Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: Increasing the power of bioavailability tests

Heck, Henry d’A.; Buttrill, S. E.; Flynn, Norman W.; Dyer, Robert; Anbar, M.; Cairns, Thomas; Dighe, Shrikant V.; Cabana, Bernard E.

doi:10.1007/bf01060015

Cited by 77 publications

(26 citation statements)

References 2 publications

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“…This has the limitation of requiring significant amounts of stable isotope to enable the manufacture of an appropriately size batch of drug product. The approach presented here is similar to that reported by Heck et al (2), that the addition of a small dose of enriched compound, such as a solution or solid, is given along with the products being tested rather than incorporating them into the formulations. However, Heck et.…”

Section: Introductionsupporting

confidence: 53%

“…Utilization of single-and dual-label stable isotopes (e.g., 13 C, 15 N, 18 O) in pharmacokinetics (PK) studies has been in existence for many years (1)(2)(3)(4)(5)(6). Utilization of a stable isotope provides the ability to measure plasma concentrations of an enriched and non-enriched drug substance from the same plasma sample (i.e., subject).…”

Section: Introductionmentioning

confidence: 99%

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Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies

Parr

Gupta

Montague

et al. 2012

AAPS J

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Abstract. The purpose of this investigation is to evaluate the scientific benefits of a novel approach in using stable isotopes to reduce the number of subjects needed to perform relative bioavailability and bioequivalence pharmacokinetic studies for formulations that are qualitatively and quantitatively the same and quality by design (QbD) pharmacokinetic studies. The stable isotope approach was investigated using simulations to determine the impact this approach would have on the estimation of variability and, subsequently, the sample size for a bioequivalence study. A biostudy was conducted in dogs in a two period crossover to explore the viability of the stable isotope approach. For a drug product with within-subject variability (CV w ) of 50% and assuming a correlation of 0.95 between the enriched and non-enriched pharmacokinetics (PK), simulations showed that the variability can be reduced by 70% and the required sample size can be reduced by 90% while maintaining 90% power to demonstrate bioequivalence. The dog study showed a strong correlation (R 2 , >0.99) between the enriched and nonenriched area under the curve and maximum observed concentration, and a significant reduction in the variability (reduction in % coefficient of variation from 79.9% to 6.3%). Utilization of a stable isotope approach can markedly improve the efficiency and accuracy of bioavailability and bioequivalence studies particularly for highly variable drugs in formulations that are qualitatively and quantitatively the same and for studies designed for QbD investigations.

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Section: Introductionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies

Parr

Gupta

Montague

et al. 2012

AAPS J

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“…The % relative standard deviation (% RSD) in the AUC values among the six subjects, a measure of intrasubject variability, ranged from 6% to 38% while the % RSD for AUC by period, a measure of the intersubject variability, ranged from 26% to 55%. The dramatic increase in power of the test in stable isotope dilution bioavailability studies noted by Heck et al (1979) and in this study is apparently due to the reduction of both the intrasubject and intersubject variability when relative AUC and relative Cmax are used as the measurements of dosage form bioavailability.…”

Section: Discussionmentioning

confidence: 72%

Comparative bioavailability of trazodone formulations using stable isotope methodology.

Gammans¹,

Mackenthun²,

Russell³

1984

Brit J Clinical Pharma

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1 The bioavailability of trazodone, a new antidepressant, from 50 mg dividose (A) or film-sealed (B) tablets relative to an oral solution was determined in six healthy male subjects using 50 mg of D4-trazodone as a stable isotope labelled standard. Concentrations of trazodone and D4-trazodone were measured by GCMS. 2 The pharmacokinetics of trazodone and D4-trazodone were identical indicating no isotope effect.3 For formulation A, B and solution, the relative (trazodone/D4-trazodone) Cma. values were 0.84 + 0.09, 0.90 + 0.05 and 1.05 + 0.04. The relative bioequivalence of the dosage formed with a power of 85% (power by conventional ANOVA was 54%). 4 Among subjects % relative standard deviations (RSD) for the D4-trazodone AUC values, a measure of intra-subject variability, were 6 to 38% while the % RSDs by period, a measure of inter-subject variability, were 26 to 55%.

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“…This consideration has also been recognized to apply for drugs that do not undergo extensive first-pass metabolism. 39 In this study, each subject was studied on 3 separate occasions. The data therefore represent the analysis of 22 study days (11 each on low-salt diets and high-salt diets).…”

Section: Limitations Of the Studymentioning

confidence: 99%

Modulation by Dietary Salt of Verapamil Disposition in Humans

Darbar

Fromm²,

Dell’Orto³

et al. 1998

Circulation

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Background-The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism. Methods and Results-Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed.

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Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: Increasing the power of bioavailability tests

Cited by 77 publications

References 2 publications

Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies

Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies

Comparative bioavailability of trazodone formulations using stable isotope methodology.

Modulation by Dietary Salt of Verapamil Disposition in Humans

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