Pharmacokinetics and Disposition of Heparin-Binding Growth Factor Midkine Antisense Oligonucleotide Nanoliposomes in Experimental Animal Species and Prediction of Human Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model.
Ontology highlight
ABSTRACT:
SUBMITTER: Bai H
PROVIDER: S-EPMC8595129 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies. Thus, in the current work we developed a pregnancy physiological based pharmacokinetic/pharmacodynamic (PBPK/PD) model for indomethacin to explain the differences in indomethacin pharmacokinetics between pregnancy and non-pregnancy. A whole-body PBPK model with key pregnancy-related physiological changes was developed to characterize indomethacin PK in pregnant women and compare these parameters to those in non-pregnant subjects. Data related to maternal physiological and biological changes were obtained from literature and incorporated into the structural PBPK model that describes non-pregnant PK data. Changes in indomethacin area under the curve (AUC), maximum concentration (Cmax) and average steady-state concentration (Cave) in pregnant women were predicted. Model-simulated PK profiles were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester (T2)) of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted steady-state apparent clearance (CL/Fss) ratio was almost similar to the observed value (0.46 vs. 0.42). Sensitivity analysis suggested changes in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non-pregnancy. The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2. Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy.
| S-EPMC4592215 | biostudies-literature
Project description:Paclitaxel is a commonly used drug in the treatment of multiple solid tumors, including cancers of the breast, lung, and ovaries. Despite the established exposure-pharmacodynamic relationships for paclitaxel, treatment is associated with wide interindividual pharmacokinetic variability that leads to unpredictability of the agent's clinical activity and toxicity. We hypothesized that physiologically-based modeling approaches could be employed to predict the human pharmacokinetics of paclitaxel following administration of the approved Cremophor-based formulation (Taxol). The model was developed from tissue distribution studies performed in mice and applied to plasma concentration-time data obtained in adult cancer patients receiving Taxol at the approved dose and schedule (175 mg/m2 by a 3-hour intravenous infusion), taking into account interspecies differences in physiological parameters. The final model adequately captured the observed concentrations in patients and allowed prediction of paclitaxel distribution profiles in multiple target organs and can be applied to further refine the chemotherapeutic treatment with a clinically important agent.
| S-EPMC6930855 | biostudies-literature
Project description:Bortezomib is a reversible proteasome inhibitor with potent antineoplastic activity that exhibits dose- and time-dependent pharmacokinetics (PK). Proteasome-mediated bortezomib disposition is proposed as the primary source of its nonlinear and apparent nonstationary PK behavior. Single intravenous (IV) doses of bortezomib (0.25 and 1 mg/kg) were administrated to BALB/c mice, with blood and tissue samples obtained over 144 h, which were analyzed by LC/MS/MS. A physiologically based pharmacokinetic (PBPK) model incorporating tissue drug-target binding was developed to test the hypothesis of proteasome-mediated bortezomib disposition. The final model reasonably captured bortezomib plasma and tissue PK profiles, and parameters were estimated with good precision. The rank-order of model estimated tissue target density correlated well with experimentally measured proteasome concentrations reported in the literature, supporting the hypothesis that binding to proteasome influences bortezomib disposition. The PBPK model was further scaled-up to humans to assess the similarity of bortezomib disposition among species. Human plasma bortezomib PK profiles following multiple IV dosing (1.3 mg/m(2)) on days 1, 4, 8, and 11 were simulated by appropriately scaling estimated mouse parameters. Simulated and observed bortezomib concentrations after multiple dosing were in good agreement, suggesting target-mediated bortezomib disposition is likely for both mice and humans. Furthermore, the model predicts that renal impairment should exert minimal influence on bortezomib exposure in humans, confirming that bortezomib dose adjustment is not necessary for patients with renal impairment.
| S-EPMC4620045 | biostudies-literature
Project description:Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodations for the unique PK properties of monoclonal antibodies (mAb). This study applied this model to extensively survey mAb PK in man in order to seek general perspectives on mAb distributional and elimination features. Profiles for 72 antibodies were successfully analyzed with this model. The model results provide assessment regarding: (1) predominant clearance site, in plasma or interstitial fluid (ISF); (2) mAb ISF concentrations in two groups of lumped tissues with continuous (V(tight)) or fenestrated (V(leaky)) vascular endothelium; (3) Transcapillary escape rate (TER), an indicator of systemic vascular permeability. For 93% of surveyed mAbs, the model assuming clearance from plasma (CL) produced better or at least equivalent model performance than the model with clearance from ISF and yielded most consistent values of vascular reflection coefficients (?1 and ?2) among all antibodies. The average mAb ISF concentration in V(tight) and V(leaky) at equilibrium was predicted to be about 6.8 and 37.9% of that in plasma. A positive correlation was detected between plasma clearance and TER among most mAbs, which could be interpreted as both parameters having common determinants related to ISF tissue distribution in this model context. The mAbs with relative higher plasma clearance (>0.035 L/h/70 kg) did not reveal such positive correlation between clearance and TER, implying that the factors contributing to high clearance may not necessarily increase tissue distribution and penetration. In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man.
| S-EPMC4226811 | biostudies-literature
Project description:Sjögren's syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid-based specialized pro-resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically-based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS-like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01-10 mg/kg). The first-in-human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.
| S-EPMC7993257 | biostudies-literature
Project description: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 (? v ) 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 (R total , K D , K ss , k int ) 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.
| S-EPMC4167346 | biostudies-literature
Project description:PurposeMonoclonal antibodies (mAbs) are commonly administered by subcutaneous (SC) route. However, bioavailability is often reduced after SC administration. In addition, the sequential transfer of mAbs through the SC tissue and lymphatic system is not completely understood. Therefore, major objectives of this study were a) To understand absorption of mAbs via the lymphatic system after SC administration using physiologically based pharmacokinetic (PBPK) modeling, and b) to demonstrate application of the model for prediction of SC pharmacokinetics (PK) of mAbs.MethodsA minimal PBPK model was constructed using various physiological parameters related to the SC injection site and lymphatic system. The remainder of the body organs were represented using a 2-compartment model (central and peripheral compartments), with parameters derived from available intravenous (IV) PK data. The IV and SC clinical PK data of a total of 10 mAbs were obtained from literature. The SC PK data were used to estimate the lymphatic trunk-lymph node (LN) clearance.ResultsThe mean estimated lymphatic trunk-LN clearance obtained from 37 SC PK profiles of mAbs was 0.00213 L/h (0.001332 to 0.002928, 95% confidence intervals). The estimated lymphatic trunk-LN clearance was greater for the mAbs with higher isoelectric point (pI). In addition, the estimated clearance increased with decrease in the bioavailability.ConclusionThe minimal PBPK model identified SC injection site lymph flow, afferent and efferent lymph flows, and volumes associated with the SC injection site, lymphatic capillaries and lymphatic trunk-LN as important physiological parameters governing the absorption of mAbs after SC administration. The model may be used to predict PK of mAbs using the relationship of lymphatic trunk-LN clearance and the pI. In addition, the model can be used as a bottom platform to incorporate SC and lymphatic in vitro clearance data for mAb PK prediction in the future.
| S-EPMC6613546 | biostudies-literature
Project description:Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug-drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro-in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis-Menten constant (Km,u) of gadoxetate was 106 μM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK-IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE-MRI profiles and elimination from the liver. Therefore, in vivo rat DCE-MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE-MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.
| S-EPMC8397403 | biostudies-literature
Project description:Delivery technologies are required for realizing the clinical potential of molecular medicines. This work presents an alternative technology to preformulated delivery systems by harnessing the natural transport properties of serum albumin using endogenous binding of gapmer antisense oligonucleotides (ASOs)/albumin constructs. We show by an electrophoretic mobility assay that fatty acid-modified gapmer and human serum albumin (HSA) can self-assemble into constructs that offer favorable pharmacokinetics. The interaction was dependent on fatty acid type (either palmitic or myristic acid), number, and position within the gapmer ASO sequence, as well as phosphorothioate (PS) backbone modifications. Binding correlated with increased blood circulation in mice (t1/2 increased from 23 to 49 min for phosphodiester [PO] gapmer ASOs and from 28 to 66 min for PS gapmer ASOs with 2× palmitic acid modification). Furthermore, a shift toward a broader biodistribution was detected for PS compared with PO gapmer ASOs. Inclusion of 2× palmitoyl to the ASOs shifted the biodistribution to resemble that of natural albumin. This work, therefore, presents a novel strategy based on the proposed endogenous assembly of gapmer ASOs/albumin constructs for increased circulatory half-life and modulation of the biodistribution of gapmer ASOs that offers tunable pharmacokinetics based on the gapmer modification design.
| S-EPMC5498835 | biostudies-other
Project description:Pharmacokinetics (PKs) in Japanese healthy subjects were simulated for nine compounds using physiologically based PK (PBPK) models parameterized with physicochemical properties, preclinical absorption, distribution, metabolism, and excretion (ADME) data, and clinical PK data from non-Japanese subjects. For each dosing regimen, 100 virtual trials were simulated and predicted/observed ratios for peak plasma concentration (Cmax ) and area under the curve (AUC) were calculated. As qualification criteria, it was prespecified that >80% of simulated trials should demonstrate ratios to observed data ranging from 0.5-2.0. Across all compounds and dose regimens studied, 93% of simulated Cmax values in Japanese subjects fulfilled the criteria. Similarly, for AUC, 77% of single-dosing regimens and 100% of multiple-dosing regimens fulfilled the criteria. In summary, mechanistically incorporating the appropriate ADME properties into PBPK models, followed by qualification using non-Japanese clinical data, can predict PKs in the Japanese population and lead to efficient trial design and conduct of Japanese phase I studies.
| S-EPMC6587435 | biostudies-literature