Satofumi Iida

A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?

Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non‐Japanese studies. Therefore, there is potential to re‐evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non‐Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non‐linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

AIMS The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E(max) model with E(max) of -11.7 mmHg and EC(50) of 423 microg l(-1) was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h. CONCLUSIONS AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.

A Pharmacokinetic/Pharmacodynamic Drug–Drug Interaction Study of Tofogliflozin (a New SGLT2 Inhibitor) and Selected Anti-Type 2 Diabetes Mellitus Drugs

OBJECTIVE Tofogliflozin is an oral hypoglycemic agent with a novel mechanism of action that reduces blood glucose levels by promoting glucose excretion in urine, achieved by selectively inhibiting sodium-glucose co-transporter 2 (SGLT2). We evaluated the effects of several selected anti-type 2 diabetes mellitus (T2DM) drugs-glimepiride, metformin, sitagliptin, pioglitazone, miglitol, nateglinide, and voglibose-on the pharmacokinetics and pharmacodynamics of tofogliflozin, and the effects of tofogliflozin on the pharmacokinetics of these anti-T2DM drugs in healthy male volunteers. METHODS A single dose of either tofogliflozin alone, one of the anti-T2DM drugs alone, or co-administration of tofogliflozin and the anti-T2DM drug was administered to 108 healthy men. Cmax, AUCinf, and cumulative urine glucose excretion after co-administration of tofogliflozin and each of the anti-T2DM drugs was evaluated relative to the values of those parameters after administration of each drug alone. RESULTS None of the anti-T2DM drugs had any effect on tofogliflozin exposure. Tofogliflozin had no or little effect on the exposure of any anti-T2DM drug. No anti-T2DM drug had any major effect on the cumulative urine glucose excretion induced by tofogliflozin. There were no safety concerns evident after administration of any drug alone or in co-administration. CONCLUSIONS Neither the pharmacokinetics nor the pharmacodynamics of tofogliflozin was affected by any of the anti-T2DM drugs evaluated in this study, nor was the pharmacokinetics of any of the anti-T2DM drugs affected by tofogliflozin in healthy male volunteers.

Erratum to: Application of Modeling and Simulation to a Long-Term Clinical Trial: A Direct Comparison of Simulated Data and Data Actually Observed in Japanese Osteoporosis Patients Following 3-Year Ibandronate Treatment

Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (MS (2) perform MS and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.

The pharmacokinetics of ceftriaxone based on population pharmacokinetics and the prediction of efficacy in Japanese adults

SummaryObjective: By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration. Methods: The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained. Results: Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.

Population pharmacokinetic-pharmacodynamic modelling and simulation of neutropenia induced by TP300, a novel topoisomerase I inhibitor.

TP300 is a novel topoisomerase I inhibitor with neutropenia as a significant toxicity. We developed and evaluated a pharmacokinetic–pharmacodynamic (PK‐PD) model, using data from Phase I and II trials to predict neutrophil decrease in patients treated with TP300.

Indications for a ceftriaxone dosing regimen in Japanese paediatric patients using population pharmacokinetic/pharmacodynamic analysis and simulation

Objectives  The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis.

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus

PURPOSE Tofogliflozin is an orally available selective inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus (T2DM). Two studies were conducted to evaluate the effect of renal impairment on pharmacokinetics and pharmacodynamics of tofogliflozin. METHODS The studies were: 1) single dose study in T2DM patients with normal renal function and mild, moderate and severe renal impairment, and 2) multiple dose study for 24 weeks in T2DM patients with normal renal function and moderate renal impairment. RESULTS Renal function did not have a clinically relevant effect on the PK of tofogliflozin. Urinary glucose excretion up to 24 h after administration of tofogliflozin (UGE24h) decreased with decreasing glomerular filtration rate. Lowering UGE24h resulted in waning glycemic control but not body weight reduction. CONCLUSIONS Single and multiple administrations of tofogliflozin were generally well tolerated in T2DM patients with various renal functions. As far as investigated here, these studies indicate no dose adjustment is required for patients with renal impairment.

Dosage Optimization of Nemolizumab Using Population Pharmacokinetic and Pharmacokinetic‐Pharmacodynamic Modeling and Simulation

Nemolizumab is a humanized anti‐interleukin‐31 receptor A monoclonal antibody for treating atopic dermatitis, and it especially improves pruritus. The objective of the simulation study was to optimize the dose regimen using a flat dose. The serum nemolizumab concentration and pruritus visual analog scale as an efficacy end point were modeled using the population analysis approach in 299 patients with atopic dermatitis who received placebo or doses between 0.1 and 3 mg/kg as a single dose once every 4 weeks or 2 mg/kg once every 8 weeks. A 1‐compartment model with first‐order absorption was employed as the pharmacokinetic model. An indirect turnover model with an inhibition component was employed as the main part of the pharmacokinetic‐pharmacodynamic model. The models well described the observations. Therefore, simulations with several dose regimens were performed to optimize the dose regimen including a flat dose. The simulated area under the concentration‐time curve at a steady state around 75 mg in the every‐4‐week regimen corresponds to that associated with the dose range of 0.5 to 2 mg/kg in the 4‐week regimen. The simulated pruritus visual analog scale also showed a similar tendency. These simulation results support dose optimization during the clinical development program of nemolizumab.

Effective use of modeling and simulation in designing bioequivalence and comparability studies of large-molecule compounds: the case of erythropoietin.

OBJECTIVE Bioequivalence and comparability studies are necessary for changing formulations of large-molecule drugs, such as antibody drugs and protein products, and in the development of their biosimilars. This study is the first application of modeling and simulation (M&S) in the design of bioequivalence and comparability studies of erythropoietin as an example of a large-molecule drug. METHODS A novel population pharmacokinetic and pharmacodynamic (PPK/PD) model was developed for erythropoietin. Based on this PPK/PD model, the probabilities of success of bioequivalence and comparability studies were simulated with various numbers of subjects and samples. RESULTS The simulation indicated that the minimum numbers of subjects and samples required to satisfy the criteria for bioequivalence and comparability studies were as follows: fewest for the area under the serum concentration-time curve, more for the area under the efficacy-time curve, and most for the maximum serum concentration of erythropoietin. CONCLUSION These results suggested that M&S could be successfully applied in the design of bioequivalence and comparability studies of large-molecule drugs.