Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers

Lappin, Graham

doi:10.1002/jcph.569

Cited by 28 publications

(47 citation statements)

References 58 publications

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“…Nonlinearity is a common concern for microdose administrations, and crossover study designs can suffer from nonequivalent clearance effects to assess absolute bioavailability. The study design presented here negates or at least minimizes both of these potential issues . Furthermore, adequate mass balance was achieved in this study, allowing the successful determination of the excretion of batefenterol.…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetics, Excretion, and Mass Balance of [¹⁴C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Ambery¹,

Young

Fuller³

et al. 2018

Clinical Pharm in Drug Dev

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Inhaled batefenterol is an investigational bifunctional molecule for the treatment of chronic obstructive pulmonary disease. The excretion balance and pharmacokinetics of batefenterol using [14C]‐radiolabeled drug administered orally and as intravenous (IV) infusion were assessed. In this 2‐period, open‐label study, 6 healthy male subjects received a single IV microtracer 1‐hour infusion of 4 μg [14C]‐batefenterol concomitant with inhaled nonradiolabeled batefenterol (1200 μg) followed by oral [14C]‐batefenterol (200 μg) in period 2 after a 14‐day washout. The primary end points included: the area under the concentration‐time curve from time zero to last time of quantifiable concentration (AUC0‐t); maximum observed concentration (Cmax); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC0‐t of [14C]‐batefenterol was 121.9 pgEq • h/mL; maximum observed concentration and time of occurrence of maximum observed concentration were 92.7 pgEq/mL and 0.8 hours, respectively; absolute oral bioavailability was 0.012%. The mean AUC0‐t ratio indicated that [14C]‐batefenterol accounted for 85% of total circulating radioactivity in the plasma initially and declined rapidly following IV administration, but only ∼0.2% of total circulating radioactivity following oral administration. Cumulative mean recovery of total radioactive [14C]‐batefenterol in urine and feces was 6.31% and 77.6%, respectively. Overall, batefenterol exhibited low systemic bioavailability after inhaled and oral administration, and high fecal excretion and low urinary excretion following IV and oral administration.

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Section: Discussionmentioning

confidence: 98%

Pharmacokinetics, Excretion, and Mass Balance of [¹⁴C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Ambery¹,

Young

Fuller³

et al. 2018

Clinical Pharm in Drug Dev

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“…25,26 However, the strong CYP3A inducer rifampicin significantly decreased the exposure of osimertinib. 28 An alternative approach is the use of an IV microtracer dose, defined as 1% of the pharmacologic dose, or 100 μg, whichever is lower. 27 Traditionally, a crossover study design has been used to determine absolute bioavailability, whereby an oral dose and an intravenous (IV) dose are administered on separate occasions, with a washout period in between.…”

mentioning

confidence: 99%

“…25 For this reason, labeling recommendations for osimertinib include avoidance of strong inducers of CYP3A. 28 This method has been used previously to determine the absolute bioavailability of a variety of drugs across a range of therapeutic areas, establishing the amount absorbed into systemic circulation following extravascular administration and evaluating the first-pass effect. 28 An alternative approach is the use of an IV microtracer dose, defined as 1% of the pharmacologic dose, or 100 μg, whichever is lower.…”

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confidence: 99%

Absolute Bioavailability of Osimertinib in Healthy Adults

Vishwanathan

Thomas

et al. 2018

Clinical Pharm in Drug Dev

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Osimertinib is a third-generation, central nervous system-active, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI sensitizing and T790M resistance mutations. This phase 1, open-label study (NCT02491944) investigated absolute bioavailability and pharmacokinetics (PK) of oral and intravenous (IV) osimertinib. Ten healthy subjects (21-61 years) received a single oral 80-mg dose concomitantly with a 100 μg (containing 1 μCi) IV microtracer dose of [ C]osimertinib. Oral and IV PK were determined simultaneously for osimertinib and its active metabolites, AZ5104 and AZ7550. High-performance liquid chromatography and accelerator mass spectrometry were used to characterize IV dose PK. Geometric mean absolute oral bioavailability of osimertinib was 69.8% (90% confidence interval, 66.7, 72.9). Oral osimertinib was slowly absorbed (median time to maximum plasma concentration [t ] 7.0 hours). Following t , plasma concentrations fell in an apparent monophasic manner. IV clearance and volume of distribution were 16.8 L/h and 1285 L, respectively. Arithmetic mean elimination half-life estimates were 59.7, 52.6, and 72.6 hours for osimertinib, AZ5104, and AZ7550, respectively (oral dosing), and 54.9, 68.4, and 99.7 hours for [ C]osimertinib, [ C]AZ5104, and [ C]AZ7550, respectively (IV dosing). Oral osimertinib was well absorbed. Simultaneous IV and oral PK analysis proved useful for complete understanding of osimertinib PK and showed that the first-pass effect was minimal for osimertinib.

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“…Thorough reviews of various applications and methods of microdose and microtracer studies are provided elsewhere. 2,5 Study Design With Regard to Intravenous Dose Administration …”

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confidence: 99%

Infusions Are the Optimal Dosing Method in Intravenous ADME Studies Rather Than Bolus Dosing

Barbour¹,

Fossler²

2017

The Journal of Clinical Pharma

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A vast majority of new drugs are developed for oral administration. However, intravenous studies are often conducted to elucidate fundamental absorption, distribution, metabolism, and excretion (ADME) properties, such as bioavailability. A common study design involves a traditional 2-way crossover with oral and intravenous dosing using doses that achieve therapeutic concentrations. More novel designs employing microdosing in a phase 0 two-way crossover or in a single arm dosing the therapeutic oral dose with a microtracer, that is, a radiolabeled intravenous microdose typically administered at the T max of the oral dose, are increasing in application. These microdose studies, defined as studies in which the dose is ࣘ100 μg, ࣘ1/100th the no adverse event limit, and ࣘ1/100th the pharmacologically active dose, 1 are growing in popularity as the value is realized because of the potential cost savings of an exploratory investigational new drug (IND) application and selection of a candidate with acceptable pharmacokinetics for further development, compared with a full IND (0.5-0.75 vs 1.5-2.5 M). 2 In addition, utilization of microdose studies may continue to grow as the potential applications expand and experience is gained with these applications, such as phase 0 exploration of a compound as a potential victim of drug-drug interactions or pharmacodynamic exploration. Finally, these study designs are used to fulfill the regulatory requirement from the Australian Healthy authorities to understand the absolute bioavailability. 3 To highlight one recent example, 4 Nav1.7 inhibitors were explored in a phase 0 microdose study whereby 100 μg of each compound was dosed both intravenously and orally. 4 Using the intravenous and in vitro ADME data, a physiologically based pharmacokinetic (PBPK) model was developed and validated using the oral data. This model was then used to predict pharmacokinetic (PK) profiles for each compound at various potential clinical doses and compare the Cmin relative to the Nav1.7 IC50, leading to the selection of the development candidate. Thorough reviews of various applications and methods of microdose and microtracer studies are provided elsewhere. 2,5 Study Design With Regard to Intravenous Dose Administration

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Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers

Cited by 28 publications

References 58 publications

Pharmacokinetics, Excretion, and Mass Balance of [¹⁴C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Pharmacokinetics, Excretion, and Mass Balance of [¹⁴C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Absolute Bioavailability of Osimertinib in Healthy Adults

Infusions Are the Optimal Dosing Method in Intravenous ADME Studies Rather Than Bolus Dosing

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Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers

Cited by 28 publications

References 58 publications

Pharmacokinetics, Excretion, and Mass Balance of [14C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Pharmacokinetics, Excretion, and Mass Balance of [14C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Absolute Bioavailability of Osimertinib in Healthy Adults

Infusions Are the Optimal Dosing Method in Intravenous ADME Studies Rather Than Bolus Dosing

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Product

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Pharmacokinetics, Excretion, and Mass Balance of [¹⁴C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

Pharmacokinetics, Excretion, and Mass Balance of [¹⁴C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men