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Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers.
Clin Drug Investig 2019; 39(12):1185-1194CD

Abstract

BACKGROUND AND OBJECTIVE

This paper describes two studies, which aimed to compare the safety and plasma antithrombin activity of recombinant human antithrombin gamma (rhAT-gamma) with plasma-derived antithrombin (pAT) 60 IU/kg, and to establish bioequivalence by adjusting the rhAT-gamma dose to that at which plasma antithrombin activity equaled that for pAT 60 IU/kg, based on results of the first study.

METHODS

Healthy adult men aged 20-45 years received once-daily doses of rhAT-gamma or pAT intravenously for 3 days (first study: 60 IU/kg of each; second study: 72 IU/kg of rhAT-gamma and 60 IU/kg of pAT). Maximum plasma antithrombin activity after three doses (Cmax,day3) and area under the plasma antithrombin activity-time curve after the third dose (AUC48-t) were analyzed. Safety was also assessed.

RESULTS

In the first study, we compared AUCs to 121 h (when the lower limit of quantification was first observed). Mean Cmax,day3 was 1.67 IU/mL in the rhAT-gamma group and 1.77 IU/mL in the pAT group; mean AUC48-121 was 58.44 and 71.94 IU·h/mL, respectively. Thus, we set the dose of rhAT-gamma in the second study to 72 IU/kg. As a result, ratios of Cmax,day3 and AUC48-t in the rhAT-gamma vs. the pAT group were 105.7% (90% confidence interval 100.3, 111.3) and 100.5% (90% confidence interval 91.5, 110.4), respectively. Adverse events were more frequent in the rhAT-gamma group.

CONCLUSIONS

As 90% confidence intervals for Cmax,day3 and AUC48-t ratios for rhAT-gamma:pAT were within the acceptability range for bioequivalence, rhAT-gamma (72 IU/kg) and pAT (60 IU/kg) are considered bioequivalent.

Authors+Show Affiliations

Osaka Pharmacology Clinical Research Hospital, 4-1-29 Miyahara, Yodogawa-ku, Osaka, 532-0003, Japan. hidetoshi.furuie@heishinkai.com.Kyowa Kirin Co, Ltd, Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31493216

Citation

Furuie, Hidetoshi, and Hironori Kanda. "Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers." Clinical Drug Investigation, vol. 39, no. 12, 2019, pp. 1185-1194.
Furuie H, Kanda H. Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers. Clin Drug Investig. 2019;39(12):1185-1194.
Furuie, H., & Kanda, H. (2019). Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers. Clinical Drug Investigation, 39(12), pp. 1185-1194. doi:10.1007/s40261-019-00847-9.
Furuie H, Kanda H. Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers. Clin Drug Investig. 2019;39(12):1185-1194. PubMed PMID: 31493216.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers. AU - Furuie,Hidetoshi, AU - Kanda,Hironori, PY - 2019/9/8/pubmed PY - 2019/9/8/medline PY - 2019/9/8/entrez SP - 1185 EP - 1194 JF - Clinical drug investigation JO - Clin Drug Investig VL - 39 IS - 12 N2 - BACKGROUND AND OBJECTIVE: This paper describes two studies, which aimed to compare the safety and plasma antithrombin activity of recombinant human antithrombin gamma (rhAT-gamma) with plasma-derived antithrombin (pAT) 60 IU/kg, and to establish bioequivalence by adjusting the rhAT-gamma dose to that at which plasma antithrombin activity equaled that for pAT 60 IU/kg, based on results of the first study. METHODS: Healthy adult men aged 20-45 years received once-daily doses of rhAT-gamma or pAT intravenously for 3 days (first study: 60 IU/kg of each; second study: 72 IU/kg of rhAT-gamma and 60 IU/kg of pAT). Maximum plasma antithrombin activity after three doses (Cmax,day3) and area under the plasma antithrombin activity-time curve after the third dose (AUC48-t) were analyzed. Safety was also assessed. RESULTS: In the first study, we compared AUCs to 121 h (when the lower limit of quantification was first observed). Mean Cmax,day3 was 1.67 IU/mL in the rhAT-gamma group and 1.77 IU/mL in the pAT group; mean AUC48-121 was 58.44 and 71.94 IU·h/mL, respectively. Thus, we set the dose of rhAT-gamma in the second study to 72 IU/kg. As a result, ratios of Cmax,day3 and AUC48-t in the rhAT-gamma vs. the pAT group were 105.7% (90% confidence interval 100.3, 111.3) and 100.5% (90% confidence interval 91.5, 110.4), respectively. Adverse events were more frequent in the rhAT-gamma group. CONCLUSIONS: As 90% confidence intervals for Cmax,day3 and AUC48-t ratios for rhAT-gamma:pAT were within the acceptability range for bioequivalence, rhAT-gamma (72 IU/kg) and pAT (60 IU/kg) are considered bioequivalent. SN - 1179-1918 UR - https://www.unboundmedicine.com/medline/citation/31493216/Randomized_Comparison_Study_of_Novel_Recombinant_Human_Antithrombin_Gamma_and_Plasma-Derived_Antithrombin_in_Healthy_Volunteers L2 - https://dx.doi.org/10.1007/s40261-019-00847-9 DB - PRIME DP - Unbound Medicine ER -