Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia.

1996 ◽  
Vol 14 (5) ◽  
pp. 1504-1511 ◽  
Author(s):  
W L Furman ◽  
S D Baker ◽  
C B Pratt ◽  
G K Rivera ◽  
W E Evans ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Continuous Infusion ◽  
Severe Combined Immunodeficiency ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Complete Response ◽  
Bayesian Algorithm ◽  
Two Compartment Model ◽  
Scid Mouse Model

PURPOSE To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia. PATIENTS AND METHODS Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course. RESULTS Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted. CONCLUSION The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.

scholarly journals 2,4,6-Tribromophenol Disposition and Kinetics in Rodents: Effects of Dose, Route, Sex, and Species

2019 ◽  
Vol 169 (1) ◽  
pp. 167-179 ◽  
Author(s):  
Gabriel A Knudsen ◽  
Andrew W Trexler ◽  
Alicia C Richards ◽  
Samantha M Hall ◽  
Michael F Hughes ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Ex Vivo ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Repeated Administration ◽  
Environmental Matrices ◽  
Rat Skin ◽  
Sd Rats ◽  
Two Compartment Model

Abstract 2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%–94% in 24 h; 5% was recovered in feces; and 1%–2% in blood/tissues. TBP administered to female SD rats (0.1–1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%–27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs.

Pharmacokinetic Model-driven Infusion of Fentanyl in Children

1996 ◽  
Vol 85 (6) ◽  
pp. 1268-1275. ◽  
Author(s):  
Brian Ginsberg ◽  
Scott Howell ◽  
Peter S. A. Glass ◽  
Judith O. Margolis ◽  
Allison K. Ross ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Pediatric Population ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Context Sensitive ◽  
Model Driven ◽  
Two Compartment Model ◽  
Performance Error ◽  
Adults And Children ◽  
Residual Performance

Background This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device. Methods Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients. Results The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults. Conclusions The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.

Association of long-term exposure to circulating platinum with adverse late effects in testicular cancer survivors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4528-4528
Author(s):  
Hink Boer ◽  
Johannes H Proost ◽  
Janine Nuver ◽  
Sophie Bunskoek ◽  
Joyce Q. Gietema ◽  
...  
Keyword(s):  
Testicular Cancer ◽  
Late Effects ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Serum Samples ◽  
Time Points ◽  
Two Compartment Model ◽  
Testicular Cancer Survivors

4528 Background: Successful platinum(Pt)-based chemotherapy for testicular cancer (TC) comes at the price of late cardiovascular morbidity and neurotoxicity. Damage induced by circulating Pt could be an etiological mechanism. We investigated the relation between circulating Pt and late effects. Methods: In 96 consecutive TC patients (med age 29 [17-53] at chemotherapy), 3 serum samples and a 24h-urine sample were collected on several time-points med 5 yrs (1-13) after treatment. Pt concentrations ([Pt]) were measured with a sensitive voltammetric method (Lancet 2000, 355:1075). Measured [Pt] combined with cisplatin dose, age, weight and height were analyzed simultaneously to construct a population pharmacokinetic (PK) model using NONMEM. Based on the PK parameters of each patient, individual [Pt] at 1, 3, 5, 10 yrs after start and AUC were calculated. Cardiovascular status, paresthesia and markers of vascular damage were assessed after a med follow-up (FU) of 9 yrs (3-15). Results: Decay of [Pt] was best described by a two compartment model. Mean terminal T1/2 was 3.7 (±0.3) yrs. At all time-points [Pt] correlated with cisplatin dose and renal function during treatment. [Pt] at 3 yrs correlated with systolic blood pressure (BP) (r=.32, p<0.01) and creatinine clearance (CRCL) (r=-.25, p=0.02) at FU. Patients with increased BP had higher Pt AUCs than patients with normal BP (table). Pt AUCs were higher in patients with paresthesia (table). Conclusions: Known late effects of cisplatin-based chemotherapy such as hypertension and paresthesia are related to higher circulating [Pt]. Long-term exposure to Pt is involved in healthy tissue damage in TC survivors. [Table: see text]

Developmental population pharmacokinetics–pharmacodynamics and dosing optimization of cefoperazone in children

2020 ◽  
Vol 75 (7) ◽  
pp. 1917-1924
Author(s):  
Hai-Yan Shi ◽  
Kai Wang ◽  
Rong-Hua Wang ◽  
Yue-E Wu ◽  
Bo-Hao Tang ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Open Label ◽  
Treatment Target ◽  
Two Compartment Model ◽  
Pharmacodynamic Analysis ◽  
Dosing Optimization

Abstract Objectives To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic–pharmacodynamic approach in order to optimize cefoperazone treatment. Methods A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic–pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). Results A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with ‘40 mg/kg/day, q8h, IV drip 3 h’ would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. Conclusions For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics–pharmacodynamics. The dose indicated in the instructions (20–160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is &gt;16 mg/L, cefoperazone is not a preferred choice.

Is it Possible to Provide a Prognosis after Radical Prostatectomy for Prostate Cancer by Means of a Psa Regression Model?

2005 ◽  
Vol 20 (2) ◽  
pp. 112-118 ◽  
Author(s):  
M. May ◽  
S. Gunia ◽  
C. Helke ◽  
K.P. Braun ◽  
S. Pickenhain ◽  
...  
Keyword(s):  
Radical Prostatectomy ◽  
Computer Program ◽  
Biochemical Recurrence ◽  
Specific Antigen ◽  
Compartment Model ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Two Compartment Model

Background For over 15 years, studies have been done to evaluate the elimination kinetics of the prostate-specific antigen (PSA) after radical prostatectomy. Even though evaluation of PSA regression in the two-compartment model has become established, no clear data are currently available as to whether a statement can be made with regard to tumor prognosis from a computation of the PSA half-life (PSA-HL). This study focuses on the determination of the PSA-HL in the two-compartment model and on its correlation with the biochemical recurrence-free survival. In addition, a computer program is being developed to simplify the determination of PSA-HL. Material and methods Seventy-seven prospective patients were examined who subsequently had a radical prostatectomy at our facility without neoadjuvant or adjuvant hormone deprivation. In addition to preoperative measurement of the PSA value (d0), PSA determinations were carried out postoperatively on days 5, 10 and 60, and at four-monthly intervals thereafter (mean follow-up: 16 months). By means of the computer program developed for this purpose, CTK. TumW, the PSA half-lives for the first (d0–d5, PSA-HL1) and second (d5–d10, PSA-HL2) compartments were subsequently determined and their effect on biochemical recurrence-free survival was assessed. Results PSA-HL1 and PSA-HL2 were 1.89 (± 0.03) and 3.39 (± 0.14) days, respectively. Whilst PSA-HL1 did not permit any prognostic statement, the median PSA-HL in the second compartment between patients with and without disease progression differed significantly (4.44 versus 3.12 days; p<0.001). Discrimination analysis produced a cutoff of 3.8 days for the second compartment; patients with a PSA-HL2 ≥3.8 days had a significantly worse biochemical recurrence-free survival after 18 months than the other patients (27% versus 93%; p<0.001). Conclusion The PSA regression kinetics after radical prostatectomy follows a two-compartment model in which the prognostic value of the PSA-HL1 is limited. When a cutoff of 3.8 days is used, evaluation of the PSA-HL in compartment 2 (d5–10) appears to permit a prognostic statement. Due to the limited postsurgical follow-up, the disease process was only assessed as biochemical recurrence-free survival, and a longer follow-up will be necessary to generate data on progression-free survival.

Pulsatility does not alter the response to a physiological increment in glucagon in the conscious dog

1994 ◽  
Vol 266 (3) ◽  
pp. E467-E478 ◽  
Author(s):  
R. L. Dobbins ◽  
S. N. Davis ◽  
D. W. Neal ◽  
C. Cobelli ◽  
A. D. Cherrington
Keyword(s):  
Continuous Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Compartment Model ◽  
Time Varying ◽  
Plasma Glucagon ◽  
Glucose Kinetics ◽  
Two Compartment Model ◽  
Hepatic Glucose ◽  
Pulsatile Infusion

The present study was designed to investigate if pulsatile hyperglucagonemia of physiological magnitude has greater efficacy in stimulating hepatic glucose production than constant glucagon. Paired studies were performed in conscious dogs. After insulin and glucagon were clamped at basal concentrations for 2 h, glucagon was elevated for 4 h with either a continuous infusion or pulses having physiological frequency and amplitude. With continuous infusion, plasma glucagon concentrations increased from 56 +/- 7 to 194 +/- 27 ng/l. With pulsatile infusion, glucagon concentrations started at 53 +/- 6 ng/l and then oscillated between 157 +/- 15 and 253 +/- 28 ng/l. Plasma insulin concentrations remained constant at basal levels. Glucose production was determined using a time-varying two-compartment model for glucose kinetics and deconvolution. After 15 min, glucose production had risen from 13.6 +/- 1.1 to 53.8 +/- 3.9 mumol.kg-1.min-1 with continuous infusion and from 12.9 +/- 0.6 to 50.6 +/- 2.9 mumol.kg-1.min-1 with pulsatile infusion. After 4 h, the production had fallen to 16.1 +/- 1.2 and 17.1 +/- 0.7 mumol.kg-1.min-1. In the present animal model with insulin held constant, no difference was noted between the response to continuous or pulsatile glucagon infusion.

Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity.

1994 ◽  
Vol 12 (9) ◽  
pp. 1946-1954 ◽  
Author(s):  
C F Stewart ◽  
S D Baker ◽  
R L Heideman ◽  
D Jones ◽  
W R Crom ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
High Performance ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Maximum Effect ◽  
Hematologic Toxicity ◽  
Time Curve ◽  
Steady State Plasma Concentration ◽  
Plasma And Urine Samples

PURPOSE Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18). METHODS Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model. RESULTS Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity. CONCLUSION These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.

Evaluation of R-CHOP and R-CVP in the treatment of elderly patient with non-Hodgkin lymphoma

MedPharmRes ◽  
2019 ◽  
Vol 3 (3) ◽  
pp. 1-6
Author(s):  
Truc Phan ◽  
Tram Huynh ◽  
Tuan Q. Tran ◽  
Dung Co ◽  
Khoi M. Tran
Keyword(s):  
Elderly Patients ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
The Elderly ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Common Sign ◽  
Related Mortality

Introduction: Little information is available on the outcomes of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) and R-CVP (rituximab with cyclophosphamide, vincristine and prednisone) in treatment of the elderly patients with non-Hodgkin lymphoma (NHL), especially in Vietnam. Material and methods: All patients were newly diagnosed with CD20-positive non-Hodgkin lymphoma (NHL) at Blood Transfusion and Hematology Hospital, Ho Chi Minh city (BTH) between 01/2013 and 01/2018 who were age 60 years or older at diagnosis. A retrospective analysis of these patients was perfomed. Results: Twenty-one Vietnamese patients (6 males and 15 females) were identified and the median age was 68.9 (range 60-80). Most of patients have comorbidities and intermediate-risk. The most common sign was lymphadenopathy (over 95%). The proportion of diffuse large B cell lymphoma (DLBCL) was highest (71%). The percentage of patients reaching complete response (CR) after six cycle of chemotherapy was 76.2%. The median follow-up was 26 months, event-free survival (EFS) was 60% and overall survival (OS) was 75%. Adverse effects of rituximab were unremarkable, treatment-related mortality accounted for less than 10%. There was no difference in drug toxicity between two regimens. Conclusions: R-CHOP, R-CVP yielded a good result and acceptable toxicity in treatment of elderly patients with non-Hodgkin lymphoma. In patients with known cardiac history, omission of anthracyclines is reasonable and R-CVP provides a competitive complete response rate.

THYROID TYPE CARCINOMA ARISING IN STRUMA OVARII. SIX CLINICAL CASES AND REVIEW

2018 ◽  
Vol 64 (6) ◽  
pp. 708-715
Author(s):  
Natalya Severskaya ◽  
Andrey Rodichev ◽  
Aleksey Ilin ◽  
Dmitriy Semin ◽  
Pavel Isaev ◽  
...  
Keyword(s):  
Radioiodine Therapy ◽  
Clinical Course ◽  
Case Reports ◽  
Thyroid Tissue ◽  
Follicular Carcinoma ◽  
Complete Response ◽  
Pelvic Surgery ◽  
Ovarian Teratoma ◽  
Struma Ovarii

Struma ovarii is a rare variant of the mature ovarian teratoma composed of more than 50% thyroid tissue. Thyroid type carcinoma can occur in 5% of struma ovarii. Given the rarity of this pathology, as well as the different clinical course, approaches to the treatment of this disease are controversial. The proposed approaches to treatment vary from ovarian resection to total hysterectomy with bilateral salpingo-oophorectomy and adjuvant therapy. We present here 6 case reports of thyroid type carcinoma in struma ovarii and outcome of patients treated in our clinic. All patients had pelvic surgery of different extent, followed by thyroidectomy and radioiodine therapy. The incidence of metastasis is 67% (4/6), 2 - intraperitoneal metas-tases, 2 - bone metastases. Among patients with metastases, 2 have reached a complete response, one with a good response continues treatment, one had progression. The follow-up period is 1 to 15 years (median 4 years). One patient with follicular carcinoma died of progression 8 years after diagnosis. The remaining patients are alive.

scholarly journals Post-Neoadjuvant Surveillance and Surgery as Needed Compared with Post-Neoadjuvant Surgery on Principle in Multimodal Treatment for Esophageal Cancer: A Scoping Review

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 429
Author(s):  
Julian Hipp ◽  
Blin Nagavci ◽  
Claudia Schmoor ◽  
Joerg Meerpohl ◽  
Jens Hoeppner ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Local Recurrence ◽  
Scoping Review ◽  
Multimodal Treatment ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Diagnostic Methods ◽  
Cochrane Library ◽  
Randomized Controlled

Background: A substantial fraction of patients with esophageal cancer show post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients, although surveillance and surgery as needed in case of local recurrence may be a treatment alternative for patients with complete response (CR). Methods: We performed a scoping review to describe key characteristics of relevant clinical studies including adults with non-metastatic esophageal cancer receiving multimodal treatment. Until September 2020, relevant studies were identified through systematic searches in the bibliographic databases Medline, Web of Science, Cochrane Library, Science Direct, ClinicalTrials, the German study register, and the WHO registry platform. Results: In total, three completed randomized controlled trials (RCTs, with 468 participants), three planned/ongoing RCTs (with a planned sample size of 752 participants), one non-randomized controlled study (NRS, with 53 participants), ten retrospective cohort studies (with 2228 participants), and one survey on patients’ preferences (with 100 participants) were identified. All studies applied neoadjuvant chemoradiation protocols. None of the studies examined neoadjuvant chemotherapeutic protocols. Studies investigated patient populations with esophageal squamous cell carcinoma, adenocarcinoma, and mixed cohorts. Important outcomes reported were overall, disease-free and local recurrence-free survival. Limitations of the currently available study pool include heterogeneous chemoradiation protocols, a lack of modern neoadjuvant treatment protocols in RCTs, short follow-up times, the use of heterogeneous diagnostic methods, and different definitions of clinical CR. Conclusion: Although post-neoadjuvant surveillance and surgery as needed compared with post-neoadjuvant surgery on principle has been investigated within different study designs, the currently available results are based on a wide variation of diagnostic tools to identify patients with pCR, short follow-up times, small sample sizes, and variations in therapeutic procedures. A thoroughly planned RCT considering the limitations in the currently available literature will be of great importance to provide patients with CR with the best and less harmful treatment.

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