Phase I crossover study of DNA-protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension.

Peposertib is an orally administered inhibitor of DNA-dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open-label, crossover three-period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences. They received a single dose of peposertib 100 mg as film-coated tablets under fasted or fed conditions ("tablet fasted" or "tablet fed") or as an OS under fasted conditions ("OS fasted"), with washout between treatments. Using healthy volunteers was possible because, despite its mechanism of action being suppression of DNA repair, peposertib has shown no genotoxic effect in animals. A mild food effect was observed with peposertib tablets. Fed-to-fasted ratios were: area under the curve from time 0 to time t (AUC0-t ), 123.81% (90% confidence interval [CI]: 108.04, 141.87%); AUC from zero to infinity (AUC0-∞ ), 110.28% (90% CI 100.71, 120.77%); and maximum concentration (Cmax ) 104.47% (90% CI: 79.15, 137.90%). Cmax was delayed under fed conditions (median time to maximum concentration [Tmax ] was 3.5 h [tablet fed] vs. 1 h [tablet fasted]). OS-to-tablet (fasted) ratios were: AUC0-t , 124.83% (90% CI: 111.50%, 139.76%); AUC0-∞ , 119.05% (90% CI: 104.47, 135.67%); and Cmax 173.29% (90% CI: 135.78, 221.16%). Median Tmax was 0.5 h (OS fasted) versus 1 h (tablet). All treatments were well-tolerated in healthy volunteers. Peposertib tablets can be taken with or without food; if combined with chemotherapy or radiotherapy, the delay in Cmax must be considered to optimize the chemo- or radiosensitizing effect. The peposertib OS form represents an alternative route of administration in patients with specific cancers causing dysphagia. However, the OS form should be part of future dose optimization strategies in relevant settings.

Thorough QT/QTc Study Evaluating the Effect of Macimorelin on Cardiac Safety Parameters in Healthy Participants.

Macimorelin is an orally active growth hormone secretagogue indicated for the diagnosis of adult growth hormone deficiency. The primary objective of this study was to evaluate the effect of macimorelin on the baseline and placebo-corrected mean QT interval using Fridericia's formula (ΔΔQTcF). Secondary objectives were to determine QTcF for moxifloxacin; evaluate the effects of macimorelin on other cardiac intervals (PR, QRS, RR), heart rate, and electrocardiogram morphology parameters; characterize pharmacokinetics; and assess safety of macimorelin. The phase 1 thorough QT/QTc study, designed according to the International Council for Harmonisation E14 guideline, was a randomized, placebo-controlled, double-blind, 3-way complete crossover study comparing the effect of macimorelin 2.0 mg/kg with placebo and moxifloxacin 400 mg (positive control). Data were collected over a 3-month span from male (n=36) and female participants (n=24) aged 18 to 55 years with body mass index between 18.5 and 30.0 kg/m2 . Fifty-six participants received all 3 treatments. The ΔΔQTcF for macimorelin showed a prolongation with a maximum mean value of 9.61 milliseconds (2-sided 90% confidence interval, 7.81 milliseconds and 11.41 milliseconds) at 4 hours after dosing. The 2-sided 90% confidence interval of this value also exceeded the 10 millisecond threshold at 3 hours after dosing. Assay sensitivity was confirmed with moxifloxacin. Other electrocardiogram parameters evaluated were not influenced by macimorelin. Macimorelin did not raise other safety concerns and was well tolerated. In summary, a single supratherapeutic dose of macimorelin prolonged cardiac repolarization according to the regulatory guideline.

No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P-glycoprotein.

Hypericum perforatum L. (St. John's wort) is used to treat mild-to-moderate depression. Its potential safety risks are pharmacokinetic drug interactions via cytochrome P450 (CYP) enzymes and P-glycoprotein, presumably caused by hyperforin. In a phase I, open-label, nonrandomized, single-sequence study, the low-hyperforin Hypericum extract Ze 117 was investigated using a drug cocktail in 20 healthy volunteers. No pharmacokinetic interactions of Ze 117 were observed for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, and P-glycoprotein. Area under the curve (AUC) and peak plasma concentration (Cmax ) of the used probe drugs showed 90% confidence intervals (CIs) of the geometric mean ratios of the drugs taken together with Ze 117 vs. probe drug alone, well within the predefined bioequivalence range of 80-125%. Though Ze 117 did not induce dextromethorphan metabolism by CYP2D6, it weakly increased dextromethorphan AUC ratio (mean 147.99, 95% CI 126.32-173.39) but not the corresponding metabolic ratio. Ze 117 does not show clinically relevant pharmacokinetic interactions with important CYPs and P-glycoprotein.

EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation.

BACKGROUND: Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid. METHODS: This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18-40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium. RESULTS: Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8-12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase. CONCLUSION: Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium.

Absolute Bioavailability and Effect of Food on the Disposition of Safinamide Immediate Release Tablets in Healthy Adult Subjects.

The objectives of this study were to establish the basic intravenous (IV) single-dose PK of safinamide and its major human metabolites, the absolute bioavailability (BA) and food effect on safinamide tablets. Fourteen healthy adult male and female subjects received 50 mg safinamide single-dose treatments according to a randomized, 3-period, 2-sequence crossover design: immediate release (IR) tablets, administered after an overnight fast and after a standardized high-fat, high-calorie breakfast, and IV solution, administered over 30 minutes. Treatments were separated by wash-out intervals of at least 17 days. Serial blood samples were collected for 240 hours postdosing to evaluate safinamide parent drug and metabolite concentrations for the determination of PK parameters. The absolute BA of safinamide 50 mg IR tablets was high, with geoMean AUC0-∞ ratios of about 95% (90% CI: 90-99%) indicating that safinamide is virtually completely absorbed after oral administration. Safinamide IR tablets did not display a food effect on exposure parameters; both 90% CIs for the ratios fed/fasted of AUC0-∞ and Cmax were entirely within the bioequivalence acceptance margins of 80-125%. Only tmax was delayed by about 30% in the fed state. Oral and IV safinamide 50 mg single-dose administrations were generally well tolerated.

Comparison of the pharmacokinetic and pharmacodynamic profiles of one US-marketed and two European-marketed epoetin alfas: a randomized prospective study.

BACKGROUND: HX575, licensed under the brand names Binocrit®, Epoetin Alfa Hexal®, and Abseamed®, was approved in 2007 as the first biosimilar recombinant human erythropoietin alfa (epoetin alfa) in the EU using Erypo®/Eprex® as reference product. OBJECTIVES: The aim of this study was to investigate the bioequivalence and potency of registered epoetin alfa products that have not been compared before in a randomized controlled clinical study. METHODS: The study was conducted in two parts: part A compared the European-marketed HX575 and the US-marketed Epogen®; part B compared the European-marketed Erypo®/Eprex® and HX575 manufactured at two different drug substance production sites (HX575-TT denoting the already-approved technology-transfer product from an additional manufacturing site). In analyses across both study parts, Epogen® was exploratorily compared with Erypo®/Eprex®. A dense-sampling 48-hour pharmacokinetic profile was recorded at steady state after 11 doses of 100 IU epoetin alfa per kg of bodyweight. The hemoglobin response over 4 weeks of study medication administration was analyzed as the primary efficacy surrogate parameter using an ANCOVA model with the baseline value as co-variate. The per-protocol population comprised a total of 268 subjects, 76 in part A (equally randomized to HX575 or Epogen®) and 192 in part B (equally randomized to HX575, HX575-TT, or Erypo®/Eprex®). Pairs of study arms were compared in terms of the ratio of the mean epoetin alfa area under the curve (AUC) and the ratio of the mean hemoglobin area under the effect curve (AUEC). RESULTS: Bioequivalence was shown in all pair-wise comparisons with the 90% confidence intervals of the AUC ratios falling within the standard bioequivalence limits of 80-125%. Moreover, an equivalent pharmacodynamic response was achieved with all compared epoetin alfa products, as confirmed by the hemoglobin AUEC ratio's 90% CI falling within the predefined acceptance margins of 96.8-103.2%. Thus, bioequivalence and equivalent potency was demonstrated for HX575 and Epogen® in part A of the study, as well as for HX575, HX575-TT and Erypo®/Eprex® in part B of the study. Pair-wise comparison across study parts indicated similar pharmacokinetic and pharmacodynamic profiles of Epogen® and Erypo®/Eprex®. All compared epoetin alfa products were well tolerated and had a similar safety profile. No subject developed anti-erythropoietin antibodies upon administration of study medication. CONCLUSION: The results show, for the first time in a prospective randomized clinical study, equivalent bioavailability at steady state and similar potency of the US-marketed Epogen® and the European-marketed Binocrit®. Differences in the formulation between the epoetin alfa products had no apparent clinical impact. The high degree of similarity between Epogen® and Erypo®/Eprex® provides justification for linking and comparing results from clinical studies that were conducted using either US- or European-marketed epoetin alfa products.

Pharmacokinetic comparison of an oral diclofenac potassium liquid-filled soft gelatin capsule with a diclofenac potassium tablet.

OBJECTIVE: To compare the pharmacokinetic profiles of diclofenac potassium liquid-filled soft gelatin capsules (DPSGC) using patented ProSorb dispersion technology with an immediate-release, diclofenac potassium 50-mg comparator tablet in two open-label, single-dose, randomized, crossover relative bioavailability studies in healthy volunteers. METHODS: In Study 1, volunteers (n = 21) received DPSGC 50 mg or a diclofenac potassium 50-mg comparator tablet in two inpatient study periods. In Study 2 (n = 54), volunteers received DPSGC 25 mg, DPSGC 50 mg, or a diclofenac potassium 50-mg comparator immediate-release tablet in three inpatient study periods. RESULTS: In both studies, DPSGC 50 mg displayed a significantly shorter T(max) and higher C(max) than the 50-mg diclofenac potassium comparator tablet. DPSGC 25 mg (Study 2) produced a shorter T(max) (0.45 h) and an equivalent C(max) (1125 ng/ml) to the 50-mg comparator drug. Plasma diclofenac concentration-time courses for the diclofenac potassium 50-mg comparator tablet showed many low, delayed, or multiple peaks compared with DPSGC treatments. CONCLUSIONS: DPSGC 25 mg and 50 mg were more rapidly and consistently absorbed than diclofenac potassium 50-mg comparator tablets. The C(max) of DPSGC 25 mg was equivalent to the 50-mg diclofenac potassium comparator tablet. These characteristics may be beneficial when fast, consistent drug absorption is needed.

Single-dose pharmacokinetic study of rapidly dispersing diclofenac potassium formulations in healthy volunteers.

OBJECTIVE: The clinical utility of diclofenac potassium, a commonly prescribed analgesic that provides mild to moderate pain relief, may be hindered by its delayed, depressed, and/or inconsistent absorption characteristics. A diclofenac potassium formulation using proprietary dispersion technology (ProSorb) was developed to overcome these limitations. The authors evaluated and compared the pharmacokinetics (PK) of 2 investigational diclofenac potassium liquid filled soft gelatin capsule (DPSGC) preparations and one investigational diclofenac liquid formulation, each incorporating the proprietary dispersion technology, to establish bioequivalence and identify a formulation for further clinical study. RESEARCH DESIGN AND METHODS: In an open-label, single-dose, three-way crossover, relative bioavailability study, 24 healthy volunteers were randomized to receive each of the 25-mg DPSGC formulations (development processes A and B) and the 1-mL (25-mg) liquid diclofenac formulation (similar to the fill liquid used in the DPSGC products) during three inpatient visits. Each dose was separated by 3 days. Plasma samples were collected at preselected time points through 6 hours post dose. Diclofenac concentrations were determined using a validated HPLC method. Bioequivalence was established within the 80% to 125% acceptance range. Safety and tolerability were monitored throughout. RESULTS: Area under the plasma concentration-time curves (AUC(0-)(t)) for the three formulations were between 577 and 585 ng-hr/mL and peak plasma concentrations (C(max)) were between 958 and 1087 ng/mL, with the DPSGC process B group having the highest C(max). The times to C(max) (t(max)) were all below 30 minutes, with the liquid formulation producing the shortest t(max) (15 minutes). Plasma concentration-time course profiles were similar for all three rapidly dispersing diclofenac potassium formulations. One mild adverse event was observed (lingual paresthesia) and one participant discontinued due to an unrelated event (acute tonsillitis). CONCLUSIONS: These data show that diclofenac potassium formulations using proprietary dispersion technology are rapidly and consistently absorbed. These characteristics may be beneficial in settings where rapid and consistent drug absorption is desirable. These results may differ in other patient populations such as those experiencing pain or illness.