Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.

The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Clinical Pharmacology Leadership Group (CPLG) held its first meeting of Japan-based representatives at Astellas Pharma headquarters in Tokyo on October 1, 2019. The meeting was also attended by Japan Pharmaceutical Manufactures Association (JPMA) Clinical Pharmacology Task Force (CPTF) members. Overall, nearly 30 clinical pharmacologists representing 14 companies attended the event. The meeting met its goal of enhancing mutual understanding of each organization's activities. In a number of break-out sessions, participants identified scientific topics for potential future collaboration between JPMA CPTF and IQ CPLG.

Consideration of Factors Affecting the Safety Index in Early Clinical Drug Development.

In drug development, a safety index-the ratio of the highest exposure that does not induce toxicity to the exposure that exerts efficacy-is used to quantify the balance between the safety and efficacy of a test drug. Here, the phase 1 index (maximum area under the curve [AUC] in phase 1/therapeutic AUC) and no-observed-adverse-effect level (NOAEL) index (AUC at NOAEL/therapeutic AUC) of recently approved drugs in Japan were calculated and characterized by therapeutic areas and indications. A large variation within both indices was observed, with a median of 3.2 for the phase 1 index and 3.5 for the NOAEL index. Furthermore, the safety indices were affected by the therapeutic area, which might be attributed to the difference in unmet medical needs for certain diseases. This study provides a qualitative measure for interpreting the phase 1 index versus the NOAEL index and might help inform the decision-making process following phase 1 trials.

The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoprotein-quantitative analysis based on information from the literature.

It is suggested that the bioavailability of CYP3A4 substrates might be low due to first-pass metabolism in the small intestine, and it is possible that P-glycoprotein (P-gp) may influence first-pass metabolism in a co-operative manner. We have collected information of the pharmacokinetics of CYP3A4 substrates to evaluate the fraction absorbed (Fa), intestinal availability (Fg) and hepatic availability (Fh) and have investigated the intestinal first-pass metabolism and the effect of P-gp on this. The pharmacokinetic data involved ten compounds metabolized by CYP3A4 in humans, with and without an inhibitor or inducer. FaFg, which is the product of Fa and Fg, and Fh were calculated using three liver blood flow rates (17.1, 21.4, 25.5 mL/min/kg) in consideration of variations in the liver flow rate. Co-administration with an inhibitor of CYP3A4 and treatment of an inducer of CYP3A4 caused an increase and decrease in the FaFg of CYP3A4 substrates, regardless of the liver blood flow, indicating that CYP3A4 substrates exhibit a first-pass effect in their metabolism. This holds true regardless of whether the compounds are P-gp substrates or not. No relationship was observed between FaFg and Fh, regardless of the hepatic blood flow rate and the P-gp substrates. The FaFg of both P-gp and non P-gp substrates decreased as the hepatic intrinsic clearance increased. FaFg was markedly reduced when the hepatic intrinsic clearance was more than 100 mL/min/kg. This in vivo intrinsic clearance corresponds to an in vitro intrinsic clearance of 78 muL/min/mg human hepatic microsomal protein, equivalent to a half-life of 8.9 min for the substrate in a commonly used metabolic stability test with human microsomes (1 mgMs protein/mL). This phenomenon was not observed in substrates of CYP isoforms other than CYP3A4. In conclusion, it is suggested that CYP3A4 substrates which have a hepatic intrinsic clearance of 100 mL/min/kg exhibit a low bioavailability due to intestinal first-pass metabolism, regardless of whether they are substrates of P-gp or not.