Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib.
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SUBMITTER: Huh KY
PROVIDER: S-EPMC8145937 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsFremanezumab is a fully humanized IgG2 Δa/κ monoclonal antibody specific for calcitonin gene-related peptide developed and approved for the preventive treatment of migraine in adults. The population pharmacokinetics (PK) of fremanezumab were characterized in healthy subjects and patients with chronic migraine and episodic migraine, including the effects of intrinsic and extrinsic factors on PK variability.MethodsNonlinear mixed effects modelling was performed using NONMEM with data from 7 phase 1-3 clinical trials evaluating selected intravenous and subcutaneous dose regimens. The influence of covariates on fremanezumab PK was assessed and model evaluation was performed through visual predictive checks.ResultsA 2-compartment model with first-order absorption and elimination described the PK data well. Typical values for fremanezumab central clearance (0.0902 L/d) and central distribution volume (1.88 L) for a 71-kg subject were consistent with previously reported values for IgG antibodies. Higher body weight was associated with increased central clearance and distribution volume. Effects of other covariates (age, albumin, renal function, sex, race, injection site, and acute, analgesic and preventive medication use for migraine) were not found to statistically significantly influence fremanezumab PK. There was no indication of reduced exposure in participants with positive anti-drug antibody status or with mild to moderate hepatic impairment. Absolute bioavailability was estimated at 0.658.ConclusionsA comprehensive population PK model was developed for fremanezumab following intravenous and subcutaneous administration in healthy subjects and patients with chronic migraine or episodic migraine, which will be used to further evaluate exposure-response relationships for efficacy and safety endpoints.
| S-EPMC6955415 | biostudies-literature
Project description:BACKGROUND:Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. OBJECTIVES:To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. METHODS:We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies. RESULTS:We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33?days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400?mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. CONCLUSIONS:Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.
| S-EPMC6753485 | biostudies-literature
Project description:PurposeGarenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens.MethodsAt the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration-time curve divided by the minimum inhibitory concentration (fAUC????/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases.ResultsLogistic regression analysis showed that fAUC????/MIC ratio was a significant variable that predicted clinical response (p?=?0.0164). Of all subjects, 92.4% reached the target value of fAUC????/MIC ratio?>?30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC???? and maximum concentration) and the incidence of adverse events by the Mann-Whitney test.ConclusionsThe antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations.
| S-EPMC3249185 | biostudies-literature
Project description:PurposeImatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects.Methods26 volunteers were administered orally with single dose of 400 mg imatinib. 16-19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated.ResultsThe popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01).ConclusionThe two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteers.
| S-EPMC9360108 | biostudies-literature
Project description:ObjectivesLack of data on the pharmacokinetics of efavirenz in pregnant women at the 400 mg reduced dose currently prevents universal roll-out. Population pharmacokinetic modelling was used to explore pharmacokinetic endpoints at 200, 400 and 600 mg daily doses in pregnant women stratified by CYP2B6 metabolic status.MethodsThe analysis was based on 252 plasma efavirenz concentrations from 77 pregnant women (77 sparse, 175 intensive) who received antiretroviral regimens containing 600 mg of efavirenz. The model was developed using NONMEM®. The effect of genetics was investigated and concentration-time courses at steady-state were simulated for individuals (n = 1000 each) classified as CYP2B6 slow, intermediate and fast metabolizers at 200, 400 and 600 mg daily doses.ResultsAt a 400 mg reduced dose, predicted mean (90% CI) mid-dose efavirenz concentration (C12) was 2.24 μg/mL (0.89-4.18) in pregnant women classified as slow metabolizers, compared with 0.87 μg/mL (0.34-1.64) in intermediate metabolizers and 0.78 μg/mL (0.30-1.47) in fast metabolizers. C12 was below the 0.47 μg/mL threshold determined within the ENCORE 1 trial in 10% at 400 mg, 4.6% at 600 mg and 3.4% with genotype-guided dosing. The 4.0 μg/mL toxicity threshold was exceeded in 4.6% at 400 mg, 13.5% at 600 mg and 5.2% with genotype-guided dosing.ConclusionsThese data provide context for the ongoing debate about reduction in efavirenz dose to 400 mg during pregnancy and should be interpreted alongside the lower toxicity expected with the lower dose. Additional research is required to investigate genotype-guided dose reduction in pregnant women.
| S-EPMC7614711 | biostudies-literature
Project description:What is already known about this subjectSorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFR? and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC).What this study addsThis is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib.AimsTo characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.MethodsPK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.ResultsA one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.ConclusionsOverall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.
| S-EPMC3162659 | biostudies-literature
Project description:Identification of optimal schedules for combination drug administration relies on accurately estimating the correct pharmacokinetics, pharmacodynamics, and drug interaction effects. Misspecification of pharmacokinetics can lead to wrongly predicted timing or order of treatments, leading to schedules recommended on the basis of incorrect assumptions about absorption and elimination of a drug and its effect on tumor growth. Here, we developed a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data. The software can be used to compare prespecified schedules on the basis of the number of resistant cells where drug interactions and pharmacokinetic curves can be estimated from user-provided data or models. We applied our approach to publicly available in vitro data of treatment with different tyrosine kinase inhibitors of BT-20 triple-negative breast cancer cells and of treatment with erlotinib of PC-9 non-small cell lung cancer cells. Our approach is publicly available in the form of an R package called ACESO (https://github.com/Michorlab/aceso) and can be used to investigate optimum dosing for any combination treatment. SIGNIFICANCE: These findings introduce a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data.
| S-EPMC7442591 | biostudies-literature
Project description:AimsThe aim of this study was to develop a population pharmacokinetic (PK) model of udenafil and its active metabolite, DA-8164, in healthy subjects and patients with hepatic impairment (HI) and to estimate the optimal dosing recommendations for patients with HI.MethodsAn open label, three parallel group, age and weight matched control study was conducted in 18 volunteers, six healthy subjects (n = 6) and patients with mild (Child-Pugh class A, n = 6) and moderate HI (Child-Pugh class B, n = 6). Serial blood samples were collected for up to 72 h after a single administration of udenafil 100 mg. A population PK model was developed using non-linear mixed effects modelling (nonmem, ver. 7.2). The simulated data from the final PK model and original data of healthy subjects were compared to identify the optimal dose for patients with HI.ResultsA two compartment model for both udenafil and DA-8164 best described the data. Prothrombin time on metabolic clearance of udenafil to DA-8164 was included in the final model as a covariate. Compared with the AUC(0,tlast ) value after administration of udenafil 100 mg to healthy subjects, the geometric mean ratios (95% confidence interval) after 100 mg and 75 mg udenafil administration were 1.21 (1.10, 1.32) and 0.74 (0.67, 0.81) in patients with mild HI, respectively. Meanwhile, those were 1.55 (1.43, 1.67) and 1.02 (0.92, 1.12) in patients with moderate HI, respectively.ConclusionsThis study suggests that the recommended doses of udenafil are 100 mg and 75 mg in patients with mild and moderate HI, respectively.
| S-EPMC4972155 | biostudies-literature
Project description:The objective of this study was to develop a simultaneous population pharmacokinetic (PK) model to describe atazanavir/ritonavir (ATV/RTV) PK (300/100 mg) and to assess the effect of RTV dose reduction on ATV PK. Simulations of ATV concentration-time profiles were performed at doses of ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily.A total of 288 ATV and 312 RTV plasma concentrations from 30 patients were included to build a population PK model using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.2 software.A one-compartment model with first-order absorption and lag-time best described the data for both drugs in the final simultaneous model. A maximum-effect model in which RTV inhibited the elimination of ATV was used to describe the relationship between RTV concentrations and ATV clearance (CL/F). An RTV concentration of 0.22 mg/L was associated with 50% maximum inhibition of ATV CL/F. The population prediction of ATV CL/F in the absence of RTV was 16.6 L/h (relative standard error, 7.0%), and the apparent volume of distribution and absorption rate constant were 106 L (relative standard error, 8%) and 0.87 per hour (fixed), respectively. Simulated average ATV trough concentrations at ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily were 45%, 63%, and 33% lower, respectively, than that of the standard dose.Although simulated median ATV trough concentrations after dose reductions were still more than the ATV minimum effective concentration (2.9-, 1.9-, and 3.6-fold for ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg, respectively); our modeling predicted a high proportion of individuals with subtherapeutic trough concentrations on the 200/50 mg dose. This suggests that 300/50 mg and 200/100 mg dosing are preferred candidate regimens in future clinical studies.
| S-EPMC3594700 | biostudies-other
Project description:Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports.
| S-EPMC6357964 | biostudies-literature