Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Pharmacokinetics of H002, a novel S1PR_1 modulator, and its metabolites in rat blood using liquid chromatography–tandem mass spectrometry

A rapid and sensitive liquid chromatography–tandem mass spectrometry(LC–MS/MS) method was developed and validated for the simultaneous determination of H002 and its phosphorylated metabolite, H002-P and hydroxylated metabolite H002-M, in rat blood. H001, an analogue of H002, was used as the internal standard.Blood samples were prepared by simple protein precipitation. The analytes and internal standard were separated on a Zorbax SB-C18 column with a gradient mobile phase consisting of methanol and water containing 0.1% formic acid at a flow rate of 0.2 mL /min with an operating temperature of 20 1C. The detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization in multiple-reaction monitoring mode.Linear detection responses were obtained from 0.2–100 ng/mL for H002 and H002-M, while 0.5–100 ng/mL for H002-P. The intra- and inter-day precision(RSD%) was within 11.76%, with the accuracy(RE%) ranging from –9.84% to 9.12%. The analytes were shown to be stable during sample storage, preparation and analytic procedures.The method was applied to determine the pharmacokinetics of H002 in rats, and a preliminary study showed that the pharmacokinetics of H002 correlated with its biological effect on peripheral blood lymphocytes.

Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study

Background:Bendamustine was approved in China on May 26th,2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma(NHL).The current study was the registration trial and the first reported evaluation of the efficacy,safety,and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment.Methods:This was a prospective,multicenter,open-label,single-arm,phase 3 study(NCT01596621;C18083/3076)with a 2-year follow-up period.Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles(and up to eight cycles).The primary endpoint was the overall response rate(ORR);and secondary endpoints were duration of response(DoR),progression-free survival(PFS),safety,and pharmacokinetics.Patients were classified according to their best overall response after initiation of therapy.Proportions of patients in each response category(complete response[CR],partial response[PR],stable disease,or progressive disease)were summarized along with a twosided binomial exact 95%confidence intervals(CIs)for the ORR.Results:A total of 102 patients were enrolled from 20 centers between August 6th,2012,and June 18th,2015.At the time of the primary analysis,the ORR was 73%(95%CI:63%–81%)per Independent Review Committee(IRC)including 19%CR and 54%PR.With the follow-up period,the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment;the median PFS was 18.6 months and 15.3 months,respectively.The most common non-hematologic adverse events(AEs)were gastrointestinal toxicity,pyrexia,and rash.Grade 3/4 neutropenia was reported in 76%of patients.Serious AEs were reported in 29 patients and five patients died during the study.Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities.Conclusion:Bendamustine is an active and effective therapy in Chinese patients with relapsed,indolent B-cell NHL,with a comparable risk/benefit relationship to that reported in North American patients.

Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates

FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats.In this study,FTY720 or IMMH002 analogues(21-24)were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms.Target compounds were synthesized via a convergent route using the key and optically pure building block 9,which was first synthesized via asymmetrically catalyzed amination.The phosphorylation rates of these analogues in rat or human blood were compared.The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound,whereas compound 23 showed improvements in rats,but not in humans.In pharmacokinetics studies of rats,compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002.Thus,our study not only yielded new compounds with therapeutic potential,but also showed species differences between rats and humans in response to the structural modifications,which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.