Yanguang Cao

Applications of minimal physiologically-based pharmacokinetic models

Conventional mammillary models are frequently used for pharmacokinetic (PK) analysis when only blood or plasma data are available. Such models depend on the quality of the drug disposition data and have vague biological features. An alternative minimal-physiologically-based PK (minimal-PBPK) modeling approach is proposed which inherits and lumps major physiologic attributes from whole-body PBPK models. The body and model are represented as actual blood and tissue (usually total body weight) volumes, fractions (fd) of cardiac output with Fick’s Law of Perfusion, tissue/blood partitioning (Kp), and systemic or intrinsic clearance. Analyzing only blood or plasma concentrations versus time, the minimal-PBPK models parsimoniously generate physiologically-relevant PK parameters which are more easily interpreted than those from mammillary models. The minimal-PBPK models were applied to four types of therapeutic agents and conditions. The models well captured the human PK profiles of 22 selected beta-lactam antibiotics allowing comparison of fitted and calculated Kp values. Adding a classical hepatic compartment with hepatic blood flow allowed joint fitting of oral and intravenous (IV) data for four hepatic elimination drugs (dihydrocodeine, verapamil, repaglinide, midazolam) providing separate estimates of hepatic intrinsic clearance, non-hepatic clearance, and pre-hepatic bioavailability. The basic model was integrated with allometric scaling principles to simultaneously describe moxifloxacin PK in five species with common Kp and fd values. A basic model assigning clearance to the tissue compartment well characterized plasma concentrations of six monoclonal antibodies in human subjects, providing good concordance of predictions with expected tissue kinetics. The proposed minimal-PBPK modeling approach offers an alternative and more rational basis for assessing PK than compartmental models.

Incorporating target-mediated drug disposition in a minimal physiologically-based pharmacokinetic model for monoclonal antibodies

Target-mediated drug disposition (TMDD) usually accounts for nonlinear pharmacokinetics (PK) of drugs whose distribution and/or clearance are affected by their targets owing to high affinity and limited capacity. TMDD is frequently reported for monoclonal antibodies (mAb) for such reason. Minimal physiologically-based pharmacokinetic models (mPBPK), which accommodate the unique PK behaviors of mAb, provide a general approach for analyzing mAbs PK and predicting mAb interstitial concentrations in two groups of tissues. This study assessed the feasibility of incorporating TMDD into mPBPK models to consider target-binding in either plasma (cTMDD) or interstitial fluid (ISF) (pTMDD). The dose-related signature profiles of the pTMDD model reveal a parallel early decay phase, in contrast with the cTMDD model that exhibits a faster initial decline for low doses. The parallel early phase in the pTMDD model is associated with the slow perivascular extravasation of mAb, which restricts the initial decline regardless of interstitial target-mediated elimination. The cTMDD and pTMDD models both preserve the long terminal phase that is typically perceived in conventional two-compartment (2CM) and TMDD models. Having TMDD in ISF impacts the typical relationships between plasma concentrations and receptor occupancy, and between saturation of apparent nonlinear clearance and saturation of receptors. The vascular reflection coefficient (σv) was found to affect receptor occupancy in ISF. In the cTMDD model, saturation of nonlinear clearance is equivalent to saturation of receptors. However, in the pTMDD model, they are no longer equal and all parameters pertaining to receptors or receptor binding (Rtotal, KD, Kss, kint) shifts such relationships. Different TMDD models were utilized in analyzing PK for seven mAbs from digitized literature data. When the target is in plasma, the cTMDD model performed similarly to the 2CM and TMDD models, but with one less system parameter. When the target exists in ISF, the pTMDD functioned well in analyzing only plasma data to reflect interstitial target binding properties. Assigning TMDD consistent with target-expressing tissues is important to obtain reliable characterizations of receptors and receptor binding. The mPBPK model exhibits excellent feasibility in integrating TMDD not only in plasma but also in ISF.

Beneficial effects of danshensu, an active component of Salvia miltiorrhiza, on homocysteine metabolism via the trans-sulphuration pathway in rats.

Background and purpose:  Elevated plasma total homocysteine (tHcy) level has been established as an independent risk factor for cardiovascular diseases. Danshensu, an active ingredient of Salvia miltiorrhiza, shows wide cardiovascular benefit. However, in terms of its own methylation, danshensu could elevate tHcy level, which would act against its cardiovascular benefit, thus posing a ‘therapeutic paradox’. As this paradox has not been fully assessed, we have evaluated the effects of danshensu on tHcy levels to uncover the underlying mechanisms.

Modeling Diabetes Disease Progression and Salsalate Intervention in Goto-Kakizaki Rats

Type 2 diabetes mellitus (T2DM) arises owing to insulin resistance and β-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and evaluate the potential role of the anti-inflammatory agent salsalate. The GK rats were divided into control groups (n = 6) and salsalate treatment groups (n = 6), which were fed a salsalate-containing diet from 5 to 21 weeks of age. Blood glucose and salicylate concentrations were measured once a week. Glucose concentrations showed a biphasic increase in which the first phase started at approximately 5 weeks, resulting in an increase by 15 to 25 mg/dl and a second phase at 14 to 15 weeks with an upsurge of more than 100 mg/dl. A mechanism-based model was proposed to describe the natural diabetes progression and salsalate pharmacodynamics by using a population method in S-ADAPT. Two transduction cascades were applied to mimic the two T2DM components: insulin resistance and β-cell dysfunction. Salsalate suppressed both disease factors by a fraction of 0.622 on insulin resistance and 0.134 on β-cell dysfunction. The substantial alleviation of diabetes by salsalate supports the hypothesis that chronic inflammation is a pathogenic factor of diabetes in GK rats. In addition, body weight and food intake were measured and further modeled by a mechanism-based growth model. Modeling results suggest that salsalate reduces weight gain by enhancing metabolic rate and energy expenditure in both GK and Wister-Kyoto rats.

Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart: New anti-angina mechanism implication

Protocatechuic acid (PA), a structurally typical phenolic acid in danshen, shows anti-angina efficacy. But until now, besides scavenging of oxygen free radicals, the understanding of its anti-angina mechanism has been limited. In our study, based on a novel metabolic route of PA identified in rat heart and its influence on fatty acid oxidation (FAO), we proposed a new mechanism for its anti-angina. In detail, three metabolites, catechol methylated metabolite, acyl-coenzyme (CoA) thioester and glycine conjugation, were identified in rat heart. A novel metabolic pathway was confirmed based on several metabolic systems incubated with heart mitochondria, cytosol, microsomes and homogenate. Results indicated that PA was firstly methylated in microsomes and cytosol, which was regarded as the prerequisite step for further metabolism and could be inhibited by tolcapone, and then the resulting methylated metabolite (vanillic acid) diffused into mitochondria where it was converted into acyl-CoA thioester, in similar with FAO. In addition, part of the acyl-CoA thioester was transformed into glycine conjugation, a step also localized within mitochondria. Furthermore, based on isolated rat heart perfusion, it was found that PA markedly decreased FAO, which was shown by higher residual fatty acid level in perfusate (p<0.05) and lower acy-CoA/CoA ratio in heart (p<0.05). The FAO inhibiting effect of PA could be largely reversed by its methylation inhibitor tolcapone, indicating the effect was closely related with the identified metabolic pathway of PA in heart. The decrease of FAO may switch heart energy substrate preference from fatty acid to glucose, which is beneficial for ischemia heart.

Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats

AbstractAim:To investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of telmisartan in spontaneously hypertensive (SH) rats using an indirect response and effect-compartment link models, and compare two PK-PD models fitting quality.Methods:The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model.Results:The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 L·kg−1·h−1, and a volume of distribution of 5.36 L·kg−1 in the study. For the indirect response PD model, the estimated Kin were 36.6, 34.1, and 32.8 %·h−1, Kout were 36.7, 34.6, and 31.9 h−1; the IC50 values were 86.2, 95.8, and 91.1 ng·mL−1; and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg·h at three doses, respectively. For the effect-compartment model, the Keo were 29.4, 33.8, and 28.7 h−1; the IC50 values were 78.2, 85.7, and 80.9 ng·mL−1, and the AUEC were 781.5, 1602.8, and 2215.7 mmHg-hat three doses, respectively.Conclusion:According to Akaikes information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.

Pharmacokinetic/Pharmacodynamic Modeling of GLP-1 in Healthy Rats

PurposeTo provide a mechanism-based model to quantitatively describe GLP-1 pharmacokinetics (PK) and pharmacodynamics (PD) in rats.MethodsIntravenous (IV), infusion (IF), subcutaneous (SC), and intraperitoneal (IP) doses of GLP-1 were administered after glucose challenge in healthy Sprague–Dawley rats. Blood was analyzed for GLP-1, glucose, and insulin. The PK-PD modeling was performed with ADAPT 5. The concentration-response curve was generated and analyzed in comparison with other incretin-related therapeutics.ResultsThe PK of GLP-1 was described using a two-compartment model with a zero-order input accounting for endogenous GLP-1 synthesis. For SC and IP dosing, sequential zero-order and first-order absorption models reasonably described the rapid absorption process and flip-flop kinetics. In dynamics, GLP-1 showed insulinotropic effects (3-fold increase) after IV glucose challenge in a dose-dependent manner. The concentration-response curve was bell-shaped, which was captured using a biphasic two-binding site Adair model. Receptor binding of GLP-1 exhibited high capacity and low affinity kinetics for both binding sites (KD = 9.94 × 103 pM, K2 = 1.56 × 10−4 pM−1).ConclusionsThe PK of GLP-1 was linear and bi-exponential and its PD showed glucose-dependent insulinotropic effects. All profiles were captured by the present mechanistic model and the dynamic analysis yields several implications for incretin-related therapies.

Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model

ABSTRACTPurposeTo examine the across-species scalability of monoclonal antibody (mAb) pharmacokinetics (PK) and assess similarities in tissue distribution across species using a recently developed minimal PBPK (mPBPK) model.MethodsTwelve sets of antibody PK data from various species were obtained from the literature, which were jointly and individually analyzed. In joint analysis, vascular reflection coefficients for tissues with either tight (σ1) or leaky endothelium (σ2) were assumed consistent across species with systemic clearance allometrically scaled (CL = a∙BWb). Four parameters (σ1, σ2, a, and b) were estimated in the joint analysis. In addition, the PK from each species was individually analyzed to assess species similarities in tissue distribution.ResultsTwelve mAb PK profiles were well-captured by the mPBPK model in the joint analysis. The estimated σ1 ranged 0.690 to 0.999 with an average of 0.908; and σ2 ranged 0.258 to 0.841 with an average of 0.579. Clearance was reasonably scaled and b ranged 0.695 to 1.27 averaging 0.91. Predictions of plasma concentrations for erlizumab and canakinumab in humans using parameters obtained from fitting animal data were consistent with actual measurements.ConclusionsTherapeutic mAbs given IV usually exhibit biexponential kinetics with their distribution properties best captured using physiological concepts. The mPBPK modeling approach may facilitate efforts in translating antibody distribution and overall PK across species.

Pharmacokinetics of salsalate and salicylic acid in normal and diabetic rats

The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto‐Kakizaki rats. Three PK studies were conducted: (1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. (2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. (3) PK during 4 months feeding of SS‐containing diet in both normal and diabetic rats. The disposition of SS and SA were evaluated simultaneously using a pharmacokinetic model comprising several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing of SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS‐diet feeding, the diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F), possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in the future usage of SS in diabetes. Copyright

Diabetes disease progression in Goto-Kakizaki rats: effects of salsalate treatment

This study investigates the antidiabetic effects of salsalate on disease progression of diabetes in non-obese diabetic Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes. Salsalate was formulated in rat chow (1,000 ppm) and used to feed rats from 5 to 21 weeks of age. At 5 weeks of age, GK and Wistar (WIS) control rats were subdivided into four groups, each composed of six rats: GK rats with standard diet (GK-C); GK rats with salsalate-containing diet (GK-S); WIS rats with standard diet (WIS-C); and WIS rats with salsalate-containing diet (WIS-S). The GK-C rats (167.2±11.6 mg/dL) showed higher blood glucose concentrations than WIS-C rats (133.7±4.9 mg/dL, P<0.001) at the beginning of the experiment, and had substantially elevated blood glucose from an age of 15 weeks until sacrifice at 21 weeks (341.0±133.6 mg/dL). The GK-S rats showed an almost flat profile of blood glucose from 4 weeks (165.1±11.0 mg/dL) until sacrifice at 21 weeks of age (203.7±22.2 mg/dL). While this difference in blood glucose between 4 and 21 weeks in GK-S animals was significant, blood glucose at 21 weeks was significantly lower in GK-S compared to GK-C animals. At sacrifice, salsalate decreased plasma insulin (GK-S =1.0±0.3; GK-C =2.0±0.3 ng/mL, P<0.001) and increased plasma adiponectin concentrations (GK-S =15.9±0.7; GK-C =9.7±2.0 μg/mL, P<0.001). Salsalate also lowered total cholesterol in GK-S rats (96.1±8.5 mg/dL) compared with GK-C rats (128.0±11.4 mg/dL, P<0.001). Inflammation-related genes (Ifit1 and Iigp1) exhibited much higher mRNA expression in GK-C rats than WIS-C rats in liver, adipose, and muscle tissues, while salsalate decreased the Ifit1 and Iigp1 mRNA only in adipose tissue. These results suggest that salsalate acts to both increase adiponectin and decrease adipose tissue-based inflammation while preventing type 2 diabetes disease progression in GK rats.