Dosing of troxacitabine (Troxatyl [T], SGX-145) based on renal function

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2025-2025
Author(s):  
M. J. Kelner ◽  
F. J. Giles ◽  
E. J. Feldman ◽  
G. J. Roboz ◽  
D. J. Deangelo ◽  
...  
Keyword(s):  
Renal Function ◽  
Steady State ◽  
Creatinine Clearance ◽  
Plasma Concentrations ◽  
Myelogenous Leukemia ◽  
Blood Levels ◽  
Upper Limit ◽  
Major Route ◽  
Cancer Agent ◽  
Dosing Strategy

2025 Background: Troxacitabine (Troxatyl [T], SGX-145) is a novel L-configuration nucleoside analog anti-cancer agent with unique mechanistic/cytotoxic properties. T is clinically active against acute myelogenous leukemia (AML), chronic myeloid leukemia, myelodysplastic syndromes (MDS), renal cell carcinoma, and pancreatic cancer. A multi-center Phase 2/3 clinical trial is currently underway to evaluate the safety and efficacy of continuous IV infusion T treatment in second salvage AML. The major route of elimination of troxacitabine is renal excretion as unchanged drug (∼70%) and there is minimal protein binding. These results suggest that renal function may have a significant effect on steady-state troxacitabine plasma concentrations (Css). Methods: Pharmacokinetic and toxicity data from four AML clinical trials (>200 patients) are being analyzed to (1) Identify a minimum Css for therapeutic efficacy; (2) Define an upper limit of Css for adverse risk; and (3) Develop a mechanism to prospectively modify the troxacitabine dose based on renal function, which would avoid excessive toxicity while maintaining therapeutic blood levels. Results: Initial results from 41 patients indicate that to induce remission in AML patients, troxacitabine steady-state plasma concentrations (Css) must be ≥ 80 ng/mL. However, higher Css values correlate with increased toxicity and, thereby, increase the risks of the treatment for an individual patient, although an upper limit for adverse risk has not yet been defined. For patients with normal renal function (creatinine clearance ≥ 50 but ≤ 125 mL/min), a Calvert style formula, based on a patient’s estimated creatinine clearance, has been developed to define the dose required to achieve a therapeutic Css ≥ 80 ng/mL. Both linear and non-linear nomogram models are also being developed to adjust troxacitabine dosage for patients with moderate renal impairment (30 mL/min < creatinine clearance < 50 mL/min) or for patients with high GFR (creatinine clearance > 125 mL/min). Conclusion: A firm relationship exists between renal function, troxacitabine clearance, and Css values. This result indicates that a dosing strategy based on renal function may be warranted to obtain optimal troxacitabine Css values. [Table: see text]

scholarly journals A reappraisal of polymyxin B dosing based on population pharmacokinetic model in patient with renal insufficiency

2020 ◽  
Author(s):  
Xuben Yu ◽  
Chunhong Zhang ◽  
Jingye Pan ◽  
Ying Dai ◽  
Ziye Zhou ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Renal Function ◽  
Steady State ◽  
Renal Insufficiency ◽  
Creatinine Clearance ◽  
Polymyxin B ◽  
Adult Patients ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Dosing Strategy

AbstractBackgroundCurrent FDA-approved label recommends polymyxin B dosing should be adjusted according to renal function, despite several studies proved poor correlation between polymyxin B PK and creatinine clearance. The study aims to assess the impact of renal function on polymyxin B metabolism and identify an alternate dosing strategy by population analysis.MethodsBlood samples from adult patients were collected at steady state during routine therapeutic drug monitoring. Nonlinear mixed effects modeling was employed to build a population PK model of polymyxin B. Monte Carlo simulations were performed to design polymyxin B dosing regimens across various renal function.ResultsPharmacokinetic analyses included 112 polymyxin B concentrations at steady state from 32 adult patients aged 37-93 received intravenous polymyxin B (100-200 mg/d). The creatinine clearance in patients was 5.91-244 mL/min. In the final population PK model, CrCL was the significant covariate on CL (typical value, 1.59 L/hr; between-subject variability, 13%). Mean (SD) individual empirical Bayesian estimates of CL was 1.75 (0.43) L/hr. A new dosing strategy combining the PK/PD targets and Monte Carlo simulation indicated that polymyxin B dose reductions improved the probability of achieving optimal exposures in simulated patients with renal insufficiency. For severe infections caused by organisms with MIC of ≥ 2 mg/L, though a high daily dose (e.g. 200mg/day) would possible for bacterial eradication, the risk of nephrotoxicity is significantly increased.ConclusionA population PK model was established to develop individualized polymyxin B dosage regimens that the dose of polymyxin B should be adjusted according to CrCL.

Drawbacks of the constant-infusion technique for measurement of renal function

1995 ◽  
Vol 268 (4) ◽  
pp. F543-F552 ◽  
Author(s):  
B. A. Van Acker ◽  
G. C. Koomen ◽  
L. Arisz
Keyword(s):  
Renal Function ◽  
Steady State ◽  
Plasma Concentrations ◽  
Constant Infusion ◽  
Urinary Recovery ◽  
Infusion Method ◽  
Pah Clearance ◽  
The Difference ◽  
Infusion Technique ◽  
Extrarenal Clearance

We investigated the validity of the steady-state constant infusion method (CIM), in which quantitative urinary recovery and constant plasma concentrations of the solute infused are required. Successive 3-h clearances of inulin and p-aminohippuric acid (PAH) were determined for 27 h in 25 patients with renal disease. Results were compared with the standard method of bladder clearance (StM) and with a modified CIM (ModCIM). The 24-h urinary recovery was incomplete for both inulin and PAH. Mean 24-h ModCIM inulin clearance overestimated StM by 4.5 ml.min-1 x 1.73 m-2 (range 0–9, P < 0.001) independent of the extent of renal impairment and pointed to slow distribution and/or extrarenal clearance of inulin. For PAH, the difference between ModCIM and StM clearance was related to the average PAH clearance by ModCIM and StM (r = 0.78). Furthermore, neither plasma inulin nor PAH became completely constant, because of the circadian rhythm in renal function. In conclusion, the conditions of the steady-state CIM technique are not fulfilled, and the method is not suitable for accurate measurement of inulin and PAH clearance, especially when the clearance is low.

scholarly journals Metformin doses to ensure efficacy and safety in patients with reduced kidney function

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246247
Author(s):  
Isabelle H. S. Kuan ◽  
Luke C. Wilson ◽  
Jed C. Leishman ◽  
Samuel Cosgrove ◽  
Robert J. Walker ◽  
...  
Keyword(s):  
Steady State ◽  
Kidney Function ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Strong Relationship ◽  
Average Concentration ◽  
Efficacy And Safety ◽  
Ckd Stage ◽  
Dosing Strategy ◽  
Reduced Kidney Function

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was <5% for most doses and kidney function levels. The lower dose of 500 mg daily was required to maintain concentrations below the safety limits for patients with an eGFR of 15–29 mL/min. Our analysis suggests that a maximum daily dose of 2250, 1700, 1250, 1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b and 4, respectively, will provide a reasonable probability of achieving efficacy and safety. Our results support the cautious of use metformin at appropriate doses in patients with impaired kidney function.

Pharmacokinetics of Oral Maribavir, a Novel Anti-Cytomegalovirus Agent, in Subjects with Renal Impairment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2863-2863
Author(s):  
Suzanne Swan ◽  
William Smith ◽  
Thomas Marbury ◽  
Mary Schumacher ◽  
Carolyn Dougherty ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Normal Renal Function ◽  
Dose Adjustment ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Terminal Phase ◽  
P Value ◽  
Solid Organ

Abstract Maribavir (MBV) is an oral antiviral drug with a unique mechanism of action against cytomegalovirus (CMV). Maribavir is currently in clinical development for use in recipients of stem cell or solid organ transplants, who are vulnerable to renal impairment caused by a variety of drugs or post-transplant complications. Characterization of the pharmacokinetic (PK) profile of maribavir in patients with renal impairment was needed to determine if dose adjustment is indicated. The effect of renal function on the PK of a single 400 mg dose of maribavir was evaluated in adults with normal renal function (creatinine clearance >80 mL/min) and adults with renal impairment classified as mild, moderate, or severe, as measured by creatinine clearance 50–80, 30–<50, and <30 mL/min, respectively. Subjects requiring dialysis were not included. PK results, based on total (bound and unbound) plasma concentrations are shown in the table. Analyses of PK parameters estimated from unbound plasma concentrations of maribavir also did not show statistically significant differences between groups. Renal impairment was associated higher AUC and Cmax values as well as with reductions in the oral clearance and terminal-phase volume of distribution of VP 44469, an inactive metabolite of maribavir. Results were consistent with those of previous studies, which showed that very little maribavir was excreted unchanged in urine while about 22% of an oral dose of maribavir is recovered in urine as VP 44469. In conclusion, renal impairment does not affect the pharmacokinetics of maribavir, although plasma concentrations of the metabolite VP 44469 tended to increase with decreasing creatinine clearance. No dose adjustment of maribavir is indicated in subjects with renal impairment as classified in this study. Mean Maribavir PK Parameters Normal Renal Function Mild/moderate Renal Impairment Severe Renal Impairment ANOVA p-value Parameter (unit) N=12 N=10 N=8 Cmax (mcg/mL) 22.6 22.0 21.5 0.869 AUC 0-∞ (mcg*h/mL) 139 145 136 0.810 T 1/2 (h) 5.51 5.61 5.28 0.780 CL/F (L/h) 3.38 3.05 3.56 0.808

MK-0457, a Novel Aurora Kinase and BCR-ABL Inhibitor, Is Active Against BCR-ABL T315I Mutant Chronic Myelogenous Leukemia (CML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 163-163 ◽  
Author(s):  
Francis Giles ◽  
Jorge Cortes ◽  
Donald A. Bergstrom ◽  
Alan Xiao ◽  
Penny Bristow ◽  
...  
Keyword(s):  
Steady State ◽  
Dose Level ◽  
Plasma Concentrations ◽  
Aurora Kinase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
T315i Mutation

Abstract Background. MK-0457 (VX-680) is a small-molecule inhibitor of aurora kinases A, B, and C, and wildtype and mutant BCR-ABL, including the T315I variant. The T315I BCR-ABL mutation mediates high level resistance to imatinib, dasatinib and nilotinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation, at a concentration of ~1μM. A Phase I study of MK-0457 is being conducted in patients with refractory hematologic malignancies, including CML. Methods. After IRB approval, 15 consenting patients with refractory CML (median 5 prior regimens), ECOG performance status ≤2, and adequate organ function were enrolled using a standard dose escalation scheme with 3 patients/dose level until dose-limiting toxicity (DLT), followed by 6 patients/level. MK-0457 was administered by continuous 5-day intravenous infusion every 2 to 3 weeks. DLT was defined as grade 3 or higher non-hematologic toxicity during cycle 1. Pharmacokinetics (PKs) were collected pre-dose through 168 h and analyzed for MK-0457 by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin. Results. Fifteen CML patients received MK-0457 dosed at 8, 12, 16, 20, 24, 28, and 32 mg/m2/hr. All but three of these patients had a history of accelerated phase or blast crisis. Eleven of these patients carried the BCR-ABL T315I mutation. All eleven BCR-ABL T315I mutant CML patients demonstrated clinical signals of anti-leukemic activity. By conventional criteria, there was one major hematological response, four minor hematological responses, one complete cytogenetic response, two partial cytogenetic responses, and one minimal cytogenetic response. Some degree of molecular response, as measured by BCR-ABL:ABL transcript ratio, was detected in five of six patients for whom such data were available. The longest a patient was treated was for 15 cycles, and is still ongoing. The patients with the best clinical response had the largest magnitude inhibition of BCR-ABL in leukemia cells as measured by levels of phosphoCRKL, a substrate of the BCR-ABL fusion kinase. None of the patients without the BCR-ABL T315I mutation showed objective responses. Remarkably, no drug-related non-hematological toxicity was observed. Some patients had apparent myelosuppression, which is an expected mechanism-based side effect of Aurora kinase inhibition. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ~15 h. Steady state plasma concentrations are ≥ 1μM at a dose level of ≥ 20 mg/m2/hr. Conclusion. MK-0457 is very well tolerated and achieves plasma levels similar to those causing efficacy in preclinical models of CML. MK-0457 is the first T315I BCR-ABL inhibitor to show activity against this highly refractory, poor prognostic subpopulation of CML. Further evaluation of MK-0457 alone and in combination with other BCR-ABL inhibitors in CML is warranted.

Plasma concentrations of 5-FU and creatinine clearance as predictive markers for severe toxicities of capecitabine in patients with colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 428-428
Author(s):  
Katsuya Makihara ◽  
Hideyuki Mishima ◽  
Sayaka Azuma ◽  
Kazuyo Miyagi ◽  
Katsuya Komori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Renal Function ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Creatinine Clearance ◽  
Plasma Concentrations ◽  
Predictive Markers ◽  
Characteristic Analysis ◽  
Severe Adverse Events ◽  
Grade 3

428 Background: Pharmacokinetically guided dose adjustment of 5-fluorouracil (5-FU) are available but management of capecitabine has not been established. Patients with renal impairment often experience severe adverse events. The aim of this study is to assess the relationship between plasma concentration of 5FU, metabolites after administration of capecitabine, renal function and adverse events. Methods: Plasma concentration–time data for capecitabine, 5’-DFUR, 5’-DFCR and 5-FU were analyzed by blood samples within 60–180 min after administration of capecitabine on day 8 in colorectal cancer patients receiving capecitabine based regimen (capecitabine with or without oxaliplatin and bevacizumab). Concentrations of 5-FU were analized by a nanoparticle antibody-based immunoassay for 5-FU(My 5-FUR assay). Correlation between the peak concentration of capecitabine metabolites (Cmax) or creatinine clearance (Ccr) and toxicity (grade 3–4 diarrhea, grade 2-3 hand–foot syndrome and grade 3–4 anorexia) were assessed. When parameter of correlation exists, logistic regression analysis was done. ROC (receiver operating characteristic) analysis was conducted to explore the cut off value of the parameter associated with severe adverse events. Results: A total of 42 patients were analyzed. The Cmax of 5’-DFUR, 5-FU and Ccr were significantly correlated with the incidence of severe adverse events. Cmax of 5-FU (p = 0.015) and Ccr (p = 0.016) were also independent parameters. According to the ROC analysis, severe adverse events were observed in the patients whose Cmax of 5-FU was higher than 295 ng/mL and Ccr was lower than 64.8 mL/min. Conclusions: Plasma concentration of 5-FU and renal function are good predictive markers of adverse events after capecitabine administration. These results would lead to the appropreate indivisual dosage adjustment of capecitabine.

Plasma D Dimer: A Useful Marker of Fibrin Breakdown in Renal Failure

1989 ◽  
Vol 61 (03) ◽  
pp. 522-525 ◽  
Author(s):  
M P Gordge ◽  
R W Faint ◽  
P B Rylance ◽  
H Ireland ◽  
D A Lane ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Monoclonal Antibodies ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Plasma Concentrations ◽  
Significant Negative Correlation ◽  
Healthy Controls ◽  
D Dimer

SummaryD dimer and other large fragments produced during the breakdown of crosslinked fibrin may be measured by enzyme immunoassay using monoclonal antibodies. In 91 patients with renal disease and varying degrees of renal dysfunction, plasma D dimer showed no correlation with renal function, whereas FgE antigen, a fibrinogen derivative which is known to be cleared in part by the kidney, showed a significant negative correlation with creatinine clearance. Plasma concentrations of D dimer were, however, increased in patients with chronic renal failure (244 ± 3l ng/ml) (mean ± SEM) and diabetic nephropathy (308 ± 74 ng/ml), when compared with healthy controls (96 ± 13 ng/ml), and grossly elevated in patients with acute renal failure (2,451 ± 1,007 ng/ml). The results indicate an increase in fibrin formation and lysis, and not simply reduced elimination of D dimer by the kidneys, and are further evidence of activated coagulation in renal disease. D dimer appears to be a useful marker of fibrin breakdown in renal failure.

Artemeter-Lumefantrine therapeutic efficacy, safety and plasma levels in patients with uncomplicated falciparum malaria from the Colombian Pacific región

Infectio ◽  
2018 ◽  
Vol 22 (4) ◽  
pp. 199
Author(s):  
Alberto Tobón-Castaño ◽  
Luisa Garcés-Murillo ◽  
Alexandra Ríos-Orrego ◽  
Jehidys Montiel-Ramos ◽  
Briegel De Las Salas ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Falciparum Malaria ◽  
Therapeutic Efficacy ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Therapeutic Failure ◽  
World Health ◽  
Blood Levels ◽  
Drug Clinical Trial ◽  
Parasitological Response

Introduction: In Colombia, the published studies for the treatment of uncomplicated Plasmodium falciparum malaria with Artemether-Lumefantrine are scarce. The aim of the study was to evaluate the therapeutic efficacy and safety profile of this combination.Methods: A clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28-day World Health Organization validated protocol. Patients received supervised antimalarial treatment and the primary efficacy endpoint was the clinical and parasitological response. Safety was assessed through adverse events surveillance and plasmatic levels of antimalarial drugs were measured.Results: 88 patients were included. Adequate clinical and parasitological response rate of 100% on day 28 was achieved in 84 patients, diagnosed by thick blood smear examination. There were four parasitological therapeutic failures (5%) detected by polymerase chain reaction.Discusion: Therapeutic efficacy similar to previous studies was established with a slight increase in therapeutic failure. The serum levels of the antimalarials were adequate and the few cases of therapeutic failure were not related.Conclusion: Treatment of uncomplicated P. falciparum malaria with Artemeter-Lumefantrine was effective and safe in the study population. All patients reached adequate plasma concentrations of the drugs; therapeutic failures were not associated with low blood levels of the drug clinical trial.

Meta-analysis comparing impact of age, sex and renal function on the efficacy and safety of new oral anticoagulants vs. vitamin K antagonists for the treatment of acute venous thromboembolisms

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J She ◽  
B.Z Zhuo
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Creatinine Clearance ◽  
Vitamin K ◽  
Meta Analysis ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Funding Source ◽  
Efficacy And Safety ◽  
Acute Venous Thromboembolism

Abstract Background New direct oral anticoagulants (NOACs), as a preferable treatment option for acute venous thromboembolism (VTE) have been recommended with practical advantages as compared to Vitamin K antagonists (VKAs) in clinical practice. Purpose In our study, we performed a meta-analysis to determine the efficacy and safety of NOACs vs. VKAs in patients with different age, sex and renal function for the treatment of VTE. Methods Electronic databases (accessed October 2019) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus VKAs for the treatment of acute venous thromboembolism. Results NOACs was associated with a borderline higher efficacy in female (OR 0.79, 95% CI 0.62–1.02), and a significantly higher efficacy in patients with age more than 75 (OR 0.51, 95% CI 0.32–0.80) and creatinine clearance less than 50 mL/min (OR 0.57, 95% CI 0.32–0.99). NOACs also show advantage in terms of major or clinically relevant non-major bleeding in male (OR 0.72, 95% CI 0.60–0.86), and patients with creatinine clearance more than 50 mL/min (OR 0.75, 95% CI 0.67–0.84). Conclusions NOACs have exhibited clinical preference among patients with acute VTE as compared to VKA with significantly decreased thrombosis events and lower bleeding complications, especially in patients with age more than 75 and creatinine clearance less than 50 mL/min. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by the National Natural Science Foundation of China (81800390) and the Natural Science Foundation of Shaanxi province (2018KW067).

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