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

Abstract

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.

Application of a Stable Isotope Approach to Evaluate Impact of Changes in Manufacturing Parameters for an Immediate-Release Tablet

“…A small (<10% of total dose, 50 mg) liquid dose of a stable [ 13 C 2 , 15 N 2 ]GSK1322322 free base was coadministered orally with each treatment to serve as an internal standard for quantitation purposes. Use of this stable‐isotope approach has recently allowed better characterization of the impact of tablet‐manufacturing processes on drug bioavailability . Sample size required was recalculated based on the %CVw obtained both with [ 13 C 2 , 15 N 2 ]GSK1322322 as a covariate in the model (ANCOVA) and without it (ANOVA).…”

“…Use of this stable-isotope approach has recently allowed better characterization of the impact of tablet-manufacturing processes on drug bioavailability. 9 Sample size required was recalculated based on the %CVw obtained both with [ 13 C 2 , 15 N 2 ]GSK1322322 as a covariate in the model (ANCOVA) and without it (ANOVA). The results showed that only a slight reduction in sample sizes could be gained by using stable isotope as an internal standard to correct for PK variability for a future relative bioavailability assessment (8 subjects vs 10 subjects for AUC), probably due to the intrinsic low PK variability of GSK1322322 (CVw% were already small without the stable isotope approach, 12.15% for AUC 0-Ý ).…”

“…Parr et al reported a time‐, resource‐, and cost‐effective approach using a stable isotope as an internal reference for each formulation evaluated in a typical bioavailability study. The coadministration of this stable isotope with each dosage form permits a better understanding of the temporal effects (eg, biological changes such as GI transit) between 1 dosing period and another, thus allowing the ability to detect true differences between formulations using a small number of subjects.…”

A Comparison of Blood Amino Acid Concentrations Following Ingestion of Rice and Whey Protein Isolate A Double-Blind Crossover Study

“…The intra-subject coefficient of variations for AUC were 3.5%-7.3% (mean=4.9%) for the essential amino acids and 1.9-12.7% (mean=6.6%) for the non-essential amino acids. The low coefficient of variation concludes that there is greater than 90% power of determining bioequivalence [26].…”

Application of the Stable Isotope Label Approach in Clinical Development—Supporting Dissolution Specifications for a Commercial Tablet Product with Tafenoquine, a Long Half-life Compound

“…A method or study design that addresses these challenges can be valuable in the drug development process [2]. The stable isotope label (SIL) method provides an effective approach for comparing qualitatively and quantitatively similar formulations and can generate in vivo (PK) data to support in vitro tests [2].…”