Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer

2000 ◽  
Vol 18 (4) ◽  
pp. 927-927 ◽  
Author(s):  
J. Zujewski ◽  
I.D. Horak ◽  
C.J. Bol ◽  
R. Woestenborghs ◽  
C. Bowden ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Performance Status ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Oral Drug ◽  
Total Daily Dose ◽  
Pharmacokinetic Data ◽  
Metastatic Colon Cancer ◽  
Phase Ii Trials ◽  
Farnesyl Protein Transferase

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1,000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Oblimersen (OBL; Genasense®), a Phosphorothioate (PS) Bcl-2 Antisense Oliogonucleotide (ASO), Can Be Safely Administered by Bolus Subcutaneous (SC) Injection and Brief IV Infusion.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4724-4724
Author(s):  
Anthony Tolcher ◽  
Thomas Julian ◽  
Anila Qureshi
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Complement Activation ◽  
Peak Plasma ◽  
Performance Status ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Drugs ◽  
Dose Proportional

Abstract Background: Oblimersen (OBL) is an 18-mer PS-ASO that down-regulates Bcl-2 and amplifies the activity of cytotoxic drugs in patients (pts) with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and melanoma. PS-ASOs like OBL are commonly administered by continuous intravenous infusion (CIV) in order to avoid high peak plasma concentrations that have been associated with cardiovascular collapse, complement activation, and death in primates. However, we consistently observed no such reactions in patients who received inadvertent overdoses of OBL. Furthermore, preclinical studies in xenograft tumors in mice indicated that intratumoral uptake and retention of OBL was enhanced with short IV infusion. Given the inconvenience of CIV and based on recent preclinical data, we evaluated the safety and pharmacokinetics (PK) of OBL administered as weekly subcutaneous (SC) injection, a brief 2-hr IV infusion for 5 days, and a weekly 2-hr infusion. Methods: Eligible pts had: advanced solid tumors; no available standard therapy; adequate organ function; and ECOG performance status of 0 to 2. In the SC study, single doses of 75, 150, and 225 mg were given to 8 pts, followed by a multiple dose study at 150 mg, 225 mg, and 300 mg. Pts received OBL by 2-hr IV infusion once weekly for 3 weeks (Days 1, 8, 15) starting at a dose of 300 mg and increasing in increments of 100 mg to the maximum tolerated dose (MTD). Blood samples were obtained for complement, Bcl-2, and PK analyses. Dose escalation utilized an accelerated dose escalation schedule. Results: Single pt cohorts were treated at each 2-hr dose level ranging from 300 to 800 mg. Syncope occurred in 1 pt treated with 900 mg, but treatment of 2 additional pts at this dose was uneventful. At the 1000 mg dose level, all pts experienced fever, chills, and moderate decreases in blood pressure, generally limited to the first infusion, which were not felt to be dose-limiting. The PK were dose-proportional over the 300 to 900 mg dose range. AUC and Cmax levels nearly were dose-proportional, and dose-normalized AUC and Cmax values were constant. Cmax values at 900 mg were > 50 μg/mL, and exceeded by >10-fold the Css of CIV schedules in solid tumor pts. There was no change in metabolism or plasma clearance with increasing doses. Large inter-patient variability was observed; however, intra-patient variability was low, as indicated by a coefficient of variation of < 20% for Cmax values obtained on Days 1, 8, and 15. No consistent pattern in complement activation was observed. One patient with metastatic NSCLC remains on study at 14 weeks with a 10% reduction in tumor size. OBL given by SC injection was associated with a Grade 1 erythematous rash at the injection site in all pts, which resolved within 7 days. AUC0–24 exposure at the 225-mg SC dose was similar to previously established 24-h steady-state AUCs after 3 mg/kg by CIV infusion. Conclusions: OBL AUC exposure from a single SC injection is similar to that observed using the 3mg/kg daily dose level administered by CIV to pts with CLL. OBL can also be administered safely by 2-hr IV infusion at weekly doses up to 1,000 mg. Corticosteroids are being tested to evaluate whether constitutional reactions can be ameliorated, and then a twice-per-week schedule will be designed to examine OBL-induced down-regulation of Bcl-2 alone and in combination with cytotoxic drugs in specific diseases.

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

1994 ◽  
Vol 12 (9) ◽  
pp. 1902-1909 ◽  
Author(s):  
D R Budman ◽  
L N Igwemezie ◽  
S Kaul ◽  
J Behr ◽  
S Lichtman ◽  
...  
Keyword(s):  
High Performance ◽  
Peak Plasma ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
High Dose ◽  
Maximum Plasma ◽  
Rapid Infusion ◽  
Etoposide Phosphate

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

The Clinical Pharmacokinetics of Quinapril

Angiology ◽  
1989 ◽  
Vol 40 (4_part_2) ◽  
pp. 351-359 ◽  
Author(s):  
Stephen C. Olson ◽  
Ann Marie Horvath ◽  
Barbara M. Michniewicz ◽  
Allen J. Sedman ◽  
Wayne A. Colburn ◽  
...  
Keyword(s):  
Half Life ◽  
Peak Plasma ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Clinical Pharmacokinetics ◽  
Q 61 ◽  
Dose Proportional

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose pro portional following single oral 2.5- to 80-mg Q doses. Q absorption and hy drolysis to QT is rapid with peak Q and QT concentrations occurring one and two hours postdose, respectively. Peak plasma QT concentrations were approximately fourfold higher than those of Q (923 vs 207 ng/mL follow ing 40-mg Q). Dose-proportional QT area under the curve and dose-inde pendent percent of dose excreted in urine as QT demonstrate that the ex tent of Q conversion to QT is con stant over the dose range studied. Q and QT were eliminated from plasma with apparent half-lives of 0.8 and 1.9 hours and apparent plasma clear ances of 1,850 and 220 mL/min, re spectively, over the 2.5- to 80-mg dose range. Following oral 14C-Q, 61% and 37% of radiolabel was recovered in urine and feces, respectively. Q plus QT accounted for 46% of radioactiv ity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketo piperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an admin istered dose excreted in urine as each of these metabolites. Peak plasma concentrations of these metabolites are similar to that of Q, and each is eliminated rapidly with a half-life of approximately one hour. Urinary ex cretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clear ance of both Q and QT is independ ent of dose, and metabolism to compounds other than QT is not ex tensive.

Plasma pharmacokinetics and cerebrospinal fluid concentrations of erlotinib in high-grade gliomas: A novel, phase I, dose escalation study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2054-2054 ◽  
Author(s):  
L. W. Buie ◽  
C. Lindley ◽  
T. Shih ◽  
M. Ewend ◽  
J. K. Smith ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Partial Response ◽  
Disease Progression ◽  
Dose Escalation ◽  
Stable Disease ◽  
Peak Plasma ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Plasma Concentrations ◽  
High Grade

2054 Background: Erlotinib (ERL) is an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. EGFR is overexpressed in glioblastoma multiforme (GBM). The primary objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to evaluate plasma and cerebrospinal fluid (CSF) ERL concentrations using a novel every 72 hour ERL dosing schedule. Methods: Patients = 18 years of age with GBM or high grade glioma with evidence of disease progression following first line therapy (surgery/XRT/chemotherapy) and Karnofsky performance status = 60 % were included. Patients were stratified based on use of enzyme-inducing antiepileptic drugs (EIAED). Patients not on EIAED were initiated on ERL 450 mg PO every 72h, while those on EIAED were initiated on 900 mg PO every 72 h. Results: Six patients have been enrolled and assessed for safety, 5 for plasma PK and 3 for CSF concentrations. For ERL, the area under the plasma concentration versus time curve (AUC) was greater and the half-life longer in patients not receiving EIAED. However, the AUC of OSI-420, the major metabolite of ERL, was lower in patients not receiving EIAED. The OSI-420 AUC: ERL AUC ratio was increased 3 fold among patients receiving EIAED, indicative of increased hepatic metabolism and increased clearance. CSF concentrations were detectable and ranged from 1 to 3% of peak plasma concentrations. Neither group has experienced a DLT or reached the MTD. The most common side effects (grade 1/2) have been diarrhea (83%), rash (100%) and fatigue (33%). To date, there has been 1 partial response, 1 patient with stable disease and 4 patients with disease progression. The partial response and stable disease have occurred in patients with GBM. Conclusions: ERL is a well tolerated therapy. Patient enrollment and subsequent dose escalation is ongoing and updated results will be presented at the ASCO 2007 meeting. [Table: see text] No significant financial relationships to disclose.

Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1054-1054
Author(s):  
Aditya Bardia ◽  
Hannah M. Linden ◽  
Gary A. Ulaner ◽  
Sarat Chandarlapaty ◽  
Alice Gosselin ◽  
...  
Keyword(s):  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Dose Escalation ◽  
Phase 1 ◽  
Performance Status ◽  
Dose Range ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Dose Escalation Study

1054 Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy (18FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18FES-PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average Ctrough was reached after repeated 400 mg QD allowing 90% of 18FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.

scholarly journals Pharmacokinetics of a Novel Form of Biotin, Magnesium Biotinate, in Healthy Subjects (P06-027-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sara Perez Ojalvo ◽  
Sarah Sylla ◽  
James Komorowski
Keyword(s):  
Clinical Study ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Blood Levels ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Post Dose ◽  
Funding Sources ◽  
Study Results

Abstract Objectives Biotin, also known as vitamin B7, plays an important role in the metabolization of nutrients into energy. Magnesium biotinate (MgB) is a novel biotin compound that has been shown to be 40 times more soluble than D-Biotin. Preclinical evidence has shown that MgB is well absorbed into the bloodstream and tissues, particularly the brain, over time. The following pharmacokinetic study was carried out to further explore the absorption and bioavailability of MgB. Methods In an open-label clinical study, 30 healthy female subjects (18–45 years, BMI 18.0–29.9 kg/m2) were randomized to receive a single oral capsule containing one of the following doses of MgB (n = 10 per group): 1) 10 mg MgB, 2) 40 mg MgB, 3) 100 mg MgB. Serial blood samples were collected in K2-EDTA tubes at pre-dose (within 1 hour of dose) and at 0.5, 1.0, 1.5, 3.0 and 6.0 hours post-dose. Plasma samples were analyzed for biotin by LC/MS/MS. Pharmacokinetic data were calculated for each dose group. Results Study results showed that plasma biotin levels increased at 0.5, 1.0, 1.5, 3.0 and 6.0 hours post-dose for all groups. However, the largest biotin increase was seen in the 100 mg group (Figure 1). Peak plasma concentrations were observed as follows: 84.8 ng/mL 1 hour after a 10 mg dose, 214.6 ng/mL 1.5 hours after a 40 mg dose, and 508.5 ng/mL 1.5 hours after a 100 mg dose. Area under the curve values increased with increasing biotin dose level (10 mg: 210.0 ng*h/mL; 40 mg: 605.1 ng*h/mL; 100 mg: 1652.4 ng*h/mL). No adverse effects were observed. Conclusions Results from this single-dose pharmacokinetic clinical study demonstrate that magnesium biotinate is a bioavailable form of biotin, with increasing blood levels associated with increasing dose levels. Funding Sources This study was funded by JDS Therapeutics, LLC. Supporting Tables, Images and/or Graphs

scholarly journals Overcoming CYP1A1/1A2 Mediated Induction of Metabolism by Escalating Erlotinib Dose in Current Smokers

2009 ◽  
Vol 27 (8) ◽  
pp. 1220-1226 ◽  
Author(s):  
Andrew N. Hughes ◽  
Mary E.R. O'Brien ◽  
W. Jeffrey Petty ◽  
Jonathan B. Chick ◽  
Elaine Rankin ◽  
...  
Keyword(s):  
Steady State ◽  
Group Performance ◽  
Performance Status ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Eastern Cooperative Oncology Group ◽  
Skin Toxicity ◽  
Maximum Tolerated Dose ◽  
Never Smokers ◽  
Nsclc Patients

PurposeCigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non–small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg.Patients and MethodsCohorts of NSCLC patients currently smoking ≥ 10 cigarettes per day for ≥ 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity.ResultsFour dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 μg/mL for 150 mg and 300 mg, respectively.ConclusionThe MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies

2005 ◽  
Vol 23 (18) ◽  
pp. 4152-4161 ◽  
Author(s):  
Udai Banerji ◽  
Anne O'Donnell ◽  
Michelle Scurr ◽  
Simon Pacey ◽  
Sarah Stapleton ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Clinical Activity ◽  
Phase Ii Trials ◽  
Pharmacodynamic Profile ◽  
Advanced Malignancies ◽  
Grade 3

Purpose To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials. Patients and Methods This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated. Results The highest dose level reached was 450 mg/m2/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m2/week and two at 450 mg/m2/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m2/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r2 = .71) over the dose range 10 to 450 mg/m2/week, with peak plasma concentrations of 8,998 μg/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m2/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment. Conclusion It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m2/week. We recommend this dose for phase II clinical trials.

scholarly journals Analgesic and Respiratory Depressant Effects of R-dihydroetorphine

2019 ◽  
Vol 131 (6) ◽  
pp. 1327-1339
Author(s):  
Erik Olofsen ◽  
Merel Boom ◽  
Elise Sarton ◽  
Monique van Velzen ◽  
Paul Baily ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Peak Plasma ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Noxious Stimulation ◽  
Orphanin Fq ◽  
Arterial Blood ◽  
Dose Dependent

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. Methods The authors performed a population pharmacokinetic–pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. Results R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. Conclusions Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Comparative Plasma Heparin Levels after Subcutaneous Sodium and Calcium Heparin

1978 ◽  
Vol 40 (02) ◽  
pp. 397-406 ◽  
Author(s):  
Joyce Low ◽  
J C Biggs
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Normal Subjects ◽  
Sodium Salts ◽  
Sodium Heparin ◽  
Significant Difference ◽  
Heparin Plasma ◽  
Calcium Heparin ◽  
Plasma Heparin

SummaryComparative plasma heparin levels were measured in normal subjects injected subcutaneously with 5,000 units of the sodium and calcium salts of heparin. Plasma heparin levels were measured up to 7 hr post-injection by an anti-factor Xa assay (Denson and Bonnar 1973). Preliminary studies indicated that heparin levels were reproducible in subjects who received two injections of the same heparin. Peak plasma concentrations (Cmax) and the time at which peak concentration was reached (Tmax) varied greatly from subject to subject. In one group of subjects (15) two commonly used heparins, a sodium heparin (Evans) and a calcium heparin (Choay) were compared. Peak heparin concentrations were not significantly different. However the Tmax for the sodium heparin (1.5 hr) was significantly earlier than the Tmax for the calcium heparin (3 hr) and this was not due to a difference in the volume of the two heparin injections. No significant difference could be detected in the plasma clearance rate and the molecular weight distribution of the two heparins.In two other groups of subjects, sodium and calcium preparations from two manufacturers were compared. In general, the sodium salts gave rise to significantly higher plasma concentrations, which could be interpreted as a greater bioavailability of sodium salts. These results indicate that the salt of the heparin can influence the plasma concentration achieved after subcutaneous injection.

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