Plasma pharmacokinetic and metabolism of [18F]THK-5317 are dependent on sex

Abstract

Introduction: Tau deposition is one of the hallmarks of Alzheimer's disease (AD) and can be visualized and quantified using [¹⁸F]THK-5317 together with kinetic modeling. To determine the feasibility of this approach, we measured blood/plasma pharmacokinetics and radiotracer metabolism in female and male rats.

Methods: Female and male rats (n = 11-12) were cannulated via the femoral artery for continuous blood sampling. Blood sampling was performed at regular intervals after intravenous injection of [¹⁸F]THK-5317. After collection of the last blood sample, animals were sacrificed, and organs were excised. Blood from minute 5, 20 and 60 was centrifuged to obtain plasma. Radiolabeled metabolites in plasma, brain, liver and urine were analyzed by radio-thin-layer chromatography (radio-TLC).

Results: Plasma pharmacokinetics and metabolism were significantly different between female and male rats. [¹⁸F]THK-5317 plasma clearance was faster in female (0.66 ± 0.08 mL/h/kg BW) than in male (0.52 ± 0.11 mL/h/kg BW) rats (p = .005). The percentage of unmetabolized parent was significantly different between both sexes at 20 min and 60 min p.i. In the liver, a 1.6-fold higher radioactivity concentration was found in male versus female animals and in addition also the percentage of unmetabolized parent was different.

Conclusion: Our results show pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [¹⁸F]THK-5317 in rats. Female animals showed a faster plasma clearance compared to males. These results underline the importance of investigating both sexes and also support the notion that individual input functions or sex-specific population-based input functions are needed for kinetic modeling analyses.

Advances in knowledge: First preclinical study in rats showing pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [¹⁸F]THK-5317.

Implications for patient care: Sex-specific differences might also be present in humans and thus clinical trials should have adequate sample size to account for effects in men and women separately.

Keywords: (S)-[(18)F]THK-5117; Metabolism; Pharmacokinetic; Sex-dependent; [(18)F]THK-5317.