Safety and immunopharmacology of ASP0892 in adults or adolescents with peanut allergy: two randomized trials.

BACKGROUND: New treatment options with improved safety and novel mechanisms of actions are needed for patients with peanut allergy. OBJECTIVES: To evaluate the safety, tolerability, and immunogenicity of ASP0892, a peanut DNA vaccine, after intradermal (id) or intramuscular (im) administration in adult or adolescent patients with peanut allergy in two phase 1 studies. METHODS: ASP0892 or placebo was administered every 2 weeks for a total of 4 doses. The doses were 1 mg or 4 mg id or 4 mg im for adults, and 1 mg or 4 mg id for adolescents. Immunologic parameters were assessed longitudinally. RESULTS: Thirty-one adults (mean age 24.3 years, 17 males) received ASP0892 (9, 8, 8 patients for 1 mg id, 4 mg id or 4 mg im, respectively) or placebo (2 patients/group). Twenty adolescents (mean age 14.2 years, 11 males) received ASP0892 (8 patients/group) or placebo (2 patients/group). In both studies, the most common treatment-emergent adverse event (TEAE) was injection site pruritus. No deaths or treatment withdrawal were related to TEAEs. No serious TEAEs related to treatment were observed in adult or adolescent patients. ASP0892 treatment led to modest increases in allergen-specific IgG and/or IgG4 in adults (1 mg id, 4 mg im) and adolescents (1 mg id, 4 mg id). No improvements in clinical outcomes, including double-blind placebo-controlled food challenge, were found after ASP0892 treatment. CONCLUSIONS: In two phase 1 studies, ASP0892 was well tolerated with modest but not clinically relevant changes in immune responses. GOV IDENTIFIERS: NCT02851277, NCT03755713.

Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults.

INTRODUCTION: Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants. METHODS: Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80-1.25. RESULTS: Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration-time curve from time zero to infinity (AUCinf) were 1.30 (90% CI 1.17-1.45) and 2.58 (90% CI 2.32-2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37-0.49) and 0.17 (90% CI 0.15-0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUCinf and C max were 0.53 (90% CI 0.47-0.61) and 0.63 (90% CI 0.50-0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUCinf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits. CONCLUSION: These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9. FUNDING: Astellas Pharma. TRIAL REGISTRATION: EudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

INTRODUCTION: Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. METHODS: Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. RESULTS: Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. CONCLUSION: Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated. FUNDING: Astellas Pharma. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.

INTRODUCTION: Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir. METHODS: These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment. RESULTS: In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated. CONCLUSION: The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5-2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance FUNDING: Astellas Pharma.

Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies.

Oral anticoagulant therapy with heparin has been challenged by formulating heparin in oral solid preparation. As heparin, low molecular weight heparin (LMWH) was used. LMWH was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with three kinds of adsorbents, microporous calcium silicate (Florite RE), magnesium alminometa silicate (Neusilin US(2)) and silicon dioxide (Sylysia 320). The in vitro release study showed that the T50%s were 3.2+/-0.1min for Sylysia 320, 4.6+/-0.2min for Florite RE, 13.7+/-0.1min for Neusilin US(2). The in vivo rat absorption study showed that Florite RE system had the highest C(max), 0.42+/-0.01IU/mL and AUC, 0.59+/-0.06IUh/mL, where plasma LMWH levels were measured as anti-Xa activity. Other preparations had the C(max) and AUC, 0.12+/-0.01IU/mL and 0.15+/-0.02IUh/mL for Neusilin US(2) and 0.25+/-0.02IU/mL and 0.40+/-0.03IUh/mL for Sylysia 320, respectively. The bioavailability (BA) of LMWH from the microporous calcium silicate preparation, Florite RE, was 18.8% in rats by comparing the AUC obtained after i.v. injection of LMWH, 40IU/kg to another group of rats. Florite RE system was evaluated in dogs after oral administration in an enteric capsule made of Eudragit S100 at the LMWH dose of 200IU/kg. High plasma anti-Xa activity levels were obtained, i.e., the C(max) was 0.48+/-0.11IU/mL and AUC was 1.64+/-0.32IUh/mL. These results suggest that adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as LMWH.

Oral solid gentamicin preparation using emulsifier and adsorbent.

Oral gentamicin (GM) therapy has been challenged by formulating GM in oral solid preparation. GM was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with several kinds of adsorbents. The used adsorbents were microporous calcium silicate (Florite RE), magnesium alminometa silicate (Neusilin US2), and silicon dioxide (Sylysia 320). In vitro release study showed that the percentage released of GM from each preparation per 2 h was 99.8+/-0.06% for Florite RE 10 mg, 96.7+/-1.16% for Florite RE 20 mg, 98.3+/-0.32% for Neusilin US2, and 94.4+/-0.23% for Sylysia 320. The T50% values were 0.35+/-0.05 h for Florite RE 10 mg, 0.34+/-0.03 h for Florite RE 20 mg, 0.26+/-0.03 h for Neusilin US2, and 0.15+/-0.01 h for Sylysia 320. The in vivo rat absorption study showed that Florite RE 10 mg preparation had the highest C(max) (2.14+/-0.67 microg/ml) and AUC (4.74+/-1.21 microg h/ml). Other preparations had C(max) and AUC of 0.69+/-0.10 microg/ml and 1.56+/-0.43 microg h/ml for Florite RE 20 mg, 1.07+/-0.31 microg/ml and 1.80+/-0.33 microg h/ml for Neusilin US2, and 0.99+/-0.21 microg/ml and 1.77+/-0.50 micorg h/ml for Sylysia 320, respectively. The bioavailability (BA) of GM from the microporous calcium silicate preparation, Florite RE 10 mg, was 14.1% in rats, derived by comparing the AUC obtained after intravenous injection of GM, 1.0 mg/kg, to another group of rats. The microporous calcium silicate preparation using Florite RE 10 mg was evaluated in dogs after oral administration in an enteric capsule, Eudragit S100 (50 mg/dog). High plasma GM levels were obtained (i.e., the C(max) was 1.26+/-0.20 microg/ml and the AUC was 2.59+/-0.33 microg h/ml). These results suggest that an adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as GM.