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Pharmacokinetic-pharmacodynamic modelling in the early development phase of anti-psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in rats.

ABSTRACT: 1. The use of pharmacokinetic/pharmacodynamic (PK/PD) analysis in early compound development was investigated in the rat for two developmental anti-psychotic compounds with clozapine as a positive control. 2. Three plasma samples were collected from each of eight animals according to a pre-defined sampling matrix allowing a total of 12 time points for PK analysis. Quantitative electroencephalography (QEEG), particularly the theta and beta frequencies, was used as a measurement of pharmacological effect. 3. PK/KD modelling of the sparse PK data available relative to a rich set of PD data was achieved using a population approach in NONMEM (IV). Individual PK parameter estimates were incorporated into a PK/PD model. 4. Qualitative EEG changes in rat and human were similar for clozapine, but different for the two developmental compounds, suggesting that changes in these PD parameters may not be specifically related to the anti-psychotic activity. 5. Although no definitive data are available concerning the signal specificity of EEG frequency bands with respect to dopaminergic or serotonergic receptor activity, qualitative and quantitative differences seen in EEG parameters are likely to result from the multiple receptor occupancy for these compounds. 6. The results confirm the value of population PK/PD modelling in conjunction with sparse sampling to enable determination of concentration effect relationships in the pre-clinical development programme of CNS-active drugs.

SUBMITTER: Parker TJ

PROVIDER: S-EPMC1572549 | biostudies-other | 2001 Jan

REPOSITORIES: biostudies-other

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Pharmacokinetic-pharmacodynamic modelling of S(-)-atenolol in rats: reduction of isoprenaline-induced tachycardia as a continuous pharmacodynamic endpoint.

Project description:BACKGROUND AND PURPOSE: For development of mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models, continuous recording of drug effects is essential. We therefore explored the use of isoprenaline in the continuous measurement of the cardiovascular effects of antagonists of beta-adrenoceptors (beta-blockers). The aim was to validate heart rate as a pharmacodynamic endpoint under continuous isoprenaline-induced tachycardia by means of PK-PD modelling of S(-)-atenolol. EXPERIMENTAL APPROACH: Groups of WKY rats received a 15 min i.v. infusion of 5 mg kg(-1) S(-)-atenolol, with or without i.v. infusion of 5 microg kg(-1) h(-1) isoprenaline. Heart rate was continuously monitored and blood samples were taken. KEY RESULTS: A three-compartment model best described the pharmacokinetics of S(-)-atenolol. The PK-PD relationship was described by a sigmoid Emax model and an effect compartment was used to resolve the observed hysteresis. In the group without isoprenaline, the variability in heart rate (30 b.p.m.) approximated the maximal effect (Emax=43+/-18 b.p.m.), leaving the parameter estimate of potency (EC50=28+/-27 ng ml(-1)) unreliable. Both precise and reliable parameter estimates were obtained during isoprenaline-induced tachycardia: 517+/-13 b.p.m. (E0), 168+/-15 b.p.m. (Emax), 49+/-14 ng ml(-1) (EC50), 0.042+/-0.012 min(-1) (k(eo)) and 0.95+/-0.34 (n). CONCLUSIONS AND IMPLICATIONS: Reduction of heart rate during isoprenaline-induced tachycardia is a reliable pharmacodynamic endpoint for beta-blockers in vivo in rats. Consequently this experimental approach will be used to investigate the relationship between drug characteristics and in vivo effects of different beta-blockers.

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| S-EPMC7608663 | biostudies-literature

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| S-EPMC2013992 | biostudies-other

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| S-EPMC2823363 | biostudies-literature

Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling

Project description: Not available

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Pharmacokinetic-pharmacodynamic modelling of the anti-FcRn monoclonal antibody rozanolixizumab: Translation from preclinical stages to the clinic.

Project description:Rozanolixizumab is a fully humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (mAb) that accelerates the removal of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibodies, via the natural lysosomal degradation pathway. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model characterizing the effect of rozanolixizumab on IgG levels in cynomolgus monkeys, translate it into humans to support the first-in-human (FIH) rozanolixizumab clinical trial study design, and, ultimately, develop a PK/PD model in humans. Simulations from the preclinical model were performed to predict IgG responses in humans and select clinically relevant doses in the FIH study. Good alignment was observed between predicted and observed reductions in IgG, which increased with increasing dose in the FIH study. The model successfully described the PK of the 4 and 7 mg/kg intravenous (i.v.) dose groups, although the PKs were underpredicted for the 1 mg/kg i.v. dose group. Updating the model with subsequent human data identified parameters that deviated from preclinical assumptions. The updated PK/PD model was able to effectively characterize the PK FcRn-IgG nonlinear system in response to rozanolixizumab in the FIH data.

| S-EPMC8752106 | biostudies-literature

Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats.

Project description:AIM: To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats. METHODS: Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 μg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments. RESULTS: Exenatide exhibited rapid absorption with k(a)=4.45 h(-1), and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated S(m1) of 0.822 and SC(50) of 4.02 μg/L. It was demonstrated that insulin stimulated glucose dissipation (S(m2)=0.0513) and inhibited the production of glucose (I(m)=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed. CONCLUSION: The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.

| S-EPMC4011360 | biostudies-other

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data.

Project description:IntroductionConcizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential.AimDetermine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy.MethodsFree TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (Emax ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations.ResultsThe Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once-daily dosing would minimize within-patient concizumab PK variability.ConclusionConcizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once-daily regimen.

| S-EPMC7379180 | biostudies-literature

Population pharmacokinetic-pharmacodynamic modelling of platelet time-courses following administration of abrocitinib.

Project description:AimsAbrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate-to-severe atopic dermatitis. Herein we describe the time-course of drug-induced platelet reduction following abrocitinib administration, identify covariates affecting platelet counts, and determine the probability of patients experiencing thrombocytopaenia while receiving abrocitinib.MethodsThis analysis included data from two Phase 2 and three Phase 3 studies in psoriasis and atopic dermatitis patient populations administered abrocitinib 10-400 mg QD orally for up to 12 weeks, with platelet counts determined up to week 16. A semi-mechanistic model was developed to assess the impact of baseline platelet counts (170, 220 and 270 × 1000/μL), age and race on the platelet nadir and week 12 counts with once-daily abrocitinib 200 mg or 100 mg.ResultsDecreases in platelet counts were transient with the nadir occurring on average 24 days (95% prediction interval, 23-24) after continuous administration of abrocitinib 200 mg QD. Following administration of once-daily abrocitinib 200 mg, the probabilities of thrombocytopaenia (<150 × 1000/μL) at the nadir were 8.6% and 95.5% for the typical patient with baseline platelet count of 270 × 1000/μL or 170 × 1000/μL, respectively. Adolescents had a lower probability of thrombocytopaenia compared with adults; platelet count distribution was similar in Asian and Western patients at the nadir and at week 12.ConclusionThis analysis supports the safety of once-daily abrocitinib 200 mg and 100 mg dosing regimens, with low probability of thrombocytopaenia during treatment, except for higher risk of low-grade thrombocytopaenia that diminished after 4 weeks in patients with low baseline platelet counts.

| S-EPMC9544602 | biostudies-literature

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