A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach

Wang, Xiaomin; Chen, Jian; Reyes, Josephine; Zhou, Simon; Palmisano, Maria; Li, Yan

doi:10.1007/s40487-019-0097-7

Cited by 4 publications

(7 citation statements)

References 18 publications

(28 reference statements)

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“…For enasidenib (AG-221) and AGI-16903 were analyzed using a validated method. 13 The LLOQ for both AG-221 and AG-16903 in human plasma was 1.0 ng/mL, with linearity demonstrated to 1000 ng/mL for AG-221 and 500 ng/mL for AG-16903. The interassay %CV values, based on the accepted calibration standards across the range, were ≤6.5% for AG-221 and AG-16903.…”

Section: Bioanalysismentioning

confidence: 91%

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Cheng

Wang

Zheng

et al. 2021

The Journal of Clinical Pharma

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As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation.An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

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Section: Bioanalysismentioning

confidence: 91%

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Cheng

Wang

Zheng

et al. 2021

The Journal of Clinical Pharma

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“…Typical clinical use of a 100 μCi 14 C label requires dosimetry assessments (including rat distribution studies), which impact study timelines due to the requirement for preclinical studies 6, 7 . However, application of sensitive 14 C‐labeled microtracer accelerator mass spectrometry (AMS), which can be used to detect ultra‐low microdoses of radiolabel (0.1–1 μCi), circumvents the need for toxicology and dosimetry assessments prior to human dosing and allows for generation of disposition data faster than conventional high‐dose 14 C approaches 7, 8, 9, 10 . These microdoses of 14 C radiolabel are considered insignificant in terms of radioactivity, therefore eliminating the need for animal studies 6, 7, 11, 12 .…”

Section: Figurementioning

confidence: 99%

“…In addition, 14 C‐microtracer approaches may present several advantages, such as measurement of multiple pharmacokinetic (PK) parameters with reduced interpatient variability (due to a cross‐over type design) and lower cost compared with traditional phase 1 studies. Consequently, this approach is being increasingly used in the evaluation of mass balance of new drugs 8, 9, 13 …”

Section: Figurementioning

confidence: 99%

“…6,7 However, application of sensitive 14 C-labeled microtracer accelerator mass spectrometry (AMS), which can be used to detect ultra-low microdoses of radiolabel (0.1-1 μCi), circumvents the need for toxicology and dosimetry assessments prior to human dosing and allows for generation of disposition data faster than conventional high-dose 14 C approaches. 7,8,9,10 These microdoses of 14 C radiolabel are considered insignificant in terms of radioactivity, therefore eliminating the need for animal studies. 6,7,11,12 In addition, 14 C-microtracer approaches may present several advantages, such as measurement of multiple pharmacokinetic (PK) parameters with reduced interpatient variability (due to a cross-over type design) and lower cost compared with traditional phase 1 studies.…”

mentioning

confidence: 99%

“…Consequently, this approach is being increasingly used in the evaluation of mass balance of new drugs. 8,9,13 Using a 14 C-microtracer approach, we report the absorption, excretion, absolute oral bioavailability, and mass balance of zimlovisertib in healthy male participants. A more detailed description of metabolites and clearance mechanisms will be reported separately.…”

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confidence: 99%

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A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a ¹⁴C‐Microtracer Approach

Singh

Dowty

Salganik

et al. 2022

Clinical Pharm in Drug Dev

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Zimlovisertib (PF‐06650833) is a selective, reversible inhibitor of interleukin‐1 receptor‐associated kinase 4 (IRAK4) with anti‐inflammatory effects. This phase 1, open‐label, fixed‐sequence, two‐period, single‐dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a 14C‐microtracer approach. All six participants received 300 mg 14C‐zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and 14C‐zimlovisertib 135 μg intravenously (IV) in Period B. Study objectives included extent and rate of excretion of 14C‐zimlovisertib, pharmacokinetics, and safety and tolerability of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces was 82.4% ± 6.8% (urine 23.1% ± 12.3%, feces 59.3% ± 9.7%) in Period A. Zimlovisertib was absorbed rapidly following oral administration, with the fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 300‐mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the dose‐normalized area under the concentration–time curve from time 0 to infinity. There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%).

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Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans

Chimalakonda,

Li,

Marchisin

et al. 2023

Clinical Pharm in Drug Dev

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Abstractitinib is an oral, selective, allosteric inhibitor of tyrosine kinase 2, an intracellular signaling kinase involved in the pathogenesis of immune‐mediated inflammatory diseases. The absolute and relative bioavailability (BA) were evaluated in phase 1, open‐label studies in healthy adults to assess (1) the absolute BA of the deucravacitinib tablet formulation following single oral administration of a 12‐mg tablet and an intravenous microdose infusion of 0.1‐mg carbon‐13 and nitrogen‐15–labeled deucravacitinib ([13C2, 15N3] deucravacitinib) solution in 8 subjects, and (2) the relative oral BA of deucravacitinib tablet and capsule formulations at the 3‐ and 12‐mg dose levels in 20 subjects. The absolute oral availability of deucravacitinib in the tablet formulation was near complete at approximately 99%. The total clearance (254 mL/min) was low relative to hepatic blood flow, and volume of distribution (∼140 L) was greater than total body water, indicating extravascular distribution. Deucravacitinib systemic exposure (maximum plasma concentration, area under the plasma drug concentration curve from time zero to the time of the last quantifiable nonzero concentration, and area under the plasma drug concentration–time curve from time zero extrapolated to infinity) after administration of the tablet formulation were similar to the capsule at the tested 3‐ and 12‐mg doses. In both studies, deucravacitinib was safe with no clinically relevant changes in laboratory values, electrocardiogram parameters, or vital signs.

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A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach

Cited by 4 publications

References 18 publications

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a ¹⁴C‐Microtracer Approach

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans

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A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach

Cited by 4 publications

References 18 publications

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a 14C‐Microtracer Approach

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans

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A Phase 1 Study to Assess Mass Balance and Absolute Bioavailability of Zimlovisertib in Healthy Male Participants Using a ¹⁴C‐Microtracer Approach