A highly sensitive and selective UPLC-MS/MS assay for the determination of enarodustat (JTZ-951) in human plasma

Pai, Sudhakar M.; Huang, Mike; Maki, Koichi; Waldron, Michael P; Yoshikawa, Tomonori; Keller, Tara; Burnett, J.

doi:10.1016/j.jchromb.2021.122754

Cited by 5 publications

(9 citation statements)

References 14 publications

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“…Plasma samples were analyzed for enarodustat concentrations by a validated liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method 7 . The calibration curve range was from 1.00 to 500 ng/mL.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics of Enarodustat in Non‐Japanese and Japanese Healthy Subjects and in Patients With End‐Stage Renal Disease on Hemodialysis

Pai¹,

Kambhampati²,

Naruhashi

et al. 2023

Clinical Pharm in Drug Dev

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The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end‐stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non‐Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration‐time curve from the time of dosing to infinity were dose‐dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t1/2 of <10 hours indicated negligible accumulation with once‐daily dosing. In general, with daily dosing (25, 50 mg), accumulation at steady‐state was ≈1.5‐fold (t1/2(eff) ≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single‐ and multiple‐dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non‐Japanese patients with ESRD on hemodialysis, following once‐daily dosing (2–15 mg), enarodustat was rapidly absorbed, steady‐state maximum plasma concentration and area under the plasma concentration‐time curve during the dosing interval were dose‐dependent, and interindividual variability in the exposure parameters was low‐to‐moderate (coefficient of variation, 27%–39%). Steady‐state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t1/2 and t1/2(eff) were similar (overall, 8.97–11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15 mg, single dose) exhibited similar pharmacokinetics with mean t1/2 of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non‐Japanese patients. Body weight‐adjusted clearance values were generally similar in non‐Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis.

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Section: Methodsmentioning

confidence: 99%

“…Urine samples were analyzed for enarodustat concentrations by a validated LC‐MS/MS method. The validated urine method had the same LC conditions and MS/MS parameters as those in the published plasma method 7 . The calibration curve range was from 5.00 to 2500 ng/mL.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Enarodustat in Non‐Japanese and Japanese Healthy Subjects and in Patients With End‐Stage Renal Disease on Hemodialysis

Pai¹,

Kambhampati²,

Naruhashi

et al. 2023

Clinical Pharm in Drug Dev

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show abstract

“…Plasma samples were analyzed for enarodustat concentrations by a validated ultra‐performance LC‐tandem mass spectrometry (UPLC/MS/MS) method 13 . The calibration curve range was from 1.00 to 500 ng/mL.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Drug–Drug Interaction Potential of Enarodustat (JTZ‐951) Using a Cytochrome P450 Probe Cocktail

Pai¹,

Yamada

Murata

2023

Clinical Pharm in Drug Dev

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The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once‐daily administration for 15 days in a phase 1 multiple‐ascending‐dose study in healthy subjects. Probe substrates specific for the enzymes, i.e., caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day 15) and without (day −3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve from the time of dosing to infinity (AUCinf) ratios (day 15/day −3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for Cmax and AUCinf were 0.99–1.06 and 1.61–1.63, respectively. The ratios for peak concentrations and total exposures were 0.98–1.07 and 0.71–1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the Cmax and AUCinf ratios were 0.83–0.90 and 1.02–1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day −3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam Cmax and AUCinf were 1.42–1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80–1.25 range, but changes in the geometric mean ratios were all <2‐fold.

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“…The intraand interassay accuracy ranged from −5.7% to 7.0%. 24 Hb levels were measured by colorimetric method. Dose-adjustment range:…”

Section: Bioanalytical Methodsmentioning

confidence: 99%

“…The intra‐ and interassay precision were within 3.6%. The intra‐ and interassay accuracy ranged from −5.7% to 7.0％ 24 . Hb levels were measured by colorimetric method.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

Naruhashi

Fujii

Yamada

et al. 2022

The Journal of Clinical Pharma

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Enarodustat (JTZ-951) is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has been approved and marketed in Japan for patients with anemia with chronic kidney disease (CKD). The pharmacometric approach was applied to assess the relationship between plasma concentrations of enarodustat and hemoglobin (Hb) levels, and to provide information regarding the optimal use of enarodustat in clinical practice by simulations based on the pharmacokinetic and pharmacodynamic (PK/PD) model that was developed. The PK/PD data of enarodusat obtained from phase 2 and phase 3 studies in Japanese patients with CKD were well described by the models: a 1-compartment model with first-order absorption and elimination for PK, and a semimechanistic model based on transit compartment model for PD. Although several factors were identified as statistically significant covariates on the PK/PD of enarodustat, model-based simulations showed that none of them had clinically relevant impacts on the treatment effect (ie, Hb levels) of enarodustat. Hence, enarodustat treatment provides the stable Hb control with the initial dose (hemodialysis-dependent CKD: 4 mg/day, non-dialysis-dependent CKD: 2 mg/day) and maintenance dose (1-8 mg/day) to the patients with varied demographic characteristics.

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A highly sensitive and selective UPLC-MS/MS assay for the determination of enarodustat (JTZ-951) in human plasma

Cited by 5 publications

References 14 publications

Pharmacokinetics of Enarodustat in Non‐Japanese and Japanese Healthy Subjects and in Patients With End‐Stage Renal Disease on Hemodialysis

Pharmacokinetics of Enarodustat in Non‐Japanese and Japanese Healthy Subjects and in Patients With End‐Stage Renal Disease on Hemodialysis

Evaluation of Drug–Drug Interaction Potential of Enarodustat (JTZ‐951) Using a Cytochrome P450 Probe Cocktail

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

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