Non‐Clinical Pharmacokinetics,Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

CNTO 5825 is a human anti‐interleukin‐13 (IL‐13) monoclonal antibody (mAb) that inhibits binding of human IL‐13 to IL‐13Rα1 and IL‐13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non‐clinical PK data in order to select the right and safe doses for first‐in‐human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 ml/day/kg in rats and from 5.78 to 7.19 ml/day/kg in cynomolgus monkeys. The volume of distribution at steady‐state (Vss) in rats was large (151.52–155.64 ml/kg) compared to cynomolgus monkey (49.77–61.10 ml/kg). The terminal half‐life (T_1/2) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1–10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within twofold of observed CL and Vss in human beings; the predicted CL and Vss in human beings (70 kg) based on time‐invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 ml/day/kg and 68.93 ± 35.55 ml/kg, respectively. The selected doses for the FIH study based on time‐invariant method and no observed adverse effect level in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings.     

Evaluation of species difference in peripheral lymphocyte reduction effect of CS‐0777, a sphingosine 1‐phosphate receptor modulator,based on a pharmacokinetic/pharmacodynamic model analysis

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS‐0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS‐0777, M1, is a selective sphingosine 1‐phosphate receptor‐1 modulator. A linear one‐ and two‐compartment model with a reversible metabolism process characterized the time courses of CS‐0777 and M1 concentrations in rats and monkeys, respectively. The relationship between lymphocyte counts and M1 concentrations in blood was well described by an indirect response model in all animals examined. An I_max of 0.815 and an IC₅₀ of 6.58 nM in healthy rats, an I_max of 0.807 and an IC₅₀ of 5.09 nM in the EAE rats, an I_max of 0.789 and an IC₅₀ of 0.484 nM in monkeys were estimated by the indirect PD model. Since the IC₅₀ values calculated in terms of the unbound plasma concentration in rats and monkeys were within a similar range, after correction of the IC₅₀ in blood described above with the blood to plasma concentration ratio and the plasma free fraction of M1, it was revealed that there is no species difference in the essential activity of M1 against lymphocyte reduction. The sensitivity of the lymphocytes to M1 was not affected by the EAE status. Comparison of the simulated lymphocyte reduction in EAE rats after multiple dosing with CS‐0777 and the actual EAE clinical scores implies that the significant suppressive effect on EAE did not require the elimination of all lymphocytes from the blood. Copyright © 2016 John Wiley & Sons, Ltd.     

Modification of the Fc Region of a Human Anti‐oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half‐life in Cynomolgus Monkeys

The purpose of this study was to evaluate the pharmacokinetics (PK) of anti‐oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half‐life (T_1/2), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two‐compartment population PK model with first‐order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V₁) = 31.3 mL/kg, volume of distribution of peripheral compartment (V₂) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T_1/2 = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V₁ = 39.8 mL/kg, V₂ = 32.6 mL/kg, F = 0.75 and T_1/2 = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V₁+V₂) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T_1/2 of CNTO 8212 was significantly (p < 0.05) longer by about 2.7‐fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti‐OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half‐life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1–20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half‐life in human beings and may likely allow less frequent dosing in the clinical setting.     

Pre‐incubation with cyclosporine A potentiates its inhibitory effects on pitavastatin uptake mediated by recombinantly expressed cynomolgus monkey hepatic organic anion transporting polypeptide

Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half‐maximal inhibitory (IC₅₀) concentrations. Pre‐incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP‐mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP‐mediated pitavastatin uptake were investigated in pre‐ and simultaneous incubation systems. Pre‐incubation with cyclosporine A, but not with rifampicin, decreased the apparent IC₅₀ values on recombinant cynomolgus monkey OATP1B1‐ and OATP1B3‐mediated pitavastatin uptake. Application of the co‐incubated IC₅₀ values toward R values (1 + [unbound inhibitor]_{inlet to the liver, theoretically maximum}/inhibition constant) in static models, 1.1 in monkeys and 1.3 in humans, for recombinant cynomolgus monkey and human OATP1B1‐mediated pitavastatin uptake might result in the poor prediction of drug interaction magnitudes. In contrast, the lowered IC₅₀ values after pre‐incubation with cyclosporine A provided better prediction with R values of 3.9 for monkeys and 2.7 for humans when the estimated maximum cyclosporine A concentrations at the inlet to the liver were used. These results suggest that the enhanced inhibitory potential of perpetrator medicines by pre‐incubation on cynomolgus monkey OATP‐mediated pitavastatin uptake in vitro could be of value for the precise estimation of drug interaction magnitudes in silico, in accordance with the findings from pre‐administration of inhibitors on pitavastatin pharmacokinetics validated in monkeys. Copyright © 2016 John Wiley & Sons, Ltd.     

Use of a Target‐Mediated Drug Disposition Model to Predict the Human Pharmacokinetics and Target Occupancy of GC1118, an Anti‐epidermal Growth Factor Receptor Antibody

GC1118 is an anti‐epidermal growth factor receptor (EGFR) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics (PK) of GC1118 were modelled in monkeys to predict human PK and receptor occupancy (RO) profiles. The serum concentrations of GC1118 and its comparator (cetuximab) were assessed in monkeys with a non‐compartmental analysis and a target‐mediated drug disposition (TMDD) model after intravenous infusion (3–25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis. The human cetuximab exposures were simulated by applying different exponents (0.7–1.0) for the EGFR synthesis rate in the allometric monkey PK model. Simulated C_max and area under the curve values therein were compared with those previously reported in the literature to find the best exponent for the EGFR synthesis rate in human beings. The TMDD model appropriately described the monkey PK profile, which showed a decrease in clearance (CL; 1.2–0.4 ml/hr/kg) as the dose increased. The exponents for CL (0.75) and volume of distribution (Vd; 1.0) were used for the allometric scaling to predict human PK. The allometric coefficient for the EGFR synthesis rate chosen by the sensitivity analysis was 0.85, and the RO profiles that could not be measured experimentally were estimated based on the predicted concentrations of the total target and the drug–target complex. Our monkey TMDD model successfully predicts human PK and RO profiles of GC1118 and can be used to determine the appropriate dose for a first‐in‐human study investigating this drug.     

Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability

Purpose To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness. Materials and Methods Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five - way crossover, placebo - controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm. Results The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC₅₀) were larger between subjects (73–118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC₅₀ for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r ²  = 0.928). Conclusions The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide

AIMS

To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans.

METHODS

An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non-linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles.

RESULTS

Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54 µg g⁻¹ were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations from 13.9 to 52.8 µg g⁻¹ (n = 4, LY2181308 750 mg) were observed associated with a median survivin mRNA and protein inhibition of 20% ± 34 (SD) (n = 9) and 23% ± 63 (SD) (n = 10), respectively. The human PK parameters were adequately estimated: central V_d, 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00) l h⁻¹, peripheral V_ds, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922) l, mean elimination clearance 23.1 l h⁻¹ (5.6, 33.4) and mean terminal half-life, 32.7 days (range 22–52 days).

CONCLUSION

The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750 mg.     

Pharmacokinetic and Pharmacodynamic Comparability Study of Moxetumomab Pasudotox,an Immunotoxin Targeting CD22, in Cynomolgus Monkeys

Moxetumomab pasudotox is an immunotoxin currently being investigated in patients for the treatment of CD22-expressing B-cell malignancies. A single-cycle pharmacokinetic (PK)–pharmacodynamic (PD) study was conducted in cynomolgus monkeys for PK comparability assessment and population PK–PD modeling after major manufacturing process and site changes. Primates were randomized by body weight and baseline CD22 lymphocyte counts to receive intravenous administrations of 1 mg/kg moxetumomab pasudotox (n = 12/group) on Days 1, 3, and 5. PK and B-lymphocyte count data were modeled using a population approach. The 90% confidence intervals of the geometric mean ratios of PK exposure were within the 80%–125% range. The B lymphocytes were depleted to a similar extent, and the immunogenicity incidences were similar across the two groups. The B-cell depletion was described by a novel lifespan model in which moxetumomab pasudotox induced random destruction of B cells in each aging compartment. The endogenous de novo influx from bone marrow was subject to a negative feedback mechanism. The estimated B cell apparent lifespan was 51 days. Covariate analysis confirmed that the manufacturing change had no impact on PK or PD of moxetumomab pasudotox. Results from this study supported continued clinical investigation of moxetumomab pasudotox using the new material.     

Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA‐14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction

YQA‐14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA‐14, then to simulate the clinical PK of YQA‐14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA‐14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA‐14 is a basic lipophilic compound, with rapid absorption (T_max ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA‐14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA‐14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic. Copyright © 2014 John Wiley & Sons, Ltd.     

Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator

Pharmacokinetic (PK) and exposure-response modeling of a selective sphingosine 1-phosphate receptor-1 modulator (CS-0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2-compartment PK model with first-order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M-1) concentrations was modeled via an indirect response model, whereby M-1 inhibited the reentry of lymphocytes to the circulation. The indirect-response model based on SAD data had an Imax of approximately 85% and an IC50 of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model-based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.     

Computer-assisted drug development (CADD): an emerging technology for designing first-time-in-man and proof-of-concept studies from preclinical experiments.

Computer-assisted drug development (CADD) is an emerging technology for accelerating drug development based on the integration of mathematical modelling and simulation. This methodology provides a knowledge-based decisional tool on alternative development strategies based on the evaluation of potential risks on drug safety, and the definition of experimental design of new trials with expected power and probability of success. An example of CADD implementation is presented to design the first-time-in-man (FTIM) and the proof-of-concept (PoC) study of a new CNS compound. The final objective of the example presented is not necessarily to supply a success story of a correct prediction of human data from animal studies but to define a credible strategy suitable to design FTIM and PoC studies using preclinical data without the support of any human in vivo information. Rhesus monkey and human PK were initially estimated using allometric scaling on data collected in dogs, cynomolgus monkeys and rats. A PK/PD model was derived from a study conducted in rodent and validated by comparing the model predicted response to the one observed in a PET experiment conducted in rhesus monkey. The final PK/PD model, incorporating potential variability and uncertainty on scaled human prediction together with a receptor affinity adjustment derived from in vitro binding studies, was used to design the first-time-in-man and the proof-of-concept study.     

Population‐based meta‐analysis of furosemide pharmacokinetics

Furosemide is a loop diuretic frequently used to treat fluid overload conditions such as hepatic cirrhosis and congestive heart failure (CHF). A population‐based meta‐analysis approach in NONMEM® was used to develop a PK model characterizing the time‐course of furosemide in plasma and excretion into the urine for healthy subjects and fluid overload patients. Furosemide PK data from healthy subjects receiving 80 mg of oral furosemide were supplemented with additional individual and aggregate plasma concentration and urinary excretion versus time data from the literature after intravenous (i.v.) or oral furosemide administration (10–500 mg) to healthy subjects or fluid overload patients. A three‐compartment model with zero‐order input following i.v. administration (or first‐order absorption using a Weibull function after oral administration) and first‐order elimination best described furosemide PK. A covariate analysis identified creatinine clearance (CL_CR) as a statistically significant predictor of renal clearance (CL_R), with a population mean CL_R of 4.67, 3.11, 1.95 and 1.17 l/h for a subject with normal renal function (CL_CR = 120 ml/min) or mild (CL_CR = 80 ml/min), moderate (CL_CR = 50 ml/min) or severe (CL_CR = 30 ml/min) renal impairment. Oral bioavailability was 59.1% and non‐renal clearance was 2.02 l/h. A PC‐VPC and other model diagnostics demonstrated that the population PK model can reasonably predict the rate of urinary furosemide excretion over time using dosing history and commonly available demographic data, allowing for convenient assessment of PK‐PD relationships for furosemide when given alone or in combination with other agents used to treat fluid overload conditions. Copyright © 2013 John Wiley & Sons, Ltd.     

Estimation of absorption rate of α‐human atrial natriuretic peptide from the plasma profile and diuretic effect after intranasal administration to rats

The absorption rate of α‐human atrial natriuretic peptide (α‐hANP) after intranasal (i.n.) administration to rats was estimated from the plasma profile and pharmacological effect (diuretic effect) using a pharmacokinetic (PK) model and a PK–pharmacodynamic (PD) model involving data obtained after intravenous (i.v.) bolus injection. The plasma concentrations of α‐hANP after i.v. administration at different doses were fitted to a two‐compartment PK model with zero‐order excretion and input of endogenous α‐rat atrial natriuretic peptide (α‐rANP) and two elimination processes represented by Michaelis–Menten and first‐order kinetics. However, the saturable process was ignored at low doses. The plasma concentrations after low doses via the i.n. route could also be expressed by this model, but with first‐order absorption, so that an absorption rate constant was calculated using a deconvolution method. In addition, the diuretic effect plotted against the i.v. dose was represented by the Hill equation and showed an anti‐clockwise hysteresis loop versus the plasma concentration. These results suggest that the diuretic effect could be estimated by a PK–PD model having an ‘effect’ compartment or a homeostatic system. Such a PK–PD model accurately expressed the diuretic effect of α‐hANP at all doses after i.v. and i.n. administrations. The resulting absorption rate constant calculated using the PK–PD model agreed closely with that obtained by the PK model alone. The absorption rate and simulated diuretic effect suggest that, for i.n. administration of α‐hANP, a higher absorption rate constant causes a more potent diuretic effect (a dramatic effect over the early period), whereas greater bioavailability is associated with a better hypotensive effect (sustained effect). Copyright © 2001 John Wiley & Sons, Ltd.     

Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition

Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R₀), body-weight (BW) normalized central elimination rate (K_el/BW^−0.25) and central volume (V_c/BW^1.0). AAFE of less than three-fold was estimated for the binding affinity constant (K_D). The other four parameters, i.e., complex turnover rate (K_int), target turnover rate (K_deg), central to peripheral distribution rate constant (K_pt) and peripheral to central rate constant (K_tp) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9690-8) contains supplementary material, which is available to authorized users.KEY WORDS: ADME of biologics, human translation, monoclonal antibodies, PK/PD modeling, TMDD     

Semi-physiological pharmacokinetic–pharmacodynamic modeling and simulation of 5-fluorouracil for the whole time course of alterations in leukocyte,neutrophil and lymphocyte counts in rats

Abstract

1. We aimed to develop a simple pharmacokinetic–pharmacodynamic (PK–PD) model to predict the onset and degree of severe toxic side effects that severely limit the use of many anticancer agents, such as myelosuppression, in rats.

2. Our PK–PD model consisted of a two-compartment PK model, with one compartment representing proliferative cells and some transit compartments consisting of maturing cells, while the other compartment represented circulating blood cells for the PD model.

3. The semi-physiological PK–PD model effectively captured the features of myelosuppression and the degree of the off-target toxicities observed after 5-fluorouracil (5-FU) chemotherapy, and helped simultaneously simulate the whole time course for alterations in leukocyte, neutrophil and lymphocyte counts after 5-FU treatment in rats. Interestingly, by plotting the nadir period of leukocyte, neutrophil and lymphocyte counts as determined by PK–PD analytical simulation curves against the area under the plasma 5-FU concentration–time curve (AUC_0–∞) after intravenous administration of 5-FU, a linear relationship was inferred, with r^2?=?0.989, 0.877 and 0.956, respectively.

4. The semi-physiological PK–PD model is a valuable tool for evaluating a variety of novel cancer chemopreventive agents or emerging therapeutic strategies that are difficult to address in humans.     

曲妥珠单抗-药物共轭物(T-DM1)临床前药物代谢动力学研究及人体药物代谢动力学预测

本试验通过临床前药物代谢动力学(PK)和毒理学研究结果,对曲妥珠单抗-药物共轭物(T-DM1)的人体PK特性进行了预测,并探讨了目前广泛采用的预测方法的不足和可能的解决途径。本试验首先进行了动物试验,包括大鼠急性毒性试验和食蟹猴PK试验,通过试验获得了T-DM1的总抗体、偶联抗体和游离小分子药物emtansine(DM1)的PK参数,随后基于这些参数,使用异速增长模型和种属-时间不变法,对总抗体和偶联抗体的人体PK特性进行了预测。此外,通过参考近年的一些相关研究,探讨了如何基于动物生理药动学(PBPK)模型,更科学地预测抗体偶联药物中小分子药物的人体PK和分布特性。     

Pharmacokinetic–Pharmacodynamic Modelling of Biomarker Response to Sitagliptin in Healthy Volunteers

Pharmacokinetic/pharmacodynamic (PK/PD) models can be useful tools in new drug development and also optimal drug therapy in patients. This study was designed to develop a PK/PD model of sitagliptin based on the physiology of incretin. The PK/PD data included information derived from two different studies. Study 1 was conducted as a one‐sequence, three‐period, repeated‐dose, dose escalation (sitagliptin 25, 50 and 100 mg q.d.) design in twelve healthy volunteers. Study 2 was a first‐in‐man study for the newly developed dipeptidyl peptidase‐4 (DPP‐4) inhibitor in healthy volunteers. In study 1, blood samples were collected to measure sitagliptin concentrations, DPP‐4 activity and active glucagon‐like peptide‐1 (GLP‐1) concentrations. In study 2, only data from the ‘placebo group’ were used, and blood samples were collected to measure DPP‐4 activity, active GLP‐1 concentrations and glucose concentrations. A PK/PD analysis was conducted using a non‐linear mixed effects modelling approach. Sitagliptin pharmacokinetics was modelled using a two‐compartment model with first‐order absorption. Changes in DPP‐4 inhibition were linked to the PK model using a sigmoid E_max model, whereas the active GLP‐1 changes were explained using an indirect response model; this model incorporated the glucose and DPP‐4 inhibition models. The PK/PD model developed adequately described the changes in sitagliptin concentration, DPP‐4 inhibition and active GLP‐1 concentration in healthy volunteers.     

Pharmacokinetics,tissue distribution,plasma protein binding,and metabolism study of mefunidone,a novel pirfenidone derivative

Mefunidone (MFD), a novel derivation of pirfenidone (PFD), exhibits promising anti‐renal fibrosis activity. To avoid early development failures and attrition in clinical phase 1, an evaluation of the preclinical pharmacokinetic (PK) properties of MFD was conducted in this study. The absolute bioavailability was evaluated in Sprague Dawley rats and cynomolgus monkeys, who received an intragastric or intravenous administration at the dose of 31.25 mg/kg and 10 mg/kg, respectively. Tissue distribution and plasma protein binding studies were performed to evaluate the distribution characteristics of MFD. The enzymes involved in the metabolism of MFD were assayed by calculating the inhibition rate using the in vitro incubation system of human liver microsomes. The metabolic pathway of MFD was also examined in the in vitro incubation system as well as in rats in vivo. The results revealed satisfactory absorption of MFD in vivo, with an absolute bioavailability of MFD in rats and monkeys of approximately 77.2% and 70.0%, respectively. MFD was rapidly distributed to all tissues and was highly concentrated in the kidney, which was the target organ of MFD. The plasma protein binding rates in rat, monkey, and human plasma were 36.40%–41.68%, 30.88%–63.92%, and 37.75%–57.77%, respectively. MFD was primarily metabolized by the enzymes CYP3A4, CYP2C9, and CYP2C8. The metabolic pathway of MFD is nitrogen demethylation of the pyridine ring of the MFD nucleus, hydroxylation of the aromatic ring, and demethylation of the piperazine ring. In conclusion, MFD exhibited good PK properties in the initial preclinical PK study. The results strongly support further research to investigate the potential of MFD as a clinical anti‐renal fibrosis drug.     

Utility of Göttingen minipigs for the prediction of human pharmacokinetic profiles after intravenous drug administration

Göttingen minipigs are increasingly used to evaluate the pharmacokinetic (PK) profiles of drug candidates. However, their accuracy in predicting human PK parameters is unclear. In this study, we investigated the utility of Göttingen minipigs for predicting human PK profiles. We evaluated the PK parameters of 30 compounds with diverse metabolic pathways after intravenous administration in minipigs. Human total clearance (CL_total) was corrected using the blood to plasma ratio, and the volume of distribution at steady state (Vd_(ss)) was corrected with plasma unbound fraction (fup). CL_total and Vd_(ss) were predicted using single-species allometric scaling using data from minipigs and other reported animal models (monkeys, human liver chimeric mice, and rats). The predicted values were compared with actual values reported in humans. Göttingen minipig were superior to rats because of their better predictability of Vd_(ss) and CL_total, as represented by lower absolute average fold error values. However, their predictability for Vd_(ss) was inferior to monkey and human liver chimeric mice. Prediction of CL_total from blood-based minipig data showed excellent correlation with human data, and comparable predictability with monkey and human liver chimeric mice. Thus, Göttingen minipigs can be used as an optional model for preclinical pharmaceutical research for predicting human CL_total.