The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers.

Pegozafermin (also known as BIO89-100) is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In cell-based assays, pegozafermin had a similar receptor engagement profile as recombinant FGF21, with approximately eightfold higher potency at fibroblast growth factor receptor 1c (FGFR1c). In diabetic monkeys, once-weekly and once-every-2-weeks regimens of subcutaneous pegozafermin provided rapid and robust benefits for an array of metabolic biomarkers, including triglycerides, cholesterol, fasting glucose, glycated hemoglobin, adiponectin, alanine aminotransferase, food intake, and body weight. In a single ascending dose study in healthy volunteers, subcutaneously administered pegozafermin was associated with statistically significant improvements in triglycerides, low- and high-density lipoprotein-cholesterol, and adiponectin, an insulin-sensitizing and anti-inflammatory adipokine. Pharmacokinetic half-lives ranged from 55 to 100 hours over the clinically relevant dose range, consistent with the expected half-life extension by glycoPEGylation. These findings provide evidence that pegozafermin is a promising candidate molecule for the treatment of patients with NASH or SHTG. SIGNIFICANCE STATEMENT: Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis. Studies presented here demonstrate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that repeated, subcutaneous dosing of pegozafermin in diabetic monkeys and healthy humans improves lipid metabolism, glucose metabolism, weight, and liver transaminases. These results support future development of pegozafermin for the treatment of metabolic diseases, including nonalcoholic steatohepatitis and severe hypertriglyceridemia.

Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults.

Cabozantinib capsules (COMETRIQ) are approved for the treatment of patients with progressive metastatic medullary thyroid cancer. Cabozantinib tablets are investigational drug products considered to be potentially preferred pharmaceutical dosing forms. Two phase I open-label single-dose studies in healthy individuals were carried out to characterize the plasma pharmacokinetics of cabozantinib capsule and tablet formulations: a two-way crossover bioequivalence study (n=77) comparing the tablet formulation and the marketed capsule formulation at the approved 140 mg dose and a dose-proportionality study (n=21 per treatment arm) evaluating the 20, 40, and 60 mg tablet strengths. In the bioequivalence study, plasma exposure [area under the plasma concentration-time curve (AUC0-t and AUC0-inf)] values were similar (<10% difference) for both formulations and the 90% confidence intervals (CIs) around the ratio of geometric least-squares means (GLSM) were within the accepted bioequivalence limits of 80-125%. However, the GLSM for Cmax was 19% higher for the tablet formulation and the upper 90% CI for the ratio of GLSM (131.65%) was beyond the 80-125% range. Thus, the tablet and capsule formulations failed to fulfill the bioequivalence study acceptance criteria. In the dose-proportionality study, single doses of the 20, 40, and 60 mg cabozantinib tablet strengths showed dose-proportional increases where the 95% CIs for the slopes of the ln-transformed Cmax, AUC0-t, and AUC0-inf values versus ln-transformed cabozantinib dose included the value of 1. These findings indicate that cabozantinib plasma exposures increased proportionally with increasing cabozantinib dose over the 20-60 mg tablet strength dose range.

A Randomized Trial Comparing the Pharmacokinetics, Safety, and Tolerability of DFN-02, an Intranasal Sumatriptan Spray Containing a Permeation Enhancer, With Intranasal and Subcutaneous Sumatriptan in Healthy Adults.

OBJECTIVE/BACKGROUND: Intranasal sumatriptan (Imitrex® ) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non-oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1-O-n-Dodecyl-ß-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer, on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability. METHODS: We conducted two studies: a randomized, three-way crossover study comparing monodose and multidose devices for delivery of single doses of DFN-02 with commercially available intranasal sumatriptan 20 mg in 18 healthy, fasted adults, and an open-label, randomized, single-dose, three-way crossover bioavailability study comparing DFN-02 with 4 mg and 6 mg subcutaneous sumatriptan in 78 healthy, fasted adults. In the study comparing DFN-02 with IN sumatriptan, subjects received a single dose of DFN-02 (sumatriptan 10 mg plus DDM 0.20%) via monodose and multidose delivery systems with at least 5 days between treatments. In the comparison with SC sumatriptan, subjects received a single dose of each treatment with at least 3 days between treatments. In both studies, blood was sampled for pharmacokinetic evaluation of sumatriptan and DDM through 24 hours post-dose; safety and tolerability were monitored throughout. RESULTS: In the comparison with commercially available intranasal sumatriptan 20 mg, DFN-02 had a more rapid absorption profile; tmax was 15 minutes for DFN-02 monodose, 10.2 minutes for DFN-02 multidose, and 2.0 hours for commercially available intranasal sumatriptan 20 mg. Compared with 4 and 6 mg subcutaneous sumatriptan, DFN-02's median tmax (10 minutes) was significantly earlier (15 minutes; P < .0001). Mean sumatriptan exposure metrics were similar for DFN-02 and 4 mg sumatriptan: AUC0-2 : 35.12 and 44.82 ng*hour/mL, respectively; AUC0-∞ : 60.70 and 69.21 ng*hour/mL, respectively; Cmax : 51.79 and 49.07 ng/mL, respectively. With 6 mg subcutaneous sumatriptan, these exposure metrics were about 50% larger (AUC0-2 : 67.17 ng*hour/mL; AUC0-∞ : 103.78 ng*hour/mL; Cmax : 72.75 ng/mL). Inter-subject variability of AUC0-2 , AUC0-∞ , and Cmax was 42-58% for DFN-02, 15-22% for 4 mg subcutaneous sumatriptan, and 15-25% for 6 mg subcutaneous sumatriptan. DDM exposure was low (mean Cmax : 1.63 ng/mL), tmax was 30 minutes, and it was undetectable by 4 hours. There were no serious adverse events, discontinuations due to adverse events, or remarkable findings for vital signs, physical examinations (including nasal and injection site examinations), or clinical laboratory assessments. The overall incidence of adverse events was comparable across treatments, and all treatment-related events were mild in severity. Adverse events occurring in ≥10% of subjects were dysgeusia (19%), headache (18%), nausea (15%), paresthesia (15%), and dizziness (12%). CONCLUSIONS: In healthy subjects, DFN-02, an intranasal spray containing 10 mg sumatriptan plus DDM, had a more rapid absorption profile than commercially available intranasal sumatriptan 20 mg, and systemic exposure from a single-dose administration of DFN-02 was similar to 4 mg SC sumatriptan and two-thirds that of 6 mg SC sumatriptan. With DFN-02, plasma sumatriptan peaked 5 minutes earlier than with both subcutaneous formulations. Systemic exposure to sumatriptan was similar with DFN-02 and 4 mg subcutaneous sumatriptan; both yielded lower systemic exposure than 6 mg subcutaneous sumatriptan. Systemic exposure to DFN-02's excipient DDM was short-lived. DFN-02's safety and tolerability appear to be comparable to subcutaneous sumatriptan. Addition of a permeation enhancer improved the absorption profile compared with commercially available intranasal sumatriptan 20 mg.

A PBPK workflow for first-in-human dose selection of a subcutaneously administered pegylated peptide.

Predicting the pharmacokinetic (PK) time course of a subcutaneously (SC) administered novel therapeutic protein using in silico approaches offers an opportunity to streamline the drug development process by facilitating selection of starting and target doses in initial human trials. Herein, we propose a workflow for predicting the human exposure time course following SC administration. Leveraging knowledge obtained following both intravenous and SC administration in monkeys, this workflow employs the development of a whole body physiologically-based pharmacokinetic (PBPK) model incorporating vascular circulation, lymphatic uptake and both renal and non-specific clearance mechanisms to predict the PK of a novel pegylated peptide. Optimization of the model was initially performed in monkeys, after which the model was scaled up to human proportion. Inclusion of a SC depot compartment allowed for precise simulation of the SC time course in monkeys. Simulated human exposure after SC administration was within approximately 20 % of the observed values and successfully predicted the time course of two subsequent dosing levels. This workflow represents one of the first publications of a PBPK workflow to predict the time course of a SC administered therapeutic protein based off of a single, non-human primate species and shows promise in facilitating the dose selection in first-in-human dose escalation studies for novel protein therapeutics.

Triple-Antibiotic Combination Exerts Effective Activity against Mycobacterium avium subsp. hominissuis Biofilm and Airway Infection in an In Vivo Murine Model.

OBJECTIVES: Slow-growing nontuberculous mycobacteria (NTMs) are highly prevalent and routinely cause opportunistic intracellular infectious disease in immunocompromised hosts. METHODS: The activity of the triple combination of antibiotics, clarithromycin (CLR), rifabutin (RFB), and clofazimine (CFZ), was evaluated and compared with the activity of single antibiotics as well as with double combinations in an in vitro biofilm assay and an in vivo murine model of Mycobacterium avium subsp. hominissuis (M. avium) lung infection. RESULTS: Treatment of 1-week-old biofilms with the triple combination exerted the strongest effect of all (0.12 ± 0.5 × 107 CFU/mL) in reducing bacterial growth as compared to the untreated (5.20 ± 0.5 × 107/mL) or any other combination (≥0.75 ± 0.6 × 107/mL) by 7 days. The treatment of mice intranasally infected with M. avium with either CLR and CFZ or the triple combination provided the greatest reduction in CLR-sensitive M. avium bacterial counts in both the lung and spleen compared to any single antibiotic or remaining double combination by 4 weeks posttreatment. After 4 weeks of treatment with the triple combination, there were no resistant colonies detected in mice infected with a CLR-resistant strain. No clear relationships between treatment and spleen or lung organ weights were apparent after triple combination treatment. CONCLUSIONS: The biofilm assay data and mouse disease model efficacy results support the further investigation of the triple-antibiotic combination.

Improved pharmacokinetics of sumatriptan with Breath Powered™ nasal delivery of sumatriptan powder.

OBJECTIVES: The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22-mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20-mg sumatriptan liquid nasal spray, a 100-mg oral tablet, and a 6-mg subcutaneous injection. BACKGROUND: A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels. METHODS: An open-label, cross-over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. Following randomization, fasted subjects received a single dose of each of the 4 treatments separated by a 7-day washout. Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis. RESULTS: Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8±0.9 mg (mean±standard deviation) of sumatriptan powder in each nostril (total dose 16 mg). Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16-mg sumatriptan powder and 20-mg liquid nasal spray (area under the curve [AUC]0-∞ 64.9 ng*hour/mL vs 61.1 ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8 ng/mL vs 16.4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0-30 minutes 5.8 ng*hour/mL vs 3.6 ng*hour/mL). The magnitude of difference is larger on a per-milligram basis. The absorption profile following standard nasal spray demonstrated bimodal peaks, consistent with lower early followed by higher later absorptions. In contrast, the profile following Breath Powered delivery showed higher early and lower late absorptions. Relative to the 100-mg oral tablet (Cmax 70.2 ng/mL, AUC0-∞, 308.8 ng*hour/mL) and 6-mg injection (Cmax 111.6 ng/mL, AUC0-∞ 128.2 ng*hour/mL), the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower. CONCLUSIONS: Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection.

Contrasting toxicokinetic evaluations and interspecies pharmacokinetic scaling approaches for small molecules and biologics: applicability to biosimilar development.

1. A 2-fold threshold typically used for prediction accuracy of interspecies scaling of clearance (CL) may be too liberal when using pharmacokinetic similarity in animals to advance biosimilar candidate selection for clinical testing. The purpose of this review is to identify interspecies scaling methods for use in de-risking biosimilar development prior to clinical testing. 2. Scaling approaches for predicting macromolecule CL were identified through literature review. Reports that evaluated predicted and observed human CLs for ≥5 individual compounds were considered. Absolute average fold-error (AAFE) was calculated for each method along with the proportion of compounds with individual fold-error values within a tighter threshold of 0.7-1.3. 3. Traditional simple allometry with a minimum of three species and the rule of exponents performed inconsistently with some groups of compounds resulting in a greater than 2-fold error (i.e. AAFE > 2). For monoclonal antibodies (mAbs), simplified allometric approaches employing a single species (monkey) with a fixed exponent of 0.85 consistently resulted in lower AAFEs and a higher proportion of compounds within the tighter range of 0.7-1.3. 4. For macromolecules, and particularly mAbs, employing single-species monkey "simplified" allometric approaches with a fixed exponent of 0.85 may be more appropriate than traditional allometric approaches.

Physiologically-based pharmacokinetic modelling to predict intragastric rifabutin concentrations in the treatment of Helicobacter pylori infection.

BACKGROUND: Sustained intragastric antibiotic exposure is important for Helicobacter pylori eradication, yet little is known about gastric pharmacology of commonly used H. pylori regimens. For rifabutin, differing intragastric concentrations based on dosing regimen may account for differences in reported eradication rates. AIM: To compare intragastric rifabutin concentrations between low-dose rifabutin (50 mg three time daily; as in RHB-105) and generically dosed rifabutin 150 mg once daily, 150 mg twice daily, and 300 mg once daily using a validated Physiologically-based pharmacokinetic (PBPK) model. METHODS: We obtained plasma pharmacokinetic data from the RHB-105 clinical development programs and used it to develop and validate a whole-body PBPK model using PK-SIM software. We modified the existing rifabutin model to include the impact of omeprazole on gastric pH and emptying time. Modelled intragastric rifabutin exposure was expressed as the time that each regimen maintained its concentration ≥MIC90 . RESULTS: Rifabutin 50 mg three times daily achieved significantly longer times with intragastric concentration above MIC90 (22.3 ± 1.1 h) than 150 mg once daily (8.3 ± 1.7 h), 150 mg twice daily (16.3 ± 2.3 h), or 300 mg once daily (8.5 ± 1.9 h) while providing the lowest mean maximal plasma concentration and mean area under the plasma concentration-time curve of all regimens studied. CONCLUSIONS: PBPK modelling showed rifabutin 50 mg three times daily had higher intragastric exposure times than 150 mg once daily or twice daily, or 300 mg once daily. This low-dose rifabutin regimen provides the highest potential for H. pylori eradication while minimising systemic rifabutin exposure.

Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment.

Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model. Results: XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1ß (IL-1ß) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5 µg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations. Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.

Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer.

BACKGROUND AND OBJECTIVES: Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. METHODS: Plasma concentration-time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). RESULTS: Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. CONCLUSIONS: Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.

Brigatinib Dose Rationale in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Exposure-Response Analyses of Pivotal ALTA Study.

Brigatinib is a kinase inhibitor indicated for patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer who progressed on or are intolerant to crizotinib. Approval was based on results from a randomized, dose-ranging phase II study (ALK in Lung Cancer Trial of AP26113 (ALTA)). Despite an apparent dose-response relationship for efficacy in ALTA, an exposure-response relationship was not discernable using static models driven by time-averaged exposure. However, exposure-response modeling using daily time-varying area under the concentration curve as the predictor in time-to-event models predicted that increasing the dose of brigatinib (range, 30 mg once daily (q.d.) to 240 mg q.d.) would result in clinically meaningful improvements in progression-free survival (PFS), intracranial PFS, and overall survival. Grade ≥ 2 rash and amylase elevation were predicted to significantly increase with brigatinib exposure. These results provided support for a favorable benefit-risk profile with the approved dosing regimen (180 mg q.d. with 7-day lead-in at 90 mg) versus 90 mg q.d.

A Randomized Comparison of the Pharmacokinetics and Bioavailability of Fluticasone Propionate Delivered via Xhance Exhalation Delivery System Versus Flonase Nasal Spray and Flovent HFA Inhalational Aerosol.

PURPOSE: The exhalation delivery system with fluticasone propionate (Xhance®) has been shown to deliver drug substantially more broadly in the nasal cavity (particularly into superior/posterior regions), with less off-target loss of drug to drip-out and swallowing, than conventional nasal sprays. This open-label study evaluated the systemic bioavailability of Xhance® by comparing the pharmacokinetic (PK) properties of a single dose of fluticasone from 3 products administering the drug using 3 different devices: Xhance®, Flonase® (fluticasone propionate inhalational nasal spray), and Flovent® HFA (fluticasone propionate inhalational aerosol). METHODS: This open-label study was conducted in 2 parts. Study part 1 compared systemic exposure with a single dose of Xhance® 186 or 372 µg versus Flonase® 400 µg (3-way, 3-treatment, 3-sequence, randomized crossover in healthy subjects; n = 90). A separate study, part 2, under the same umbrella protocol, compared systemic exposure with Xhance® 372 µg versus Flovent® HFA 440 µg (2-way, 2-treatment, 2-sequence, randomized crossover in patients with mild to moderate asthma; n = 30). FINDINGS: With Xhance® 186 µg, the geometric least squares mean (LSM) Cmax was higher than with Flonase® 400 µg (16.02 vs 11.66 pg/mL, respectively; geometric mean ratio [GMR], 137.42%) and the geometric LSM AUC0-∞ values were similar (97.30 vs 99.61 pg · h/mL; GMR, 97.78%). With Xhance® 372 µg, the geometric LSM Cmax and AUC0-∞ were higher than with Flonase® 400 µg (Cmax, 23.50 vs 11.66 pg/mL [GMR, 201.53%]; AUC0-∞, 146.61 vs 99.61 pg · h/mL [GMR, 147.19%]). In part 2, the geometric LSM Cmax and AUC0-∞ values were lower with Xhance® 372 µg than with Flovent® HFA 440 µg (Cmax, 25.28 vs 40.02 pg/mL [GMR, 63.18%]; AUC0-∞, 205.78 vs 415.16 pg · h/mL [GMR, 49.57%]). IMPLICATIONS: Similar intranasal doses of Xhance® (372 µg) and Flonase® (400 µg) are clearly not bioequivalent. Systemic exposure is very low with all products. Systemic exposure is higher with Xhance® than with Flonase® and substantially lower than with Flovent® HFA 440 µg and, based on dose normalization, Flovent® HFA 220 µg. ClincalTrials.gov identifier: NCT02266927.

No Effect of Omega-3 Carboxylic Acids on Pharmacokinetics/Pharmacodynamics of Warfarin or on Platelet Function When Co-administered with Acetylsalicylic Acid: Results of Two Phase I Studies in Healthy Volunteers.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels. OBJECTIVE: Our objective was to assess the effects of OM3-CA on warfarin pharmacokinetics and pharmacodynamics and on acetylsalicylic acid (ASA)-dependent and independent platelet activation when co-administered with ASA in two phase I studies. METHODS: In ECLIPSE II (NCT01431690), 26 participants received warfarin 25 mg on days 1 and 22 and OM3-CA 4 g once daily from day 8 to day 28. In OM-EPA-007 (NCT01486433), 52 participants received simvastatin 40 mg plus ASA 81 mg once daily for 14 days, with or without OM3-CA 4 g. Lack of a drug-drug interaction was indicated when 90% confidence intervals (CIs) fell entirely within the range 80-125% for least-squares mean (LSM) ratios of area under the concentration-time curve (AUC), maximum observed plasma concentration (C max), international normalized ratio (INR) AUC to 168 h and maximum INR. RESULTS: In ECLIPSE II, 90% CIs for LSM ratios of with:without OM3-CA fell within 80-125% for AUC and C max of S- and R-warfarin enantiomers. The 90% CIs for LSM ratios of with:without OM3-CA fell within 80-125% for INR AUC to 168 h after dosing and for maximum INR of warfarin. In OM-EPA-007, no significant effect of OM3-CA was observed on ASA-dependent or ASA-independent platelet activation. No deaths or serious adverse events occurred in either study. CONCLUSION: OM3-CA did not affect the pharmacokinetics or pharmacodynamics of warfarin or the pharmacodynamic effects of ASA. OM3-CA did not affect platelet function when co-administered with ASA.

Assessment of pharmacokinetic interaction between omega-3 carboxylic acids and the statins rosuvastatin and simvastatin: Results of 2 phase I studies in healthy volunteers.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels. OM3-CA is often prescribed concomitantly with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). OBJECTIVE: The aim of the article was to assess the potential for pharmacokinetic interaction between OM3-CA and the statins rosuvastatin and simvastatin. METHODS: Data from 2 phase I studies (ECLIPSE III and OM-EPA-007 [NCT01486433]) were analyzed. In ECLIPSE III, 59 participants received OM3-CA 4 g once daily for 13 days, with rosuvastatin 40 mg (single dose) co-administered with the 11th dose. In OM-EPA-007, 52 participants received simvastatin 40 mg plus acetylsalicylic acid 81 mg daily for 14 days, with or without OM3-CA. Lack of a drug-drug interaction was declared if the 90% confidence interval (CI) of the geometric least-squares mean ratio of pharmacokinetic parameters was in the range 80% to 125%. RESULTS: For rosuvastatin, values for the geometric mean ratio (90% CI) with:without OM3-CA were 86.38% (80.68-92.48), 90.50% (85.99-95.25), and 89.01% (84.30-93.98), respectively, for maximum plasma concentration (Cmax), area under the concentration-time curve up to last measurable concentration (AUC0-t) and extrapolated to infinity (AUC0-inf). Co-administration with a single dose of rosuvastatin did not affect the multiple-dose pharmacokinetics of constituent OM3-CA fatty acids eicosapentaenoic acid and docosahexaenoic acid. For simvastatin, values for steady state geometric mean ratio (90% CI) with:without OM3-CA were 91.61% (82.82-101.33) and 87.47% (80.19-95.41), respectively, for Cmax and AUC0-t. No deaths or serious adverse events occurred in either trial. CONCLUSION: OM3-CA can be administered with either rosuvastatin or simvastatin without affecting the pharmacokinetics of these statins.

Pharmacokinetic Time Course Scaling of a Subcutaneously Administered Pegylated Peptide Conjugate for a First-in-Human Investigation.

BACKGROUND AND PURPOSE: Predicting absorption of macromolecules in humans following subcutaneous administration is complicated by interspecies differences in skin anatomy. The objective of this research was to test the hypothesis that an empiric relationship exists between non-human primates (NHPs) and humans in the absorption of a subcutaneously administered macromolecule which was then used to predict the time course of a pegylated peptide conjugate for planning of a first-in-human investigation. METHODS: Concentration data obtained from NHPs receiving intravenous and subcutaneous doses of a novel pegylated peptide conjugate were fit to a pharmacokinetic model. The model was then scaled to a virtual population of humans through incorporation of allometric scaling factors on clearance, volume and first-order rate absorption processes. Several scenarios of simulated data were compared with observed data obtained from a first-in-human investigation. RESULTS: NHP data were best described by a 2-compartment model with dual-parallel, first-order absorption processes, one of which exhibited a lag time. Empirically selected scaling factors, assuming an inverse relationship of body weight and absorption provided reasonable prediction of the peptide's time course in plasma. Employing fitted exponents based on observed human data improved the fit somewhat, however, did not correct entirely for over prediction observed with the empiric exponents. CONCLUSION: For macromolecules where the absorption can be described by first-order rate processes, an assumption of an inverse relationship in species size may predict the time course after subcutaneous administration and may support optimal study design for a first-in-human investigation.

A Novel NF-κB Inhibitor, Edasalonexent (CAT-1004), in Development as a Disease-Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects.

In Duchenne muscular dystrophy (DMD), NF-κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT-1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF-κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF-κB upon intracellular cleavage to these bioactive components. Preclinical data demonstrate disease-modifying activity in DMD animal models. Three placebo-controlled studies in adult subjects assessed the safety, pharmacokinetics, and pharmacodynamics of single or multiple edasalonexent doses up to 6000 mg. Seventy-nine adult subjects received edasalonexent, and 25 received placebo. Pharmacokinetic results were consistent with the intracellular cleavage of edasalonexent to its active components. Food increased plasma exposures of edasalonexent and salicyluric acid, an intracellularly formed metabolite of salicylic acid. The NF-κB pathway and proteosome gene expression profiles in peripheral mononuclear cells were significantly decreased (P = .02 and P = .002, respectively) after 2 weeks of edasalonexent treatment. NF-κB activity was inhibited following a single dose of edasalonexent but not by equimolar doses of salicylic acid and DHA. Edasalonexent was well tolerated, and the most common adverse events were mild diarrhea and headache. In first-in-human studies, edasalonexent was safe, well tolerated, and inhibited activated NF-κB pathways, suggesting potential therapeutic utility in DMD regardless of the causative dystrophin mutation, as well as other NF-κB-mediated diseases.

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines.

INTRODUCTION: The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment. Areas covered: The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA's draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed. Expert commentary: We summarize how 'one size does not fit all' for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines.

Systemic Bioavailability and Dose Proportionality of Omega-3 Administered in Free Fatty Acid Form Compared With Ethyl Ester Form: Results of a Phase 1 Study in Healthy Volunteers.

BACKGROUND: Omega-3 carboxylic acids (OM3-CA) contains eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in free fatty acid form. Per gram, OM3-CA includes approximately half as much EPA as icosapent ethyl (IPE), an ethyl ester formulation of EPA. OBJECTIVE: The study aim was to assess systemic EPA and EPA + DHA exposures and plasma lipid parameters following multiple OM3-CA or IPE doses under low-fat dietary conditions, and dose proportionality after OM3-CA administration. METHODS: In this phase 1, two-cohort, open-label study (N = 114), participants following the Therapeutic Lifestyle Changes diet received either OM3-CA 2 g once daily for 10 days then OM3-CA 4 g once daily for 10 days, or IPE 2 g twice daily for 20 days. Exposure was considered similar if the 90% confidence intervals (CIs) of geometric least-squares mean (LSM) ratios for key pharmacokinetic parameters were within 80-125%. RESULTS: Baseline-adjusted steady-state EPA exposure was similar after dosing with OM3-CA 4 g/day versus IPE 4 g/day (LSM ratio, area under the concentration-time curve from time 0 to 24 h: 93.9%; 90% CI 85.6, 103.0). Combined molar-equivalent EPA + DHA exposure was 30.6% higher following OM3-CA 4 g/day than IPE 4 g/day. EPA and DHA exposure increased approximately proportionally with OM3-CA dose (2-4 g/day). Changes from baseline in lipid parameters were similar in the two cohorts. CONCLUSION: EPA exposure from OM3-CA and IPE was similar under low-fat dietary conditions, despite OM3-CA containing only approximately half as much EPA as IPE. EPA and DHA exposure from OM3-CA increased proportionally with dose.

Evaluation of the Potential for Drug Interactions With Patiromer in Healthy Volunteers.

INTRODUCTION: Patiromer is a potassium-binding polymer that is not systemically absorbed; however, it may bind coadministered oral drugs in the gastrointestinal tract, potentially reducing their absorption. METHODS: Twelve randomized, open-label, 3-period, 3-sequence crossover studies were conducted in healthy volunteers to evaluate the effect of patiromer (perpetrator drug) on absorption and single-dose pharmacokinetics (PK) of drugs (victims) that might be commonly used with patiromer. Subjects received victim drug alone, victim drug administered together with patiromer 25.2 g (highest approved dose), and victim drug administered 3 hours before patiromer 25.2 g. The primary PK endpoints were area under the curve (AUC), extrapolated to infinity (AUC0-∞), and maximum concentration ( Cmax). Results were reported as 90% confidence intervals (CIs) about the geometric mean AUC0-∞ and Cmax ratios with prespecified equivalence limits of 80% to 125%. RESULTS: Overall, 370 subjects were enrolled, with 365 receiving ≥1 dose of patiromer; 351 subjects completed the studies and all required treatments. When coadministered with patiromer, the 90% CIs for AUC0-∞ remained within 80% to 125% for 9 drugs (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). The AUC0-∞ point estimate ratios for levothyroxine and metformin with patiromer coadministration were ≥80%, with the lower bounds of the 90% CIs at 76.8% and 72.8%, respectively. For ciprofloxacin, the point estimate for AUC0-∞ was 71.5% (90% CI: 65.3-78.4). For 8 of 12 drugs, point estimates for Cmax were ≥80% with patiromer coadministration; for ciprofloxacin, clopidogrel, metformin, and metoprolol, the point estimates were <80%. When patiromer was administered 3 hours after each victim drug, the 90% CIs for AUC0-∞ and Cmax for each drug were within the prespecified 80% to 125% limits. CONCLUSION: For 9 of the 12 drugs coadministered with patiromer, there were no clinically significant drug-drug interactions. For 3 drugs (ciprofloxacin, levothyroxine, and metformin), a 3-hour separation between patiromer and their administration resulted in no clinically significant drug-drug interactions.

Population physiologically-based pharmacokinetic model incorporating lymphatic uptake for a subcutaneously administered pegylated peptide.

PURPOSE: Physiologically-based pharmacokinetic (PBPK) models provide a rational mechanistic approach for predicting the time course of macromolecules in plasma. Population PBPK models for large molecules necessitate incorporation of lymphatic circulation to mechanistically account for biodistribution. Moreover, characterization of subcutaneous absorption requires consideration of the microvascular transit from the injection site to the systemic circulation. A PBPK model for a pegylated peptide conjugate, previously developed for primates, was modified to describe the lymphatic uptake in a population of humans by incorporation of interindividual variability in the lymphatic circulation and a unique lymphatic drainage compartment (LDC). The model was then used to simulate the time course of the drug in a population of humans and compared to the same drug administered to a group of human subjects participating in a first-in-human study. METHODS: Organ, blood and lymph masses for the population were sampled from either normal or log-normal distributions. Blood flows were calculated for each organ based on mean organ perfusion per gram of organ tissue and lymphatic flow was set as a fixed fraction of blood flow. Interindividual variability in lymphatic volume was assumed to be similar to that of blood volume. The volume of the LDC was parameterzed as a fraction of the injection volume. Sensitivity analysis was performed to study uncertain parameters and distribution assumptions. RESULTS: The population generator was capable of simulating a virtual population incorporating the lymphatic circulation. Incorporation of a LDC resulted in similar line shape relative to the observed data and incorporation of anthropometric variability accounted for individual differences in the absorption and elimination phases across all dose cohorts. Line shape was sensitive to the inclusion of LDC while peak and elimination portions of the time course were influenced by the magnitude of variance assumed for blood volume and renal clearance, respectively. CONCLUSION: Lymphatic circulation can be incorporated into a population PBPK model assuming similar interindividual variability as observed for blood volume. Incorporation of an LDC, where the volume of this transit compartment is proportional to the SC injection volume may be an important mechanistic means of predicting the transit from the SC depot to the systemic circulation.