Tolerability and Pharmacokinetics of a New P-Glycoprotein Inhibitor, HM30181, in Healthy Korean Male Volunteers: Single- and Multiple-Dose Randomized, Placebo-Controlled Studies

Kim, Tae Eun; Gu, Namyi; Yoon, Seo Hyun; Cho, Joo Youn; Park, Kyung Mi; Shin, Sang Goo; Jang, In Jin; Yu, Kyung‐Sang

doi:10.1016/j.clinthera.2012.01.003

Cited by 18 publications

(16 citation statements)

References 9 publications

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“…Therefore, it is less likely that HM30181 alters non‐P‐gp hepatic clearance of xenobiotics, which may be mediated by MRP2 , located at the canalicular membrane of the hepatocyte . This specificity of HM30181 may explain the favourable tolerability profile shown not only in this study, but also in a previous study .…”

Section: Discussionsupporting

confidence: 51%

“…To overcome those limitations, third‐generation P‐gp inhibitors have been developed . HM30181 [2‐(2‐[6]‐2 H tetrazol‐5‐yl)‐4, 5‐dimethoxy‐phenyl]‐amide is a new third‐generation P‐gp inhibitor, which is currently under development . HM30181 showed a high potency (IC50 = 0.63 nM) and selectivity for P‐gp inhibition in ATPase assays performed with P‐gp‐enriched vesicles .…”

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confidence: 99%

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Sustained Increase in the Oral Bioavailability of Loperamide after a Single Oral Dose of HM30181, a P‐glycoprotein Inhibitor, in Healthy Male Participants

Jung

Lee

et al. 2013

Basic Clin Pharma Tox

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HM30181 is a new P-glycoprotein (P-gp) inhibitor. This study was conducted to investigate the effect of HM30181 and its duration of action on P-gp inhibition using loperamide as a probe drug. An open-label, five-period, fixed-sequence, cross-over study was conducted in 25 healthy Korean participants, who received a single oral dose of loperamide at 16 mg in five periods lasting for 17 days. In period II, participants also randomly received a single oral dose of HM30181 at 1, 5, 10, 15 mg simultaneously with loperamide. Serial pharmacokinetic blood samples were obtained up to 72 and 336 hr after loperamide and HM30181 administration, respectively. A mixed-effects analysis was performed to compare the area under the plasma concentration versus time curve from time 0 to 72 hr (AUC0-72 hr ) between periods and HM30181 dose groups. Tolerability was also assessed. The AUC0-72 hr of repeatedly administered loperamide was significantly increased 1.18-1.62 times for up to 14 days after a single oral administration of HM30181, particularly at doses ≥10 mg although the between-group difference failed to reach statistical significance. Plasma HM30181 was not detected in many participants including none at any sampling points beyond 48 hr after administration. Most adverse events (AEs) were mild to moderate and resolved spontaneously. The oral bioavailability of loperamide was significantly enhanced by a single oral administration of HM30181, which was sustained for up to 14 days. HM30181 was well tolerated in this selected population.

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Section: Discussionsupporting

confidence: 51%

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confidence: 99%

Sustained Increase in the Oral Bioavailability of Loperamide after a Single Oral Dose of HM30181, a P‐glycoprotein Inhibitor, in Healthy Male Participants

Jung

Lee

et al. 2013

Basic Clin Pharma Tox

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“…Although the C max and AUC values of HM30181 were increased as the dose increased, they were not dose‐proportional. The 90% confidence intervals for the coefficients of the slopes in the power model were 0.1446, 0.5012 and 0.2991, 0.5590 for C max and AUC(0, t last ), respectively, similar to those seen in a previous study .…”

Section: Resultssupporting

confidence: 83%

Effects of HM30181, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers

Kim

Lee

Lim

et al. 2014

Brit J Clinical Pharma

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AIMSHM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. METHODSEighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. RESULTSPupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone.

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“…In this study, authors used a new P-gp inhibitor HM30181, which is chemically 4-oxo-4H-chromene-2-carboxylic acid, [2-(2-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]amide and the structure of which could be referred elsewhere 58 . HM30181 is a novel third generation P-gp inhibitor currently under development, that inhibits P-gp transporters specifically in the intestinal endothelium with no systemic effects, whose effect has been confirmed in various preclinical studies and clinical trials [59][60][61][62][63] . The dose of HM30181 was set at 30 mg for one dog and was administered in form of tablets.…”

Section: Pharmacokinetics Of Sdg-tmentioning

confidence: 95%

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

Shanmugam

Sohn

et al. 2015

Drug Development and Industrial Pharmacy

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The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20 min. Finally, the PK profile of SDG-T and a reference formulation Oraxol™ (oral solution formulation used in Phase I clinical study) at a dose of 60 mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10 mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol™ solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol™ solution was 132.25% at a dose of 60 mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10-150 ng/mL for a period of 24 h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.

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Tolerability and Pharmacokinetics of a New P-Glycoprotein Inhibitor, HM30181, in Healthy Korean Male Volunteers: Single- and Multiple-Dose Randomized, Placebo-Controlled Studies

Cited by 18 publications

References 9 publications

Sustained Increase in the Oral Bioavailability of Loperamide after a Single Oral Dose of HM30181, a P‐glycoprotein Inhibitor, in Healthy Male Participants

Sustained Increase in the Oral Bioavailability of Loperamide after a Single Oral Dose of HM30181, a P‐glycoprotein Inhibitor, in Healthy Male Participants

Effects of HM30181, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

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