scholarly journals An Enterohepatic Recirculation Population Pharmacokinetic and MIC-1 Pharmacokinetic-Pharmacodynamic Model for the MDM2 Inhibitor Navtemadlin (KRT-232) in Healthy Subjects

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4350-4350
Author(s):  
Lu Zhang ◽  
Bill Poland ◽  
Michelle Green ◽  
Shekman Wong ◽  
J. Greg Slatter
Keyword(s):  
Healthy Subjects ◽  
Food Effect ◽  
Plasma Concentrations ◽  
Effect Study ◽  
Time Data ◽  
Publicly Traded ◽  
First Order ◽  
The Past ◽  
Concentration Time ◽  
Mdm2 Inhibitor

Abstract Background: Murine double minute 2 (MDM2) is the primary negative regulator of the tumor suppressor protein, p53. Navtemadlin (KRT-232), a potent and selective, orally available MDM2 inhibitor restores p53 activity to drive apoptosis of cancer cells in TP53 WT malignancies. Navtemadlin is currently being evaluated in a phase 3 trial of patients with relapsed or refractory myelofibrosis, as well as in numerous phase 1b/2 trials in various hematologic malignancies and solid tumors. Serum macrophage inhibitor cytokine-1 (MIC-1) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with navtemadlin (Allard et al. HemaSphere. 2020). Using pharmacokinetic (PK) and PD data from a healthy subject food effect study (Wong et al. Blood. 2020), we developed a population PK (PPK) model that characterized enterohepatic recirculation (EHR) as a half-life extending element in the PK profiles of navtemadlin and its major acyl glucuronide metabolite M1. MIC-1 PD data were incorporated into the model to quantify plasma concentration-driven MIC-1 excursions and to simulate PK and PD across time and dose in healthy subjects. Methods: PPK and PK-PD models were developed using the first-order conditional estimation with interaction (FOCE-I) method in NONMEM 7.4, with model covariates selected using a stepwise forward addition and backward elimination method based on a 5% significance level. Model quality was checked by inspecting model parameters and confidence intervals, as well as standard residual-based and simulation-based diagnostics, and prediction-corrected visual predictive checks. Navtemadlin plasma concentration and MIC-1 serum concentration-time data from the food effect study (KRT-232-105) were modeled (N=30 subjects after a single 60 mg navtemadlin dose). Candidate PPK semi-mechanistic models that described EHR with multi-compartment structures (gut, central, and peripheral compartments for navtemadlin, and central and gallbladder [GB] compartments for M1), first-order elimination, and mealtime effects on GB emptying were tested. Post hoc parameter estimates from the final PPK model were used to generate individual predicted navtemadlin plasma concentrations for the PK-PD model. Based on exploratory plots, the pharmacological mechanism of action of navtemadlin, and a bile acid recycling model (Guiastrennec et al. CPT Pharmacometrics Syst Pharmacol. 2018), an indirect response equation was selected for the MIC-1 effect compartment (Figure 1a). Results: Navtemadlin and M1 plasma concentrations, including a second peak attributed to EHR at ~8-12 h, were well described by a model with central and peripheral compartments, constant basal M1 release rate into bile (KBR BASAL), and incremental mealtime GB emptying rate (KBR MEAL, Figure 1a). Figure 1b shows simulated navtemadlin and M1 amounts in various compartments over time. Median oral clearance of navtemadlin was estimated at 36.35 L/h. Estimated median apparent oral clearance of navtemadlin in healthy subjects was higher than PPK estimates for patients with advanced solid tumors (24.9 L/h [Ma et al. Blood. 2019]). The median central and peripheral volumes of navtemadlin were 159 L and 390 L, respectively. Navtemadlin exposure was higher in healthy female subjects relative to male subjects. Between-subject variability in clearance was 31%. Typical MIC-1 maximum stimulatory effect (S max) was estimated at 6.82, close to the median maximum ratio of MIC-1 to baseline MIC-1 (7.29) in the observed data. SC 50 was estimated at 85.22 ng/mL, with a Hill coefficient of 2.02, indicating a relatively steep increase in MIC-1 serum concentration with increasing navtemadlin concentration. For both PPK and PK-PD models, diagnostic plots confirmed an adequate fit. Subjects with lower baseline MIC-1 had a larger response and reached a maximum MIC-1 concentration later. Older subjects had the largest covariate impact, with a higher MIC-1 response. Conclusion: A two-compartment PPK model with basal and incremental mealtime GB emptying rates captured concentration-time data for navtemadlin and its metabolite M1. EHR was evident and navtemadlin reabsorption following hydrolysis of biliary M1 in the intestine contributed to navtemadlin half-life. An indirect stimulatory PK-PD model effectively described the relationship between navtemadlin and MIC-1 in healthy subjects. Figure 1 Figure 1. Disclosures Zhang: Certara, Inc.: Current Employment; Milad Pharmaceutical Consulting, LLC.: Ended employment in the past 24 months. Wong: Kartos Therapeutics: Current Employment; AbbVie Biotherapeutics: Current equity holder in publicly-traded company. Slatter: Telios Pharma: Current holder of stock options in a privately-held company; Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company; AstraZeneca: Current equity holder in publicly-traded company; Amgen: Divested equity in a private or publicly-traded company in the past 24 months. OffLabel Disclosure: Yes, navtemadlin (KRT-232) is an investigational small molecule MDM2 inhibitor.

scholarly journals Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

1997 ◽  
Vol 41 (5) ◽  
pp. 982-986 ◽  
Author(s):  
T P Kanyok ◽  
A D Killian ◽  
K A Rodvold ◽  
L H Danziger
Keyword(s):  
Healthy Subjects ◽  
Randomized Clinical Trials ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Multiple Drug ◽  
Time Data ◽  
Time Curve ◽  
First Order ◽  
Significant Difference

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

scholarly journals Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

2008 ◽  
Vol 53 (2) ◽  
pp. 428-434 ◽  
Author(s):  
Joseph S. Bubalo ◽  
Myrna Y. Munar ◽  
Ganesh Cherala ◽  
Brandon Hayes-Lattin ◽  
Richard Maziarz
Keyword(s):  
Median Time ◽  
Intravenous Infusion ◽  
Plasma Concentrations ◽  
Neutropenic Fever ◽  
Time Data ◽  
Bacteriostatic Effect ◽  
Oncology Patients ◽  
Time Zero ◽  
Concentration Time ◽  
Free Plasma

ABSTRACT Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C max) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to C max was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved C max/MIC and AUC from time zero to 24 h (AUC0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C max/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

scholarly journals Induction of Fetal Hemoglobin By FTX6058, a Novel Small Molecule Development Candidate

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Peter Rahl ◽  
Ivan Efremov ◽  
Billy Stuart ◽  
Keqiang Xie ◽  
Mark Roth ◽  
...  
Keyword(s):  
Small Molecule ◽  
Plasma Concentrations ◽  
Fetal Hemoglobin ◽  
Target Engagement ◽  
Publicly Traded ◽  
In Vivo Models ◽  
Α Subunit ◽  
The Past

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Analysis of a phase I pharmacokinetic (PK)/food effect study of AT-101 in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2557-2557
Author(s):  
H. C. Pitot ◽  
D. Mould ◽  
J. Maleski ◽  
L. Leopold
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Effect Study ◽  
Noncompartmental Analysis ◽  
Time Data ◽  
Phase 1 Study ◽  
Concentration Time ◽  
Effect Of Food ◽  
Ongoing Phase ◽  
High Calorie

2557 Background: AT-101 is an oral, pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, Mcl-1). Overexpression of Bcl-2 family proteins is common in human cancers. AT-101 activity as a single agent as well as in combination with docetaxel has been reported. The ongoing Phase 1 study of AT-101 as a single agent was expanded to include a cohort of patients to determine the PK of AT-101 in fed and fasted states. Methods: Twelve patients (pts) were enrolled and randomized into cohorts of six pts each. Cohort A received AT-101 (80 mg) orally on day 1 on an empty stomach (fasted) and again on day 8 with a high fat high calorie breakfast (fed), per FDA guidelines. Cohort B received AT-101 on day 1 fed and on day 8 fasted. Preliminary plasma concentration time data for AT-101 from 10 patients administered 80 mg orally were evaluated using noncompartmental analysis. Log transformed peak concentration (Cmax) and exposure (AUC) were compared the between fed and fasted groups with the fasted group as the reference treatment. Results: Preliminary PK results from the first 10 pts are shown in the Table. For AUC and Cmax, the effect of food resulted in an approximately 42% and 5% increase, respectively. However the confidence intervals were not wholly outside the 80–125% intervals. Conclusions: These data indicate that food may increase AT-101 exposure in terms of AUC and Cmax. Updated results from all 12 pts will be presented at the meeting. Based on our preliminary results, it is recommended that AT-101 be taken at least an hour (or more) before or after food. [Table: see text] [Table: see text]

scholarly journals Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Shekman Wong ◽  
Cecile Marie Krejsa ◽  
Dana Lee ◽  
Anna Harris ◽  
Emilie Simard ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Small Molecule ◽  
Geometric Mean ◽  
Wild Type ◽  
High Fat ◽  
Publicly Traded ◽  
Meal Test ◽  
Median Tmax ◽  
The Past ◽  
Mdm2 Inhibitor

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

Phase I Trial and Pharmacokinetics of Gemcitabine in Children With Advanced Solid Tumors

2004 ◽  
Vol 22 (12) ◽  
pp. 2445-2451 ◽  
Author(s):  
Joel M. Reid ◽  
Wenchun Qu ◽  
Stephanie L. Safgren ◽  
Matthew M. Ames ◽  
Mark D. Krailo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase I Trial ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Time Data ◽  
Serious Adverse Events ◽  
Concentration Time ◽  
Major Toxicity ◽  
Life Values ◽  
Dose Limiting Toxicity

Purpose To determine the maximum tolerated dose, toxicity, and pharmacokinetics of gemcitabine in children with refractory solid tumors. Patients and Methods Gemcitabine was given as a 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks, to 42 patients aged 1 to 21 years. Doses of 1,000, 1,200 and 1,500 mg/m2 were administered for 3 weeks. Subsequently, gemcitabine was given for only 2 consecutive weeks at 1,500, 1,800, and 2,100 mg/m2. Plasma concentrations of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine, were measured in 28 patients. Results Forty patients who received 132 courses of gemcitabine were assessable for toxicity. The maximum tolerated dose of gemcitabine given weekly for 3 weeks was 1,200 mg/m2. Dose-limiting toxicity was not seen in one-third of children treated at any doses given for 2 weeks. The major toxicity was myelosuppression in three of five patients at 1,500 mg/m2 for 3 weeks, and one of seven patients at 1,800 mg/m2 for 2 weeks. Other serious adverse events were somnolence, fever and hypotension, and rash in three patients. Gemcitabine plasma concentration–time data were fit to a one- (n = 5) or two-compartment (n = 23) open model. Mean gemcitabine clearance and half-life values were 2,140 mL/min/m2 and 13.7 minutes, respectively. One patient with pancreatic cancer had a partial response. Seven patients had stable disease for 2 to 17 months. Conclusion Gemcitabine given by 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks was tolerated well by children at doses of 2,100 mg/m2 and 1,200 mg/m2, respectively.

scholarly journals Randomized, Double-Blind, Placebo-Controlled Studies of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eravacycline

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Joseph V. Newman ◽  
Jian Zhou ◽  
Sergey Izmailyan ◽  
Larry Tsai
Keyword(s):  
Healthy Subjects ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Aerobic And Anaerobic

ABSTRACT Eravacycline is a novel, fully synthetic fluorocycline antibiotic with in vitro activity against aerobic and anaerobic Gram-positive and Gram-negative pathogens, including multidrug-resistant (MDR) bacteria. The pharmacokinetics (PK), urinary excretion, and safety/tolerability of intravenous (i.v.) eravacycline were evaluated in single- and multiple-ascending-dose studies. Healthy subjects received single i.v. doses of 0.1 to 3 mg/kg of body weight or 10 days of treatment with 0.5 or 1.5 mg/kg every 24 h (q24h) over 30 min, 1.5 mg/kg q24h over 60 min, or 1 mg/kg q12h over 60 min. After single doses, total exposure (the area under the plasma concentration-time curve [AUC]) and the maximum plasma concentrations (Cmax) of eravacycline increased in an approximately dose-proportional manner. After multiple doses, steady state was achieved within 5 to 7 days. Accumulation ranged from approximately 7% to 38% with the q24h dosing regimens and was 45% with 1 mg/kg q12h. Eravacycline was generally well tolerated, with dose-related nausea, infusion site effects, and superficial phlebitis that were mild or moderate occurring. These results provide support for the 1-mg/kg q12h regimen used in clinical studies of eravacycline.

Population pharmacokinetics (PK) of tremelimumab in patients (pts) with melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3048-3048 ◽  
Author(s):  
D. Kang ◽  
E. Wang ◽  
D. Wang ◽  
M. Amantea ◽  
P. Hsyu
Keyword(s):  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Time Data ◽  
Time Curve ◽  
Mixed Effect ◽  
Factors Affecting ◽  
Concentration Time ◽  
Potential Factors

3048 Background: Tremelimumab is a fully human monoclonal antibody targeted against CTLA4, a protein on T cells critical for regulating T-cell activities, which is under development for treatment of various cancers, including melanoma. Population PK analysis was conducted using concentration-time data from 450 pts, most with melanoma or solid tumors, enrolled in four phase I or II studies that evaluated PK, tolerability, and efficacy of single-agent tremelimumab. Methods: Tremelimumab was administered intravenously either as single dose or multiple doses every 4 or 12 weeks; doses varied between 0.01 and 15 mg/kg. PK was determined using nonlinear mixed-effect modeling implemented in NONMEM VI. Baseline characteristics, including body weight, ECOG score, age, sex, serum creatinine, AST, ALT, and bilirubin, and formulation effects were investigated as potential factors affecting PK. Tremelimumab plasma concentrations were determined using a sensitive, specific, validated ELISA assay. Results: A two-compartment linear model adequately described tremelimumab concentration-time data; an additive residual error model was employed on log-transformed data. Initial and terminal half-lives were 2.5 days and 22 days, respectively. Estimated parameter values were: 0.0109 L/hr for CL (clearance), 3.72 L for V1 (central volume of distribution), 0.0172 L/hr for Q (intercompartment clearance), and 3.31 L for V2 (peripheral volume of distribution). Females had 29.6% smaller V2 compared with males. Both CL and central V1 increased with weight. An ECOG score of ≥1 showed 20.2% increase in CL compared with a score of 0. New commercial formulation decreased CL by 18.5%. The model-predicted area under concentration-time curve value in females was 13.3% greater than males (p=0.5). None of the other covariates tested significantly affected PK. Furthermore, tremelimumab was tolerated in most pts at all doses tested. Conclusions: PK of tremelimumab were shown to be affected by weight, baseline ECOG score, and formulation. However, no effects other than weight were considered clinically significant enough to warrant treatment regimen change. Further investigation of PK-response relationships is warranted. [Table: see text]

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