Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Co-administered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults

Despite repeated malaria infection, individuals living in malaria endemic areas remain vulnerable to re-infection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with anti-malarial therapy. This randomized, single-blind, placebo-controlled, single center phase 1 trial investigated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants aged 18–55 years were randomized to either ruxolitinib (20 mg) ( n = 6) or placebo ( n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for three days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether) and lumefantrine exposure were not affected by ruxolitinib co-administration. Ruxolitinib co-administration resulted in a 3-fold greater pSTAT3 inhibition compared to placebo (geometric mean ratio: 3.01 [90%CI 2.14, 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634).

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1335. Safety and Pharmacokinetic Profile of PC786, a Novel Inhibitor of Respiratory Syncytial Virus L-protein Polymerase, in a Single and Multiple-Ascending Dose Study in Healthy Volunteer and Mild Asthmatics

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1167 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S407-S408

Author(s):

Lindsey Cass ◽

Amanda Davis ◽

Alison Murray ◽

Kathy Woodward ◽

Kazuhiro Ito ◽

...

Keyword(s):

Half Life ◽

Board Member ◽

Phase 1 ◽

Geometric Mean ◽

Plasma Concentrations ◽

Systemic Exposure ◽

Preclinical Studies ◽

Laboratory Findings ◽

L Protein ◽

Syncytial Virus

Abstract Background RSV is the most common cause of bronchiolitis in infants and is responsible for severe respiratory infections in the elderly and immunocompromised populations. RSV replicates in the columnar epithelial cells of the proximal and distal airways which are accessible to inhaled therapies. PC786 is a potent non-nucleoside RSV L-protein polymerase inhibitor designed for inhaled delivery. In preclinical studies, PC786 exhibits prolonged lung tissue residence with minimal systemic exposure, thus limiting the potential for adverse systemic effects. Methods A phase 1 study was conducted to evaluate the safety and pharmacokinetics of PC786 delivered in a suspension formulation by nebulizer (PARI LC SPRINT® device). Healthy volunteers (HVs) received placebo or PC786 as single ascending doses (0.5–20 mg, Cohort (C) 1), 5 mg BD for 7 days (C2), or 10 mg BD for 7 days (C3). Mild asthmatics received a single dose of PC786 5 mg or placebo (C4). PC786 PK was measured in plasma and in nasal mucosal lining fluid (MLF) collected using a synthetic absorptive matrix. Results PC786 was well tolerated, with no significant adverse clinical nor laboratory findings. Following single inhaled doses PC786 appeared rapidly in the plasma; mean plasma Cmax of 190, 571, 1,760, and 3,270 pg/mL, for the 0.5, 2, 8, and 20 mg doses, respectively, were measured on average at 0.68 to 0.93 hours (Tmax) post-inhalation. Following administration of 5 mg BD (C2) the extent of accumulation was approximately 2-fold. The geometric mean apparent terminal half-life measured following 10 mg BD (C3) was 97 hours. The ratio of MLF:plasma concentrations ranged from 6,347 (+2 hours) to 1,050 (+24h). Conclusion PC786 was well tolerated by HVs and asthmatics. The compound showed a rapid Tmax, suggesting rapid exposure of the respiratory epithelium. The PC786 concentrations in MLF exceed the IC90 for RSV, but circulating plasma concentrations were low. The MLF:plasma measured in this study was consistent with lung:plasma ratios measured in preclinical studies. The long plasma half-life is consistent with slow absorption from the lung being the dominant process controlling systemic kinetic behavior. The long t½ and 2-fold accumulation ratio observed on repeat dosing supports once daily dosing in subsequent studies. Disclosures L. Cass, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Davis, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Murray, Pulmocide Ltd.: Employee and Shareholder, Salary. K. Woodward, Pulmocide Ltd.: Consultant, Consulting fee. K. Ito, Pulmocide Ltd.: Employee and Shareholder, Salary. P. Strong, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary. G. Rapeport, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary.

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Pharmacokinetic Results from a Phase 1 Study of a Multi-Targeted Tyrosine Kinase Inhibitor, ABT-869, in Patients with Refractory or Relapsed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v112.11.4008.4008 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4008-4008

Author(s):

Wendy Stock ◽

Karen WL Yee ◽

Eunice S. Wang ◽

Sari Enschede ◽

Joyce Steinberg ◽

...

Keyword(s):

Confidence Interval ◽

Tyrosine Kinase ◽

Dose Escalation ◽

Safety Profile ◽

Phase 1 ◽

Geometric Mean ◽

Myelogenous Leukemia ◽

Vegf Receptor ◽

Geometric Mean Ratio ◽

Phase 1 Study

Abstract ABT-869 is an orally bioavailable, potent and specific inhibitor of multiple receptor tyrosine kinases (RTKs) including vascular endothelial and platelet growth factor, FLT3, STAT5, and ERK receptors. Since multiple RTKs, particularly FLT3, are commonly expressed and activated in AML/MDS, ABT-869 may prove to be an attractive therapeutic option. The current multi-center, two arm, dose-escalation study was designed to assess the safety, pharmacodynamics, pharmacokinetics (PK) and preliminary anti-tumor activity of ABT-869 as monotherapy in arm A, and to determine the PK, safety profile and potential of a PK or PD mediated drug interaction in patients with AML or MDS treated with ABT-869 plus Cytosine arabinoside (Ara-C) in arm B. No dose was administered on D7 (arm A) and D12 (arm B). In single-agent Arm A enrollment is complete (N=29) with 9, 4, 12 and 4 patients enrolled in each of the 10, 12.5, 15, and 20 mg cohorts, respectively. Dosing began with the 10 mg/day cohort and escalated to the 20 mg/day cohort to define a recommended phase 2 dose (RP2D) of 15 mg. During dose escalation, in the 10 mg cohort, 2 patients experienced DLTs of fatigue while in the 20 mg cohort, 3 patients experienced DLTs of fatigue and 1 patient experienced a DLT of proteinuria. In currently enrolling arm B (N=17), ABT-869 was administered in combination with Ara-C. ABT-869 was initiated on day 6 following administration of Ara-C at 1.5 mg/m2 on days 1–3 (patients ≥64 years old) or days 1–4 (patients <64 years old); dosing began at 10 mg and escalated to 12.5 mg. In arm B, 2 patients on the 12.5 mg cohort experienced DLTs, one of gr 3 fatigue and one of gr 3 proteinuria, leading to selection of an RP2D of 10 mg. In arm A, the average effective half-life for ABT-869 ranged from 11.7–13.5 h, and the average CL ranged from 4.9–6.6 L/h. The dose-normalized (DN) Cmax were similar between arm A (N=27) and arm B (N=9) at 0.016 ± 0.007 (mean ± SD) and 0.014 ± 0.004 (μg/mL/mg), respectively. The DN Cmax geometric mean ratio of arm B vs. A was 0.938 (90% confidence interval 0.71 – 1.24). DN AUC24 was different between arm A and arm B (0.21 ± 0.10 vs. 0.10 ± 0.04 μg*hr/mL/mg, respectively). The DN AUC24 geometric mean ratio of arm B vs. A was 0.494 (90% confidence interval 0.36–0.68). The DLTs observed in this study were consistent with VEGF receptor tyrosine kinase inhibition including fatigue and proteinuria as seen in both arms A and B. The most common adverse events across all grades (majority being grade 1/2) as reported from the available arm A data were diarrhea, fatigue, dry mouth, nausea, vomiting, asthenia, anorexia, and decreased appetite. In addition, grade 3 events observed were; asthenia (12%), fatigue (6%), febrile neutropenia (6%) and pancytopenia (6%). The latter two events are reflective of the pancytopenia present at the time of study enrollment. ABT-869 has an acceptable safety profile. Preliminary results from this ongoing phase 1 study demonstrate that in arm A the PK of ABT-869 are dose proportional over the 10–20 mg dose range. Differences in ABT- 869 AUC between arm A and arm B are being further investigated and will be correlated with pharmacodynamic endpoints.

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Phase 1 study of atrasentan (ABT627), novel endothelin receptor-A antagonist, in Japanese patients with hormone refractory prostate cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14602 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14602-14602

Author(s):

Y. Fujisaka ◽

Y. Fujiwara ◽

K. Yamada ◽

T. Shimizu ◽

A. Horiike ◽

...

Keyword(s):

Prostate Cancer ◽

Adverse Events ◽

Half Life ◽

Phase 1 ◽

Plasma Concentrations ◽

Study Drug ◽

Japanese Patients ◽

Maximum Plasma ◽

Hormone Refractory Prostate Cancer ◽

Hormone Refractory

14602 Background: Endothelin (ET)-1 and its primary receptor, the ETA receptor, contribute to tumor cell growth, survival, angiogenesis and invasion. Atrasentan is a highly potent, selective ETA receptor antagonist. This study assessed safety and pharmacokinetics (PK) in Japanese patients with hormone refractory prostate cancer. Methods: This open-label, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5, 10 or 20 mg) given daily on day 1 and day 4 through 27 (except day 2 and 3). Dose-limiting toxicity (DLT) was defined as Grade 3 or greater adverse events related to study drug. Results: Eighteen patients, aged 54–74 (median; 66) were treated in cohorts of 6 patients each. The compliance of all patients was 100%. The most common toxicities were rhinitis, peripheral edema, headache, hypotension and anemia, all of which were well tolerated. These events were consistent with the anticipated vasodilatory effects or with a hemodilution effect of the study drug. DLTs were not observed. Atrasentan was rapidly absorbed following oral administration of 2.5 to 20 mg, maximum plasma concentrations averaged from 0.4 to 0.8 hours. After peaking, plasma concentrations declined bi-exponentially with a terminal half-life of approximately 25 hours. In the 10 mg dosing group, the steady-state maximum plasma concentration (Cmax) and the area under the curve (AUC0–24h) averaged 135.5 ng/mL and 533 ng h/mL, respectively. The Cmax and AUC values generally increased linearly with increasing dose after single- and multiple-dose administration. Compared to baseline, PSA decreased 50% or more in 1 patient (20 mg) and increased 25% or more in 10 patients (2.5 mg;2, 10 mg;5, 20 mg;3). The PSA of the remaining 7 patients (2.5 mg;4, 10 mg;1, 20 mg;2) ranged from < 25% increase to < 50% decrease. Fourteen patients continued on study drug in an extension study. Conclusions: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 20 mg in Japanese patients. The main adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing. No significant financial relationships to disclose.

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Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2617 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2617-2617

Author(s):

Todd Michael Bauer ◽

Jeffrey R. Infante ◽

Ramesh K. Ramanathan ◽

Glen Weiss ◽

Jasgit C. Sachdev ◽

...

Keyword(s):

Adverse Events ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Plasma Concentrations ◽

Hsp90 Inhibitor ◽

Low Grade ◽

Advanced Solid Tumors ◽

Two Phase ◽

Blurry Vision

2617 Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX-2112 and SNX-5422. Methods: Two phase 1, open-label, 3 + 3 dose-escalation studies evaluated SNX-5422 when given daily (QD) or every-other-day (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.

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A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Relapsed/Refractory Multiple Myeloma Patients

Blood ◽

10.1182/blood-2018-99-119274 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1988-1988

Author(s):

James R Berenson ◽

To Jennifer ◽

Tanya M. Spektor ◽

Carley Turner ◽

Regina Swift ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Gastrointestinal Bleeding ◽

Macrophage Polarization ◽

Phase 1 ◽

Janus Kinase ◽

M2 Macrophage ◽

Inadequate Response ◽

Phase 1 Trial ◽

Grade 3

Abstract Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with expansion once a MTD was determined. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results Thirty-four patients have been enrolled, and 31 were evaluable for response as of July 13, 2018. The median age was 68 years (range, 49-81), and 20 (59%) were male. Patients received a median of 6 prior treatments including lenalidomide and a PI. No DLTs occurred, and DL+3 was expanded (n=25). Among all 31 evaluable patients, the CBR and ORR were 48% and 39%, respectively (1 CR, 9 PR, 2 VGPR, and 3 MR), and 11 and 5 showed SD and PD, respectively. Notably, all 15 patients achieving ≥ MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 7.4 months. Grade 3/4 adverse events included transient thrombocytopenia (11.1%), anemia (8.8%), neutropenia (6.7%), hypoxia (4.4%) and gastrointestinal bleeding (4.4%). Common serious adverse events included abdominal pain (6.7%), gastrointestinal bleeding (6.7%) and hypoxia (6.7 %). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to other clinical trials using immunomodulatory agents, steroids and RUX, for treating RRMM patients, and this may represent a new therapeutic approach for these patients. Disclosures Berenson: BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Daiichi: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

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Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase 1, randomized, blinded, placebo-controlled trial

10.1101/2020.03.12.20034983 ◽

2020 ◽

Author(s):

Anne Camille La Flamme ◽

David Abernethy ◽

Dalice Sim ◽

Liz Goode ◽

Michelle Lockhart ◽

...

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Controlled Trial ◽

Phase 1 ◽

Progressive Multiple Sclerosis ◽

Ataxic Gait ◽

Serious Adverse Events ◽

Titration Period ◽

Pharmacodynamic Profile ◽

Increased Sensitivity

ABSTRACTObjectiveBecause clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the CRISP trial was conducted to determine whether clozapine and risperidone are suitable for progressive multiple sclerosis (pMS).MethodsThe CRISP trial (ACTRN12616000178448) was a blinded, randomized, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomized to clozapine (100 to 150 mg/day), risperidone (2 to 3.5 mg/day), or placebo for six months. The primary outcome measures were safety (adverse events/serious adverse events) and acceptability (TSQM-9).ResultsAn interim analysis (n=9) revealed significant differences in the time-on-trial between treatment groups and placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day). Participants receiving clozapine or risperidone reported a significantly higher rate of adverse events than placebo (p=0.00001) but not serious adverse events. Specifically, low doses of clozapine appeared to cause an acute and dose-related intoxicant effect in patients with pMS, who had fairly severe chronic spastic ataxic gait and worsening over all mobility, which resolved on drug cessation.InterpretationThe CRISP trial results suggest that pMS patients may experience increased sensitivity to clozapine and risperidone and indicate that the dose and/or titration schedule developed for schizophrenia may not be suitable for pMS. While these findings do not negate the potential of these drugs to reduce MS-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in pMS patients.

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Phase 1 Safety and Immunogenicity Study of a Respiratory Syncytial Virus Vaccine With an Adenovirus 26 Vector Encoding Prefusion F (Ad26.RSV.preF) in Adults Aged ≥60 Years

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa193 ◽

2020 ◽

Vol 222 (6) ◽

pp. 979-988 ◽

Cited By ~ 6

Author(s):

Kristi Williams ◽

Arangassery Rosemary Bastian ◽

Robert Allen Feldman ◽

Edmund Omoruyi ◽

Els de Paepe ◽

...

Keyword(s):

Older Adults ◽

Respiratory Syncytial Virus ◽

Adverse Events ◽

Immune Responses ◽

Phase 1 ◽

Geometric Mean ◽

High Dose ◽

Serious Adverse Events ◽

Syncytial Virus ◽

Vector Particles

Abstract Background Despite the high disease burden of respiratory syncytial virus (RSV) in older adults, there is no approved vaccine. We evaluated the experimental RSV vaccine, Ad26.RSV.preF, a replication-incompetent adenovirus 26 vector encoding the F protein stabilized in prefusion conformation. Methods This phase 1 clinical trial was performed in healthy adults aged ≥60 years. Seventy-two participants received 1 or 2 intramuscular injections of low-dose (LD; 5 × 1010 vector particles) or high-dose (HD; 1 × 1011 vector particles) Ad26.RSV.preF vaccine or placebo, with approximately 12 months between doses and 2-year follow-up for safety and immunogenicity outcomes. Results Solicited adverse events were reported by 44% of vaccine recipients and were transient and mild or moderate in intensity. No serious adverse events were related to vaccination. After the first vaccination, geometric mean titers for RSV-A2 neutralization increased from baseline (432 for LD and 512 for HD vaccine) to day 29 (1031 for LD and 1617 for HD). Pre-F–specific antibody geometric mean titers and median frequencies of F-specific interferon γ–secreting T cells also increased substantially from baseline. These immune responses were still maintained above baseline levels 2 years after immunization and could be boosted with a second immunization at 1 year. Conclusions Ad26.RSV.preF (LD and HD) had an acceptable safety profile and elicited sustained humoral and cellular immune responses after a single immunization in older adults.

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Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.3.532 ◽

1994 ◽

Vol 12 (3) ◽

pp. 532-538 ◽

Cited By ~ 84

Author(s):

D S Sonnichsen ◽

C A Hurwitz ◽

C B Pratt ◽

J J Shuster ◽

M V Relling

Keyword(s):

Solid Tumors ◽

High Performance ◽

Phase 1 ◽

Plasma Concentrations ◽

Systemic Exposure ◽

Compartment Model ◽

Data Sets ◽

Pharmacokinetics And Pharmacodynamics ◽

Time Curve ◽

Elimination Clearance

PURPOSE Our aim was to evaluate the pharmacokinetics and pharmacodynamics of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in children, and to determine whether paclitaxel exhibited saturable pharmacokinetics. PATIENTS AND METHODS We evaluated the pharmacokinetics and pharmacodynamics of paclitaxel (200 to 420 mg/m2) administered as a 24-hour intravenous (i.v.) infusion in a phase 1 study of 30 pediatric patients (age, 2.3 to 22.8 years) with refractory solid tumors. Fourteen serial blood samples were obtained during and up to 48 hours after the infusion, and paclitaxel concentrations were measured by a high-performance liquid chromatography-UV (HPLC-UV) method. Four pharmacokinetic models were compared for their ability to describe the patients' data. RESULTS Paclitaxel disposition was not consistent with a first-order, two-compartment pharmacokinetic model. Rather, the majority of data sets were best described by a two-compartment model that incorporated both saturable tissue distribution and saturable elimination; a smaller number of patient data sets were best described by models that incorporated either saturable distribution or saturable elimination. Clearance was dose-dependent, with a median clearance at the lower dosages (< 400 mg/m2) of 161 mL/min/m2, and at the highest dosages (> 400 mg/m2) of 123 mL/min/m2 (P = .044). The duration that paclitaxel plasma concentrations exceeded 0.1 mumol/L was highly variable (range, 26 to 71 hours). There was a trend toward higher median area under the concentration-versus-time curve (AUC) in those children with musculoskeletal (72 mumol/L.h; P = .054) or neurologic toxicity (54 mumol/L.h; P = .062) versus those without toxicity (30 mumol/L.h). Toxicity was not significantly correlated with dosage. CONCLUSION We conclude that paclitaxel distribution and elimination are saturable, and that estimates of paclitaxel systemic exposure correlate better with toxicity than does dosage.

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Dasatinib Can Be Administered Orally with or without a Meal.

Blood ◽

10.1182/blood.v110.11.4569.4569 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4569-4569 ◽

Cited By ~ 2

Author(s):

Sanjeev Kaul ◽

Chiyuan Wu ◽

Shelley Mayfield ◽

James Manning ◽

Anne Blackwood-Chirchir

Keyword(s):

Adverse Events ◽

Healthy Adult ◽

Geometric Mean ◽

Plasma Concentrations ◽

Mass Spectrometric Method ◽

High Fat ◽

Low Fat ◽

Fasted State ◽

Tandem Mass Spectrometric ◽

Fat Meal

Abstract Background: Food can change the bioavailability of a drug, which can have clinically significant consequences. This study was conducted to investigate the effect of food on the oral bioavailability of dasatinib (SPRYCEL®) in healthy adult subjects. Methods: Fifty-four healthy adult subjects received a single dose of dasatinib 100 mg dose, as 2 x 50 mg film-coated tablets after an overnight fast and within 10 minutes after the ingestion of a low-fat meal (315 kcal [20% fat, 68% carbohydrates, and 12% protein]) and a high-fat meal (985 kcal [52% fat, 34% carbohydrates, and 14% protein]) in a randomly assigned sequence. Individual treatments were separated by at least a 7-day washout period. Serial blood samples were collected for 24 hours after each treatment to determine dasatinib plasma concentrations using a validated liquid chromatography/tandem mass spectrometric method. Dasatinib pharmacokinetic (PK) parameters were determined using a non-compartmental method. Safety was monitored throughout the study. Results: Of the 54 healthy adult subjects (85% male, 61% Caucasian, mean age 32 y, and weight 80 kg), 48 completed the study. There were no serious adverse events. Adverse events and laboratory abnormalities were, in general, typical of those seen with dasatinib administration. PK results are summarized in the table below. Conclusions: Compared to the fasted state, a low-fat meal decreased Cmax and AUC of dasatinib by 21%; a high-fat meal decreased Cmax by 24% and increased AUC by 14%. These results are not expected to be of clinical relevance and, therefore, dasatinib may be taken without regard to meals. The drug was generally safe and well-tolerated when administered in the fed or fasted state. Statistical Analysis of PK Parameters for Dasatinib Treatment PK Parameter Geometric Mean Ratios (95% Confidence Intervals) Fed versus Fasted Low-Fat Meal Cmax 1.216 (1.047, 1.413) AUC 1.212 (1.100, 1.336) High-Fat Meal Cmax 0.758 (0.651, 0.882) AUC 1.140 (1.034, 1.257)

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Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00717-19 ◽

2019 ◽

Vol 63 (9) ◽

Cited By ~ 4

Author(s):

Nadine G. Rouphael ◽

Selwyn J. Hurwitz ◽

Mari Hart ◽

Allison Beck ◽

Evan J. Anderson ◽

...

Keyword(s):

Adverse Events ◽

Clinical Laboratory ◽

Subcutaneous Tissue ◽

Phase 1 ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Plasma Exposure ◽

Serious Adverse Events ◽

Double Blind ◽

Time Curve

ABSTRACT Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

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