Maxacalcitol Pharmacokinetic-Pharmacodynamic Modeling and Simulation for Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis.

BACKGROUND: Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available. OBJECTIVES: This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol. METHODS: We developed population pharmacokinetic (PK) and pharmacodynamic (PD) models using a modeling and simulation approach. The data for these analyses were obtained from two studies: a clinical pharmacology study in Japanese patients and an ethnic comparison study in healthy Japanese and -Taiwanese volunteers. We then conducted a simulation study with a PK-PD model comprising the PK and PD models developed here. RESULTS: Serum maxacalcitol concentration profile was modeled using a two-compartment model that took into consideration the distribution of concentrations below the lower limit of quantification. An ethnic difference in clearance was included in the PK model as a covariate. A PD model that used a PTH/Ca feedback loop best described the observed data. There were no significant differences in Ca or PTH concentrations between Taiwanese and Japanese based on the simulation results from our PK-PD model, even though maxacalcitol exposure was approximately 40% higher in Taiwanese than in Japanese. CONCLUSIONS: On the basis of these population PK and PD analyses and the clinical study conducted in Japan, there is no clinically relevant difference between Taiwanese and Japanese in terms of serum Ca or PTH levels.

Risk of CYP2C9 induction analyzed by a relative factor approach with human hepatocytes.

By using the Relative Factor (RF) method-a method that can simply assess cytochrome P450 (CYP) induction risk based on a maximum induction effect model-we evaluated the risk of CYP2C9 induction and examined its relationship with risk of CYP3A4 induction. In cryopreserved human hepatocytes, the magnitude of CYP2C9 induction by eight drugs known to induce CYP3A4 was lower than the magnitude of CYP3A4 induction, but the magnitudes of induction of both were correlated. The RF values determined for CYP2C9 had a one-to-one linear relationship with values determined for CYP3A4, supporting reports that the induction mechanism of both enzymes is the same. Furthermore, clinical CYP2C9 induction data of compounds reported to induce CYP2C9 clinically were shown to be lower than those of CYP3A4. The thresholds for CYP2C9 induction risk assessment by the RF approach were determined to be at higher steady-state plasma concentrations than those for CYP3A4. Based on these results, induction of CYP2C9 was correlated with that of CYP3A4, and induction risk could be evaluated by the RF method using hepatocytes. The CYP2C9 induction risk of a compound was confirmed to be lower than its CYP3A4 induction risk.

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.

Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma.

AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16MESF ) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 µg ml-1 and high CD16MESF level (>5.26 × 105 MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16MESF level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.

BACKGROUND: Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. METHODS: Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. RESULTS: The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 µg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. CONCLUSIONS: A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

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.

The optimal oral dose selection of ibandronate in Japanese patients with osteoporosis based on pharmacokinetic and pharmacodynamic properties.

Ibandronate is a drug widely used outside Japan for the treatment of osteoporosis. It is available in formulations for intermittent intravenous (i.v.) administration and for intermittent (once monthly) oral administration. Ibandronate was recently approved in Japan as an i.v. injection with a dosing regimen of 1.0 mg once a month. To establish the optimal dose for oral administration of ibandronate in Japanese osteoporotic patients, we investigated the pharmacokinetics of and pharmacodynamic response to ibandronate following oral and intravenous administrations to Japanese subjects. Ibandronate (20, 50, 100, or 150 mg) was given orally to healthy postmenopausal Japanese women and to Japanese patients with primary osteoporosis. Serial measurements were obtained for the concentrations of serum ibandronate and urinary cross-linked C-telopeptide of Type I collagen (uCTX). Pharmacokinetic parameters and the time profiles of creatinine-corrected uCTX were compared with those obtained from postmenopausal Japanese women with osteopenia after administration of 1.0 mg i.v. ibandronate. Following oral administration of ibandronate, the area under the serum ibandronate concentration-time curve (AUCinf) increased dose-proportionally for doses up to 100 mg; at 150 mg, AUCinf increased beyond the dose-proportionality seen with doses up to 100 mg. The AUCinf within the linear range following administration of 100 mg oral ibandronate was similar to that following 1.0 mg i.v. ibandronate. Additionally, corrected uCTX decreased after administration of 100 mg oral ibandronate and remained decreased for 1 month; the magnitude of the decrease was similar to or greater than that obtained after 1.0 mg i.v. ibandronate. From a clinical pharmacological perspective, administration of 100 mg/month oral ibandronate was equivalent to that of 1.0 mg/month i.v. ibandronate.

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.

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 (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; 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.

Modeling and simulation of orlistat to predict weight loss and weight maintenance in obesity patients.

Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. Modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat.

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

OBJECTIVES: 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. METHODS: Plasma drug concentrations of TP300, its active form TP3076 and active metabolite TP3011 and absolute neutrophil counts (ANCs) from a Phase I trial were analysed as a training dataset. A two-plus-two-compartment model was applied to the pharmacokinetics of TP3076 and TP3011. A semi-mechanistic model was used to describe the PK-PD relationship between the plasma concentration of TP3076 and TP3011, and changes in ANC. KEY FINDINGS: The model fitted well to plasma concentrations of TP3076 and TP3011. Model appropriateness was confirmed in a Phase II trial validation dataset. Body weight and liver biochemistry values were identified as covariates. A semi-mechanistic PK-PD model was applied and the longitudinal decrease in ANC was simulated. Neutrophil counts reached their nadir approximately 2 weeks after administration of TP300, and the proportion of subjects affected increased with dose. CONCLUSIONS: This PK-PD model to predict neutropenia following treatment with TP300 fitted well the decrease in ANC with total concentration of TP3076 and TP3011.

Population pharmacokinetic-pharmacodynamic modeling and simulation of platelet decrease induced by peg-interferon-alpha 2a.

Peg-interferon-alpha-2a (PEG-IFN) has been used all over the world including Japan as the standard of care for chronic hepatitis C (CHC). PEG-IFN causes platelet count decrease, while CHC patients with compensated liver cirrhosis have a low baseline of platelets. To use PEG-IFN more safely in these patients, we analyzed the effect of PEG-IFN on the longitudinal platelet profile with a pharmacokinetic-pharmacodynamic model. Platelet count and serum PEG-IFN concentration obtained from a Japanese clinical study on 40 patients were analyzed. The serum PEG-IFN concentration profile was fitted with an open 1-compartment model and the platelet profile was fitted with a turnover model. After the final model was fixed, the platelet profiles were simulated with various platelet baselines. The simulation revealed that according to PEG-IFN administration platelets decreased gradually and reached steady state within 12 weeks, and almost subjects would not have a lower platelet count than the criteria for discontinuation of the treatment. Once administration was discontinued, platelets recovered up to the baseline within several weeks. In conclusion, platelet count was predicted to be about a 30% (5th-95th percentiles in 1,000 simulation: 11-66%) decrease and to return to the baseline value in 4 to 8 weeks after the last administration of PEG-IFN.

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. METHODS: The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters. KEY FINDINGS: The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two-compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms. CONCLUSIONS: A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required.

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

OBJECTIVE: 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 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.