered orally with high-fat meal, NVS123 formulated as dry filled capsules displayed a positive food effects in humans. Three alternative formulations were developed and assessed in in vitro and in vivo preclinical and/or clinical studies. By integrating preclinical in vitro and in vivo data, the PBPK model successfully estimated the magnitude of food effects and the predicted values were within ± 30% of the observed results. A model-guided parameter sensitivity analysis illustrated that enhanced solubility and longer precipitation times under fed condition were the main reason for enhanced NVS123's exposure in presence of food. Eventually, exposure after an amorphous formulation was found to be not significantly altered because of remarkably enhanced intestinal solubility and reduced precipitation. Gastroplus population simulations also suggested that the amorphous formulation is promising in mitigating a clinically significant food effect. Overall, these efforts supported the rationale of clinical investigation of the new formulation, and more importantly, highlighted a practical application of PBPK modeling solving issues of undesirable food effects in weakly basic compounds based on preclinical in vitro/in vivo data.

Nilotinib preclinical pharmacokinetics and practical application toward clinical projections of oral absorption and systemic availability.

Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatment of patients who are in the chronic and accelerated phases of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Nilotinib preclinical data and its use for practical predictions of systemic exposure profiles and oral absorption are described. The systemic clearance (CL) of nilotinib was relatively low in rodents with a value of less than 25% of hepatic blood flow (Q(H)), while it was moderate in monkeys and dogs (CL/Q(H) = 32-35%). The steady state volume of distribution (V(ss) ) ranged from 0.55 to 3.9 l/kg across the species tested. The maximum concentration (C(max)) of nilotinib occurred at 0.5-4 h and the bioavailability was moderate (17-44%). The plasma protein binding was high (> 97.5%) in preclinical species and humans. The human CL (~ 0.1 l/h/kg) and V(ss) (~2.0 l/kg) were best predicted by the rat-dog-human proportionality method and allometric scaling method, respectively. The human intravenous pharmacokinetic profile was projected by the Wajima 'C(ss)-MRT' method. The predicted micro-constants from human intravenous profiles were incorporated into the advanced compartmental absorption and transit model within the GastroPlus program to simulate the oral concentration-time curves in humans. Overall, the simulated oral human pharmacokinetic profiles showed good agreement with observed clinical data, and the model predicted that the C(max) , AUC, t(½) , V(z) /F and CL/F values were within 1.3-fold of the observed values. The absolute oral bioavailability of nilotinib in healthy humans was predicted to be low (< 25%).

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.

9cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers.

Studies were performed in female Sprague-Dawley rats to determine the efficacy of a new RXR specific retinoid (9cUAB30) when combined with tamoxifen in the prevention of mammary cancers and to determine various pharmacokinetic parameters of the retinoid. When administered by gavage, 9cUAB30 was rapidly absorbed and had a serum t(1/2) of 13.5 h. Since the retinoid was administered in the diet for the chemoprevention study, a 28-day study in which 9cUAB30 was given at dose levels of 200, 400, and 600 mg/kg diet revealed fairly constant serum levels regardless of dose or length of treatment; possibly accounting for the observed low toxicity of this compound. When suboptimal doses of 9cUAB30 were given in the methylnitrosourea (MNU)-induced mammary cancer model, the following average number of mammary cancers were observed: 9cUAB30 (150 mg/kg diet), 4.3; tamoxifen (0.4 mg/kg diet), 4.6; 9cUAB30 (150 mg/kg diet)+tamoxifen (0.4 mg/kg diet), 2.6; and controls, 6.0. Thus, the combination of the agents resulted in an increased effect in preventing mammary cancers; suggesting that cancer cell proliferation was inhibited by the compounds blocking different pathways.

Case studies for practical food effect assessments across BCS/BDDCS class compounds using in silico, in vitro, and preclinical in vivo data.

Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration-time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1-4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound's BCS/BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions.

Novel physiologically based pharmacokinetic modeling of patupilone for human pharmacokinetic predictions.

PURPOSE: Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated for cancer treatment. A novel physiologically based pharmacokinetics (PBPK) model was developed based on nonclinical data to predict the disposition of patupilone in cancer patients. METHODS: After a single intravenous dose (1.2 mg/kg) in male Han-Wistar rats, the tissue distribution of (14)C-patupilone was investigated by quantitative whole-body autoradiography (QWBA). The blood radioactivity and patupilone concentration were determined by LC-MS/MS and liquid scintillation counting. A novel PBPK model was developed based on rat tissue concentration data to predict blood concentration-time profiles of patupilone in cancer patients. PBPK parameters derived from the rat were applied to a human PBPK model. Phase I clinical pharmacokinetic data in Caucasian and Japanese cancer patients at various doses ranging from 0.75 to 10 mg/m(2) were successfully described using the PBPK approach. RESULTS: Patupilone dispositions in lung, heart, muscle, spleen, liver, brain, adipose, and testes of rats were well described using the PBPK model developed assuming a perfusion rate-limited distribution between different compartments. For skin and bone marrow, concentration-time profiles were modeled assuming a permeability-limited distribution between different compartments. The simulated human pharmacokinetic profiles from the PBPK model showed good agreement with observed clinical pharmacokinetic data, where the model predicted AUC, t(1/2), V(ss), and CL values were within approximately twofold of the observed values for all dose groups. CONCLUSIONS: The distribution of patupilone in rats was well described by a PBPK model based on measured tissue distribution profiles generated by QWBA combined with metabolism data. The human PBPK model adequately predicted blood pharmacokinetics of patupilone in cancer patients. The PBPK model based upon preclinical tissue distribution data can aid in successful prediction of pharmacokinetics in humans.

Unsymmetrical squaraines incorporating the thiophene unit for panchromatic dye-sensitized solar cells.

Two unsymmetrical squaraines, where the electron-rich 3,4-ethylenedioxythiophene or bithiophene conjugated fragment was used to link unconventionally the squaraine core and the hexyloxyphenyl amino group, were applied for DSCs. The corresponding photovoltaic devices exhibit an attractively panchromatic response and also convert a portion of the near-infrared photons into electricity.

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.

Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study.

BACKGROUND: Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%. OBJECTIVE: This study compared the pharmacokinetics of nilotinib in subjects with hepatic impairment and subjects with normal hepatic function. METHODS: Hepatic impairment was classified as mild (Child-Pugh grade A), moderate (Child-Pugh grade B), or severe (Child-Pugh grade C). Healthy control subjects were matched with hepatically impaired subjects by age (+/-10 years) and body weight (+/-20%). All subjects received a single oral dose of nilotinib 200 mg under fasted conditions, and serial blood samples were collected at specific times up to 120 hours after dosing. Serum nilotinib concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification of 2.5 ng/mL. The pharmacokinetic parameters analyzed were C(max), T(max), AUC(0-last), AUC(0-infinity), t(1/2), CL/F, and Vz/F. Tolerability assessments included adverse events (AEs), regular monitoring of clinical laboratory measures (eg, hematology, blood chemistry, urinalysis), physical examinations, vital signs, and ECGs. Each AE was evaluated in terms of its clinical significance, severity, duration, relation to study drug, and action taken. RESULTS: The study enrolled 18 subjects with hepatic impairment (all male; age range, 47-67 years; weight range, 73.9-103.9 kg) and 9 healthy controls (all male; age range, 36-62 years; weight range, 73.3-109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC(0-infinity) was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t(1/2) was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in Vz/F in the latter 2 groups. All AEs were mild or moderate, and the frequency of AEs was not associated with the degree of hepatic impairment. AEs included abdominal pain (1 subject with mild impairment), dyspepsia (2 with mild impairment), flatulence (1 with severe impairment), nausea (1 with mild impairment), urinary tract infection (1 with mild impairment), back pain (1 each with mild impairment and severe impairment, 1 control subject), and headache (1 each with mild impairment and severe impairment). CONCLUSIONS: After a single 200-mg dose, nilotinib pharmacokinetics were modestly affected by hepatic impairment. The extent of change in nilotinib exposure in subjects with hepatic impairment was generally within the range of variability that has been observed clinically. The results of this study suggest that dose adjustment may not be necessary in patients with hepatic impairment. Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626.