Metabolism and clinical pharmacokinetics of 2-methyl-n-(2′-(pyrrolidinyl-1-ylsulfonyl)-n-[1,1′-biphenyl]-4-yl)propran-1-amine: insights into monoamine oxidase- and CYP-mediated disposition by integration of in vitro ADME tools

Abstract

1. In early discovery stages, 2-methyl-N-(2′-(pyrrolidinyl-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)propan-1-amine (PBPA) demonstrated monoamine oxidase A (MAO-A) and cytochrome P450 (CYP)-mediated clearance. While human liver microsomes predicted low CL_b PBPA demonstrated a moderate CL_p/F in humans. The plasma pharmacokinetic (PK) of PBPA was characterized by unexpected high inter-individual variability. Hence, a retrospective analysis was undertaken to understand the disposition processes of PBPA, by applying in vitro mechanistic tools.

2. The in vitro-to-in vivo of rat CL_b of PBPA was calculated as similar to that of human, suggesting rat to be a better predictor of a MAO-A/CYP substrate, but not dog or monkey; this is consistent with differences in expression of MAO-A in rat, dog, monkey and human. Fraction metabolized (f_m) of human MAO A (hMAO-A) (50%), CYP3A4 (8%), CYP3A5 (16%) and CYP2D6 (29%) was determined, in vitro.

3. While the f_m of CYP3A5 was <50%, Michaelis–Menten kinetics demonstrated that it was a higher capacity pathway compared with MAO-A, 2D6 and 3A4. This was consistent with strong association of dose-normalized plasma C_max and area under the plasma concentration time curve (AUC_0-tlast) of PBPA with CYP3A5 genotype, but not with genotype of CYP2D6.

4. This investigation demonstrates the value of integrating in vitro mechanistic tools to gain comprehensive understanding of disposition properties of drug candidates, in a discovery paradigm and prior to the investment in clinical trials.

• Clinical pharmacokinetics
• CYP3A5
• genotype
• human hepatocytes
• metabolism
• monoamine oxidase
• phenotype
• polymorphism

Acknowledgements

The authors would like to acknowledge the contributions of Julie Poe, Dr Joanne Brodfuehrer, Dr Alfin Vaz and Dr Jennifer Liras at Pfizer Global Research and Development.