Analysis of pharmacokinetics and pharmacodynamics for capecitabine during new chemotherapy regimen by bevacizumab (Bev) in combination with XELOX in unresectable colorectal cancer
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ABSTRACT:
DISEASE(S): Unresectable Colorectal Cancer
PROVIDER: 2628391 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Interventions: XELOX+BV 5-days on/ 2-days off Schedule
Primary outcome(s): Progression free survival.
Study Design: Single arm Non-randomized
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Project description:Phase I dose-finding trials in oncology seek to find the maximum tolerated dose of a drug under a specific schedule. Evaluating drug schedules aims at improving treatment safety while maintaining efficacy. However, while we can reasonably assume that toxicity increases with the dose for cytotoxic drugs, the relationship between toxicity and multiple schedules remains elusive. We proposed a Bayesian dose regimen assessment method (DRtox) using pharmacokinetics/pharmacodynamics (PK/PD) to estimate the maximum tolerated dose regimen (MTD-regimen) at the end of the dose-escalation stage of a trial. We modeled the binary toxicity via a PD endpoint and estimated the dose regimen toxicity relationship through the integration of a dose regimen PD model and a PD toxicity model. For the first model, we considered nonlinear mixed-effects models, and for the second one, we proposed the following two Bayesian approaches: a logistic model and a hierarchical model. In an extensive simulation study, the DRtox outperformed traditional designs in terms of proportion of correctly selecting the MTD-regimen. Moreover, the inclusion of PK/PD information helped provide more precise estimates for the entire dose regimen toxicity curve; therefore the DRtox may recommend alternative untested regimens for expansion cohorts. The DRtox was developed to be applied at the end of the dose-escalation stage of an ongoing trial for patients with relapsed or refractory acute myeloid leukemia (NCT03594955) once all toxicity and PK/PD data are collected.
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Project description:Colistin methanesulfonate (CMS) is an important treatment option for infections caused by carbapenem-resistant Gram-negative organisms (CROs). This study evaluated the pharmacokinetic/pharmacodynamic (PK/PD) profiles and safety of CMS in Chinese subjects following a recommended dosage. A total of 12 healthy Chinese subjects received CMS injections at 2.5 mg/kg once every 12 h for 7 consecutive days. The PK/PD profiles of the active form of CMS, colistin, against CROs were analyzed with the Monte Carlo simulation method. No serious adverse events were observed. The average steady-state plasma concentrations of CMS and colistin were 4.41 ± 0.75 μg/mL and 1.27 ± 0.27 μg/mL, and the steady-state exposures (AUC0–12,ss) were 52.93 ± 9.05 h·μg/mL and 15.28 ± 3.29 h·μg/mL, respectively. Colistin, at its minimum inhibitory concentration (MIC) of 0.5 μg/mL, has >90% probability to reduce CROs by ≥1 log. The PK/PD breakpoints for the ≥1 log kill were ≥MIC90 for carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa, but were ≤MIC50 for carbapenem-resistant Acinetobacter baumannii. The recommended dose regimen of CMS for 7 consecutive days was safe in Chinese subjects. The systemic exposure of colistin showed a high probability of being sufficient for most CROs, but was not sufficient for some carbapenem-resistant A. baumannii.
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Project description:YH4808 is a novel potassium-competitive acid blocker developed for gastric acid-related disorders. Previous studies indicate its potential to improve symptoms of gastric acid-related disorders. The current study was aimed to find the optimal regimen of YH4808 for night time pH control. This study was performed in two parts. Each was a randomized, open-label, active-controlled, multiple-doses, two-treatment, two-period crossover study conducted in 20 healthy Korean volunteers. Subjects were randomly assigned to one of the four groups. The three groups received different dosage regimens of YH4808 (100 mg twice a day, 200 mg once a day, or 200 mg twice a day), and the fourth group received esomeprazole 40 mg twice a day. The pharmacokinetic parameters demonstrated that the systemic exposure of YH4808 increased in a dose-proportional manner. The difference in the proportion of time above pH 4 over 24 h from the baseline was the greatest in the group receiving YH4808 200 mg twice a day. The values of the area under the effect curve at night time (12 A.M.-7 A.M.) were higher in all YH4808 groups than in the esomeprazole group. However, the differences among the YH4808 groups were not statistically significant (p > 0.05). YH4808 exhibited potential for better pH control during the night in comparison to esomeprazole. The optimal regimen for night time pH control among all the YH4808 regimens was 200 mg twice a day.Trial registrationClinicalTrials.gov Identifier: NCT01761513.
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Project description:SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M. tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1). Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h. The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.
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Project description:Interventions: Capecitabine 5-days on/ 2-days off schedule
Primary outcome(s): Occurrence rate of side effect
Study Design: Single arm Non-randomized
| 2628166 | ecrin-mdr-crc
Project description:SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice.After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasmaC. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1-200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss.Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha.In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties.
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Project description:The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.
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Project description:Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.
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Project description:Cefiderocol is a new broad-spectrum cephalosporin antibiotic with promising activity against various Gram-negative bacteria including carbapenem-resistant strains. A chlorocatechol group in the C-3 side chain provides cefiderocol with a siderophore activity, improving its stability against β-lactamases and facilitating the transportation of cefiderocol across outer bacterial membranes. Cefiderocol shows linear pharmacokinetics over a broad range of clinically relevant doses, with unchanged renal excretion constituting the main route of elimination. Geometric means (coefficient of variation) of the volume of distribution and clearance in individuals with normal kidney function were 15.8 (15%) L and 4.70 (27%) L/h, respectively. In patients with end-stage renal disease, clearance was 1.10 (24%) L/h. Time above the minimum inhibitory concentration is the main predictor of efficacy. There is no evidence for clinically relevant interactions of cefiderocol with other drugs mediated by metabolizing enzymes or drug transporters. Simulations based on population pharmacokinetic modeling suggest that dosing regimens should be adjusted based on kidney function to optimize therapeutic exposure to cefiderocol. Clinical efficacy trials indicated that cefiderocol is non-inferior to imipenem/cilastatin in the treatment of complicated urinary tract infections and acute uncomplicated pyelonephritis, and to meropenem in the treatment of nosocomial pneumonia. In the one study currently available, cefiderocol performed similarly to the best available therapy in the treatment of severe carbapenem-resistant Gram-negative infections regarding clinical and microbiological efficacy. In summary, cefiderocol shows favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol might be a viable option to treat infections with bacteria resistant to other antibiotics.
| S-EPMC8613110 | biostudies-literature