A Chinese pharmaceutical company contracted Aptuit for an integrated program of radiolabeled synthesis and preclinical testing that included Absorption, Distribution, Metabolic and Excretion (ADME) animal studies, and in vivo profiling. Aptuit is one of just a few drug development companies that offer GLP and cGMP radiolabeled synthesis through its API Development & Manufacture group and ADME services through its Pharmaceutical Development & Manufacture team. Aptuit was chosen based on prior experience in conducting similar combined studies within specified timelines.

Studies utilizing radiolabeled compounds provide essential data in establishing a drug safety profile. It can avert the high financial risk associated with finding safety issues during the later stages of compound development. Basically, radio synthesis provides a radiolabeled drug that is used to investigate the pharmacokinetics of a new compound in preclinical species. This enables the prediction of the behavior of the new compound in humans. Studies can be conducted utilizing either carbon 14 (14C) or tritium (3H ) labeled compounds. At times, stable isotopes, (commonly 2H and 13C) may be used; however, the project cited here relied on radioactive compounds. Aptuit’s API scientists are specialists in designing the synthesis that will result in the most ideal position for the label. Several factors are taken into account, most importantly that the label be in a metabolically stable and cost effective position. One of the more challenging aspects of these studies is the development of a synthesis protocol that produces a labeled compound, chemically identical to the original, with high specific activity and high yield. Scientific specialists conduct this synthesis work from dedicated radiochemistry laboratories at Aptuit’s Kansas City site in the United States where one third of the laboratory is exclusively used for radiolabeling and complies with state and federal mandated regulations.

Aptuit’s preclinical team paves the way for a novel compound to be developed as a safe and effective treatment. Safety Pharmacology, Toxicology, Bioanalysis and Drug Metabolism and Pharmacokinetics (DMPK) services, combined with high quality standards, enable clients to make an early and accurate selection of lead candidates. Aptuit’s team can optimize drug development programs to ensure IND submission. They work from state-of-the-art, dedicated facilities in the United Kingdom. The site features advanced preclinical pathology and histopathology laboratories, on-site bioanalytical and DMPK support, compliant with worldwide regulatory GLP requirements.

Since the chemistry and specific details of this study are proprietary, the Aptuit capabilities associated with combined radiolabeling and preclinical services are presented herein.

The Challenge

Combining and integrating the processes so that the project moved forward without interruption required the coordination of API Development and the Preclinical team of DMPK specialists, from two different locations.

This project required technical expertise in both API development and preclinical services, which necessitated strong project management across multiple locations.

The Aptuit Solution

Whatever the intricacies of integrating the teamwork of two separate business lines, the coordinated effort was a much more efficient process than when handled by two separate companies. Any concerns about shipping radioactive materials, acquiring permits or transferring technology from one company to another were eliminated.

The disposition, distribution, metabolism and structural elucidation of the metabolites were investigated in rodent and non rodent species. The program was completed within 20 weeks. (Figure 1).

Aptuit provides comprehensive radiochemistry services in the US, with the portfolio of advanced capabilities shown below. (Figure 2).

A Soxhlet extractor is sometimes used in the course of synthesis. (Figure 3).

Aptuit maintains several dedicated cGMP radiosynthesis suites to generate labeled compounds that are used to evaluate important information regarding pharmacokinetic reaction to specific compounds. (Figure 4).

The ADME package used by Aptuit offers a full range of in vivo and in vitro services to evaluate ADME and drug-drug interaction of a new compound (Figure 5).

Distribution of compound related radioactivity in animals was measured via Quantitative Whole Body Phosphate Imaging (QWBPI). A typical example of QWBPI results (as obtained in this study) is shown here. (Figure 6).

Conclusion

The project was completed on schedule through the conscientious collaboration of two scientific teams within Aptuit. Their efforts were guided by Project Management, tracking the project and ensuring ongoing communications to team members and the client. Weekly status updates were a vital aspect of the project’s success. The client recognized Aptuit’s strong knowledge of radiolabeling and the company’s ability to determine the best position for the label within the compound. They acknowledged the particular difficulties in cGMP radiolabeling, noting that Aptuit was one of just a few companies that could provide this service. The client recognized that by taking advantage of Aptuit’s preclinical capabilities, they could partner with a single company to achieve timely results.

The work cited in this study is an example of how Aptuit can successfully provide integrated services to accelerate clients’ development time frames. Other Aptuit projects that combined the services of more than one business group involved solid state chemistry, formulation development, pharmacokinetics and bioanalytical studies. All of these projects were completed according to anticipated timelines. In every case, the coming together of exceptional science, dedicated people and an exemplary service commitment was the crucial element that led to seamless success in achieving the client’s objectives.

At Aptuit, it’s all about the science, supported by dedicated people and exceptional service.