Pharmacokinetic Interactions between Tegoprazan and Metronidazole/Tetracycline/Bismuth and Safety Assessment in Healthy Korean Male Subjects.

PURPOSE: Tegoprazan is a potassium-competitive acid blocker used for gastric acid suppression, which may be used with Helicobacter pylori eradication therapies. The goal of this study was to evaluate the pharmacokinetic interaction between tegoprazan and triple-antibiotic therapy containing metronidazole, tetracycline, and bismuth. METHODS: An open-label, 2-cohort, randomized, multiple-dose, crossover study was conducted in healthy subjects. In cohort 1, tegoprazan (100 mg/d) was administered orally with or without triple-antibiotic therapy (1500 mg/d metronidazole, 2000 mg/d tetracycline, and 1200 mg/d bismuth) for 7 days in each period. In cohort 2, triple-antibiotic therapy was administered orally with or without tegoprazan for 7 days in each period. Pharmacokinetic blood samples were collected within 24 h after the last dose. Safety assessments were performed. FINDINGS: Eleven cohort 1 subjects and ten cohort 2 subjects were included in the pharmacokinetic analysis. The AUCτ and Cmax at steady state geometric mean ratios (90% CIs) were 0.78 (0.73-0.83) and 0.75 (0.68-0.82) for tegoprazan; 0.77 (0.68-0.88) and 0.84 (0.72-0.98) for tegoprazan metabolite M1; 1.03 (0.98-1.08) and 1.08 (0.99-1.18) for metronidazole; 0.63 (0.56-0.70) and 0.64 (0.56-0.74) for tetracycline; and 1.55 (0.99-2.44) and 1.38 (0.72-2.66) for bismuth, respectively. All reported adverse events were mild. IMPLICATIONS: Changes in the tegoprazan, tetracycline, and bismuth pharmacokinetic parameters were detected after concurrent administration. These changes were considered mainly due to the pharmacodynamic effect of tegoprazan. The adverse events were predictable and reported as frequent adverse events during triple-antibiotic therapy. There were no significant differences in safety or tolerability between quadruple therapy, including tegoprazan and triple-antibiotic therapy. ClinicalTrials.gov identifier: NCT04066257.

Utilization of PEGylated cerosomes for effective topical delivery of fenticonazole nitrate: in-vitro characterization, statistical optimization, and in-vivo assessment.

In this investigation, we focused on ceramide IIIB, a skin component whose depletion tends to augment multiple skin disorders and fungal infections. Ceramide IIIB was included into PEGylated surfactant-based vesicular phospholipid system to formulate 'PEGylated cerosomes' (PCs) loaded with fenticonazole nitrate (FTN). FTN is a potent antifungal agent adopted in the treatment of mixed mycotic and bacterial infections. The ceramide content of the vesicles may provide protective and regenerative skin activity whereas Brij®; the PEGylated surfactant, can enhance drug deposition and skin hydration. Both components are expected to augment the topical effect of FTN. PCs were prepared by thin-film hydration technique. A 23 full-factorial design was applied to study the effect of ceramide amount (X1), Brij type (X2) and Brij amount (X3) on the physicochemical properties of the formulated PCs namely; entrapment efficiency (EE%;Y1), particle size (PS;Y2), polydispersity index (PDI;Y3) and zeta potential (ZP;Y4). The optimal formula was selected for further in-vivo dermatokinetic and histopathological study. The optimal FTN-loaded PC (PC6) showed nanosized cerosomes (551.60 nm) with high EE% (83.00%w/w), and an acceptable ZP value of 20.90 mV. Transmission electron micrographs of the optimal formula illustrated intertwined tubulation form deviated from the conventional spherical vesicles. Finally, the dermatokinetic study of PC6 showed higher drug concentration and localization of FTN in skin layers when compared with FTN suspension and the histopathological study confirmed its safety for topical application. The overall findings of our study verified the effectiveness of utilizing PEGylated cerosomes to augment the activity of FTN as a topical antifungal agent.

Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine.

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat.

Lanabecestat is a human ß-site amyloid precursor protein-cleaving enzyme 1 inhibitor in development to slow disease progression in patients with early Alzheimer's disease. The study evaluated the breast cancer resistance protein (BCRP) inhibition potential of lanabecestat on the pharmacokinetics (PK) of rosuvastatin, a probe for BCRP activity, in healthy white subjects who were not carriers of SLCO1B1 (c.521T>C), not homozygotes for ABCG2 (c.421C>A or c.34G>A), and not heterozygotes of ABCG2 (c.421C>A and c.34G>A). The safety of lanabecestat + rosuvastatin, the effects of rosuvastatin on the PK of lanabecestat, and the effects of multiple genetic polymorphisms on rosuvastatin exposure were assessed. Geometric mean ratios of the maximum observed rosuvastatin concentration (Cmax ), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax ) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax at steady state increased 8% in the presence of rosuvastatin. Except for an approximately 80% increase of rosuvastatin AUC (P < .05) in the heterozygotes of ABCG2 c.421C>A relative to the CC genotype, there were no statistically significant associations between rosuvastatin exposure and polymorphisms assessed. Lanabecestat + rosuvastatin was associated with few treatment-emergent adverse events, all of which resolved and were mild. Lanabecestat does not meaningfully impact BCRP activity; therefore, restriction of concomitant administration with BCRP substrates, such as rosuvastatin, may be unnecessary.

Assessment and Confirmation of Species Difference in Nonlinear Pharmacokinetics of Atipamezole with Physiologically Based Pharmacokinetic Modeling.

Atipamezole, an α 2-adrenoceptor antagonist, displayed nonlinear pharmacokinetics (PK) in rats. The aim of this study was to understand the underlying mechanisms of nonlinear PK in rats and linear PK in humans and develop physiologically based PK models (PBPK) to capture and validate this phenomenon. In vitro and in vivo data were generated to show that metabolism is the main clearance pathway of atipamezole and species differences exist. Where cytochrome P450 (P450) was responsible for the metabolism in rats with a low Michaelis constant, human-specific UDP-glucuronosyltransferase 2B10- and 1A4-mediated N-glucuronidation was identified as the leading contributor to metabolism in humans with a high V max capacity. Saturation of metabolism was observed in rats at pharmacologically relevant doses, but not in humans at clinically relevant doses. PBPK models were developed using GastroPlus software to predict the PK profile of atipamezole in rats after intravenous or intramuscular administration of 0.1 to 3 mg/kg doses. The model predicted the nonlinear PK of atipamezole in rats and predicted observed exposures within 2-fold across dose levels. Under the same model structure, a human PBPK model was developed using human in vitro metabolism data. The PBPK model well described human concentration-time profiles at 10-100 mg doses showing dose-proportional increases in exposure. This study demonstrated that PBPK is a useful tool to predict human PK when interspecies extrapolation is not applicable. The nonlinear PK in rat and linear PK in human were characterized in vitro and allowed the prospective human PK via intramuscular dosing to be predicted at the preclinical stage. SIGNIFICANCE STATEMENT: This study demonstrated that PBPK is a useful tool for predicting human PK when interspecies extrapolation is not applicable due to species unique metabolism. Atipamezole, for example, is metabolized by P450 in rats and by N-glucuronidation in humans that were hypothesized to be the underlying reasons for a nonlinear PK in rats and linear PK in humans. This was testified by PBPK simulation in this study.

Nonlinear mixed-effects pharmacokinetic modeling of the novel COX-2 selective inhibitor vitacoxib in dogs.

The objective of this study was to develop a nonlinear mixed-effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two-compartment mamillary model with first-order elimination and first-order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low-to-moderate systemic clearance (0.35 L hr-1  kg-1 ) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs.

Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment.

Quality by design (QbD) principles were implemented to understand the product and process variables of sonoprecipitation technique, for preparation of eprosartan mesylate (EM) nanosuspension. Quality risk management approach was utilized to identify and assess high-risk attributes affecting critical quality attributes (CQA's), prioritizing the number of experiments. The effect of critical material attributes (CMA's) and critical process parameters (CPP's) (soluplus concentration, drug concentration ultrasonication amplitude) on z-average particle size and PDI were investigated using a central composite face-centered design (CCF). Further, design space with criteria set of CMA's and CPP's was established to offer assurance of quality. The optimal formulation, identified using numerical optimization method, was further lyophilized and evaluated for redispersibility, solubility saturation, dissolution kinetic and in-vitro dissolution behavior. The EM nanoparticles were in an amorphous state as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The stability study conducted for a span of 6 months attests physical and chemical stability of EM dry nanosuspension in an amorphous state when stored at 4 °C. The enhanced solubility and in-vitro dissolution of EM nanosuspension may be attributed to the reduced particle size and alteration of the physical state from a crystalline to an amorphous state. Further, the optimized formulation was subjected to in-vitro and ex-vivo transport study using parallel artificial membrane permeability assay (PAMPA) and rat everted gut sac model respectively. The transport studies revealed successful permeation enhancement of EM nanoparticle when compared with EM API and physical mixture (PM). The absolute bioavailability of EM API was 7.1% and improved to 39.9% for EM nanosuspension, suggesting that nanoformulation had overcome solubility and permeability limited bioavailability which was observed with EM API.

Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis.

Azeliragon is an inhibitor of the receptor for advanced glycation end products being developed for the treatment of Alzheimer's disease. The objective of the current analysis was to evaluate the relationship between plasma azeliragon concentrations and QT interval. Simultaneous QT values and plasma concentrations were available from 711 subjects (6236 records), pooled from 5 studies in healthy volunteers, 2 studies in patients with mild to moderate Alzheimer's disease, and 1 study in patients with type 2 diabetes and persistent albuminuria. Nonlinear mixed-effects modeling was conducted to describe azeliragon concentration-related changes in QT interval, after correcting for heart rate, using Fridericia's criteria (QTcF) and sex-related differences in baseline QTcF. Azeliragon-related changes in QTcF were predicted using 2 methods: simulation and bias-corrected 90% confidence interval approaches. A small positive relationship between azeliragon plasma concentration and QTcF was noted with a slope of 0.059 ms/ng/mL. Simulations predicted mean (90% prediction interval) changes in QTcF of 0.733 milliseconds (0.32-1.66 milliseconds) with the phase 3 dose (5 mg once daily steady state) and 4.32 milliseconds (1.7-8.74 milliseconds) at supratherapeutic doses (20 mg once daily steady state or 60 mg once daily × 6 days). Bias-corrected upper 90% confidence intervals for therapeutic and supratherapeutic doses were 0.88 and 5.01 milliseconds, respectively. Model-based analysis showed a small, nonclinically meaningful, positive relationship between azeliragon plasma concentration and QTcF with a slope close to zero. Neither the prediction interval nor the upper bound of the 90% confidence interval reached 10 milliseconds, demonstrating no clinically meaningful drug-related effect on QTcF at expected therapeutic and supratherapeutic doses of azeliragon.

Assessment of drug interaction potential between the HCV direct-acting antiviral agents elbasvir/grazoprevir and the HIV integrase inhibitors raltegravir and dolutegravir.

BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier.

A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(-/-)Bcrp1(-/-)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(-/-) or Mdr1a/b(-/-)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with Mdr1a/b(-/-)Bcrp1(-/-) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.

Clinical Bioavailability of the Novel BACE1 Inhibitor Lanabecestat (AZD3293): Assessment of Tablet Formulations Versus an Oral Solution and the Impact of Gastric pH on Pharmacokinetics.

The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single-center, open-label, randomized, 3-period crossover study involved healthy male and nonfertile female subjects aged 18-55 years (NCT02039180). Subjects received a single 50-mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0-∞ (area under the plasma drug concentration-time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1.052 (90% confidence interval [CI], 1.001-1.106); tablet B, 1.040 (0.989-1.093). These 90%CIs for geometric mean ratios are within accepted standard bioequivalence boundaries for all other pharmacokinetic (PK) parameters for both lanabecestat and metabolite (AZ13569724). All 3 formulations had similar plasma lanabecestat concentration-time profiles. Six adverse events were reported by 6 subjects (37.5%, all mild). GastroPlus modeling predicted a negligible impact of gastric pH changes on systemic PK (up to pH 7.4). Both tablet formulations fall within standard accepted bioequivalence criteria versus the oral solution. A single 50-mg lanabecestat dose was well tolerated as a solution or tablet formulation in this population.

Simple Determination of Plasma Ponatinib Concentration Using HPLC.

Ponatinib, a novel tyrosine kinase inhibitor marketed in 2016, is a key drug used for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. This study aimed to develop a simple method for determining plasma ponatinib concentration. The analysis required extraction of a 400-µL sample of plasma and precipitation of proteins using an Oasis HLB cartridge. Ponatinib and bosutinib, which is used as an internal standard, were separated by HPLC using a mobile phase of acetonitrile : 0.037 mol/L KH2PO4 (pH 4.5) (39 : 61, v/v) on a Capcell Pack C18 MG II (25×4.6 mm) monitored at 250 nm, with a flow rate of 1.0 mL/min. This assay method was then used for determining plasma ponatinib concentration in a 42-year-old man treated with ponatinib at 15 mg/d. The calibration curve was found to be linear for the plasma concentration range of 5-250 ng/mL with a regression coefficient (r2) of 0.9999. The coefficients of intra-day and inter-day validation under these concentrations were 2.1-6.0 and 4.5-8.0%, respectively. The assay accuracy was -1.5-9.0%, and the recovery was greater than 86%. The plasma concentration of the patient at 2.5 and 3 h after 15 mg ponatinib administration was 43.6 and 49.3 ng/mL, respectively. This method of HPLC equipped with UV detection for determining plasma ponatinib concentration has several advantages, such as simplicity and applicability to routine therapeutic drug monitoring at hospital laboratories.

Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-ß.

Non-invasive imaging of amyloid-ß in the brain, a hallmark of Alzheimer's disease, may support earlier and more accurate diagnosis of the disease. In this study, we assessed the novel single photon emission computed tomography tracer (123)I-ABC577 as a potential imaging biomarker for amyloid-ß in the brain. The radio-iodinated imidazopyridine derivative (123)I-ABC577 was designed as a candidate for a novel amyloid-ß imaging agent. The binding affinity of (123)I-ABC577 for amyloid-ß was evaluated by saturation binding assay and in vitro autoradiography using post-mortem Alzheimer's disease brain tissue. Biodistribution experiments using normal rats were performed to evaluate the biokinetics of (123)I-ABC577. Furthermore, to validate (123)I-ABC577 as a biomarker for Alzheimer's disease, we performed a clinical study to compare the brain uptake of (123)I-ABC577 in three patients with Alzheimer's disease and three healthy control subjects. (123)I-ABC577 binding was quantified by use of the standardized uptake value ratio, which was calculated for the cortex using the cerebellum as a reference region. Standardized uptake value ratio images were visually scored as positive or negative. As a result, (123)I-ABC577 showed high binding affinity for amyloid-ß and desirable pharmacokinetics in the preclinical studies. In the clinical study, (123)I-ABC577 was an effective marker for discriminating patients with Alzheimer's disease from healthy control subjects based on visual images or the ratio of cortical-to-cerebellar binding. In patients with Alzheimer's disease, (123)I-ABC577 demonstrated clear retention in cortical regions known to accumulate amyloid, such as the frontal cortex, temporal cortex, and posterior cingulate. In contrast, less, more diffuse, and non-specific uptake without localization to these key regions was observed in healthy controls. At 150 min after injection, the cortical standardized uptake value ratio increased by ∼ 60% in patients with Alzheimer's disease relative to healthy control subjects. Both healthy control subjects and patients with Alzheimer's disease showed minimal (123)I-ABC577 retention in the white matter. These observations indicate that (123)I-ABC577 may be a useful single photon emission computed tomography imaging maker to identify amyloid-ß in the human brain. The availability of an amyloid-ß tracer for single photon emission computed tomography might increase the accessibility of diagnostic imaging for Alzheimer's disease.

Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats.

Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t ½) of Orteronel with intravenous (i.v.) route was found to be 1.65 ± 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 ± 3.09 mL/min/kg and 3.94 ± 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 ± 76.4, 1,764 ± 166, 4,652 ± 300 and 17,518 ± 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t ½ by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.

Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.

The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.

Comparison of the circulating metabolite profile of PF-04991532, a hepatoselective glucokinase activator, across preclinical species and humans: potential implications in metabolites in safety testing assessment.

A previous report from our laboratory disclosed the identification of PF-04991532 [(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid] as a hepatoselective glucokinase activator for the treatment of type 2 diabetes mellitus. Lack of in vitro metabolic turnover in microsomes and hepatocytes from preclinical species and humans suggested that metabolism would be inconsequential as a clearance mechanism of PF-04991532 in vivo. Qualitative examination of human circulating metabolites using plasma samples from a 14-day multiple ascending dose clinical study, however, revealed a glucuronide (M1) and monohydroxylation products (M2a and M2b/M2c) whose abundances (based on UV integration) were greater than 10% of the total drug-related material. Based on this preliminary observation, mass balance/excretion studies were triggered in animals, which revealed that the majority of circulating radioactivity following the oral administration of [¹4C]PF-04991532 was attributed to an unchanged parent (>70% in rats and dogs). In contrast with the human circulatory metabolite profile, the monohydroxylated metabolites were not detected in circulation in either rats or dogs. Available mass spectral evidence suggested that M2a and M2b/M2c were diastereomers derived from cyclopentyl ring oxidation in PF-04991532. Because cyclopentyl ring hydroxylation on the C-2 and C-3 positions can generate eight possible diastereomers, it was possible that additional diastereomers may have also formed and would need to be resolved from the M2a and M2b/M2c peaks observed in the current chromatography conditions. In conclusion, the human metabolite scouting study in tandem with the animal mass balance study allowed early identification of PF-04991532 oxidative metabolites, which were not predicted by in vitro methods and may require additional scrutiny in the development phase of PF-04991532.

Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively.

Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir.

BACKGROUND: Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy. METHODS: Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate. RESULTS: Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies. CONCLUSIONS: The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.