Pharmacokinetic (PK) and Pharmacodynamics (PD) Study of Two Doses of Bortezomib (Btz) in Patients with Relapsed Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3533-3533 ◽  
Author(s):  
A. Keith Stewart ◽  
Dan Sullivan ◽  
Sagar Lonial ◽  
Ann F. Mohrbacher ◽  
Gurkamal Chatta ◽  
...  
Keyword(s):  
Whole Blood ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Proteasome Inhibition ◽  
Volume Of Distribution ◽  
20S Proteasome ◽  
Multiple Time ◽  
Phase 2 ◽  
Pivotal Phase ◽  
Multiple Time Points

Abstract Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of btz at 2 doses (1.0, 1.3mg/m2) after single- and multiple-dose administration, and evaluated their relationship. 24 pts with relapsed MM and creatinine clearance ≥50mL/min were randomized to btz 1.0 (n=12) or 1.3mg/m2 (n=12) on D 1, 4, 8 and 11 of a 21-D cycle (C). Pts could continue therapy for ≥8 Cs if beneficial. PK/PD samples were drawn at multiple time points on D1 and D11 of C1 and C3 over 48h. Plasma concentrations of btz were similar following administration of 1.0 and 1.3mg/m2; differences in mean plasma Cmax and AUC values were within the degree of intersubject variability (Table). There was a decrease in clearance and an increase in terminal half-life of btz on D11 vs D1 of C1.The volume of distribution of btz suggests extensive peripheral tissue distribution. After single or repeat administration, mean maximum percent inhibition of 20S proteasome activity (vs baseline) in whole blood was 70–84% and 73–83% for the 1.0 and 1.3mg/m2 doses, respectively. The percentage of pts who had >90% inhibition was greater in subsequent doses vs first dose. Reversibility of 20S proteasome inhibition in whole blood was demonstrated. PK/PD modeling revealed an exposure-response relationship, with Emax and EC50 values consistent across study days. These results confirm btz is a potent inhibitor of the 20S proteasome. The efficacy of single-agent btz has been explored and validated in the pivotal phase 2 SUMMIT and phase 3 APEX trials at 1.3mg/m2, and explored in the phase 2 CREST trial at 1.0mg/m2. Complete safety and efficacy data by dose will be presented. Mean±SD PK parameters of btz in plasma 1.0mg/m2 1.3mg/m2 1.0mg/m2 1.3mg/m2 D1/C1 (n=11) D11/C1 (n=12) an=5;bn=11;cn=10;dn=7;en=11;fn=9 Tmax (h) 0.13±0.13 0.11±0.06 0.07±0.03 0.20±0.29 Cmax (ng/mL) 56.7±36.3 112±122 106.2±46.7 88.6±47.6 AUC48h(ng·h/mL) 26.5±12.4 34.6±19.8 82.8±35.9b 82.4±28.6b AUClast (ng·h/mL) 22.6±12.6 31.5±18.6 137±106 122.2±67.4 CL (L/h) 102.1±48.1 111.6±73.6 23.2±17.8 28.0±19.8 Vβ (L) 1976±2498a 2015±2974d 1659±752c 2415±1711 t1/2λz(h) 30.7±44.8a 11.5±12.7d 78.9±50.9c 75.6±49.9 D1/C3 (n=12) D11/C3 (n=12) Tmax (h) 0.12±0.12 0.10±0.05 0.16±0.17 0.10±0.05 Cmax (ng/mL) 66.5±42.6 120.3±70.7 83.9±69.3 114.9±98.3 AUC48h(ng·h/mL) 66.4±24.1 79.4±24.5b 101.6±58.2b 85.2±18.7f AUClast (ng·h/mL) 74.8±35.8 86.0±27.6 227±181 160.7±67.1 CL (L/h) 32.2±19.0 32.1±15.4 15.1±13.9 18.2±9.2 Vβ (L) 1852±951d 2059±1231 3294±2993e 2505±1641 t1/2λz (h) 39.9±14.4d 49.1±34.6 193±169e 108.6±64.8

Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3024-3024 ◽  
Author(s):  
Kyriakos Papadopoulos ◽  
David Samuel diCapua Siegel ◽  
Seema B. Singhal ◽  
Jeffrey R. Infante ◽  
Edward A. Sausville ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Response Assessment ◽  
Phase 2 ◽  
Peripheral Blood Mononuclear ◽  
Phase 1B

Abstract Abstract 3024 Background: Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters. Methods: This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts). Results: To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table. Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity. Conclusions: In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial. Disclosures: Papadopoulos: Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.

Phase I trial of bortezomib in adults with recurrent malignant glioma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1567-1567 ◽  
Author(s):  
S. Phuphanich ◽  
J. Supko ◽  
K. A. Carson ◽  
S. A. Grossman ◽  
L. B. Nabors ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Malignant Glioma ◽  
Dose Level ◽  
Whole Blood ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
20S Proteasome ◽  
Weekly Dose ◽  
Recurrent Malignant Glioma ◽  
Grade 3

1567 Background: Bortezomib is a selective inhibitor of the proteasome that has been approved for the treatment of multiple myeloma and has also shown promising evidence of clinical activity against solid tumors. This study was undertaken to determine the maximum tolerated dose (MTD), toxicity profile, and biologic activity of bortezomib for the treatment of recurrent malignant glioma (MG). Methods: Eligible patients (pts) had supratentorial progressive MG upon radiotherapy and ≤ 1 prior regimen of chemotherapy. Dose escalation was conducted separately for pts taking enzyme inducing antiseizure drugs (EIASD+) and for those not (EIASD-). Bortezomib was given by bolus iv injection on weeks 1 and 2 of each 3 week cycle of therapy. The starting dose in both groups was 0.9 mg/m2. Cohorts of at least 3 patients were evaluated at each dose level. 20S proteasome activity was determined in whole blood lysates before and at 1 and 24 h after the first dose. Results: Fifty-nine evaluable pts (41 male/18 female) with a median age of 51 years and median KPS of 90% have been enrolled. All but 2 pts had received 1 prior chemotherapy regimen. In the EIASD- group, the weekly dose was escalated from 0.9 to 1.9 mg/m2 through 3 intermediate dose levels, with 1.7 mg/m2 established as the MTD. DLT experienced by 2 of 6 pts in the 1.90 mg/m2 dose level were grade 3 thrombocytopenia and grade 3 fatigue plus neurosensory toxicities. In the EIASD+ group, the dose has been escalated to 2.3 mg/m2 without the occurrence of any DLT. Ten additional EIASD- pts were treated at 1.7 mg/m2, with the most common adverse events being thrombocytopenia and peripheral neuropathy. The extent of proteasome inhibition in whole blood increased in a dose-dependent manner in both treatment groups. Mean proteasome inhibition in EIASD+ pts 1 h after receiving 2.1 mg/m2 of bortezomib (77 ± 12%) was similar to the 1.7 mg/m2 dose in EIASD- pts (79 ± 6%). Conclusions: The MTD for the weekly x 2 schedule of bortezomib in EIASD- patients, 1.7 mg/m2, is higher than the approved dose of 1.3 mg/m2 for the treatment of multiple myeloma. The enhanced tolerability of the drug when given together with EIASDs, for which the MTD is at least 2.1 mg/m2, is consistent with the diminished inhibition of 20S proteasome activity in these pts. No significant financial relationships to disclose.

Pharmacodynamics and pharmacokinetics of AUY922 in a phase I study of solid tumor patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3533-3533
Author(s):  
S. Ide ◽  
M. Motwani ◽  
M. R. Jensen ◽  
J. Wang ◽  
N. Huseinovic ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phase I ◽  
Single Agent ◽  
Xenograft Model ◽  
Heat Shock Protein 90 ◽  
Post Treatment ◽  
Multiple Time ◽  
Heat Shock Factor 1 ◽  
Multiple Time Points ◽  
Hsp70 Induction

3533 Background: AUY922 is a synthetic inhibitor of Heat Shock Protein 90. Disruption of the HSP90 chaperone hetero- complex results in the loss of repression of heat shock factor-1 (HSF1), and subsequent induction of HSP70. We evaluated HSP70 as a pharmacodynamic (PD) marker of AUY922 activity in a phase I/II clinical trial in patients (pts) with solid tumors. Methods: Single agent AUY922 was administered by IV infusion once a week to pts with advanced solid malignancies. HSP70 levels in PBMC were quantitated by ELISA in samples taken at baseline and multiple time-points post the 1st and 5th treatments over two cycles. Fold change of HSP70 induction was calculated and compared to dose level and AUY922 blood exposure obtained within the first week of treatment (single dose) at 6, 24, 48, and 168 hours post-treatment. Results: Of the 40 pts treated to date, HSP70 levels in PBMC has been evaluated in 36, encompassing seven dose levels ranging from 2 mg/m2 to 40mg/m2. Baseline levels of HSP70 in PBMC ranged from 26.0 to 95.1 ng/mg protein, with a median of 42.5ng/mg. The highest level of HSP70 induction obtained over two cycles was increasing with dose from 2 to 40 mg/m2, with a range of 1.4 to 12.1 fold, and the amount of HSP70 induction was frequently higher in the second cycle of treatment. In the first cycle of treatment, HSP70 induction is correlated to blood AUC. The degree of HSP70 upregulation in PBMCs at 40 mg/m2 exceeds the 8-fold upregulation seen in BT474 xenograft tumor tissue when treated with efficacious doses of AUY922. Conclusions: PK/PD analyses show that the highest level of HSP70 achieved post-treatment increases with dose, and at the highest dose tested thus far (40mg/m2), this pharmacodynamic effect has not yet reached a maximum response. Additionally, our analysis suggests that in humans, the PD effect of AUY922 is reaching the level corresponding to that required for anti-tumor effect in the BT474 xenograft model. [Table: see text]

Pharmacokinetic study of aldoxorubicin in solid tumor patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13572-e13572
Author(s):  
Ronald B. Natale ◽  
Alain C. Mita ◽  
Edward M. Wolin ◽  
Brenda Laabs ◽  
Hillary Dinh ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Volume Of Distribution ◽  
Multiple Time ◽  
Serious Adverse Events ◽  
Minor Response ◽  
Free Doxorubicin ◽  
Multiple Time Points ◽  
A Minor ◽  
Ecog Ps

e13572 Background: Aldoxorubicin consists of doxorubicin conjugated to a pH sensitive linker that binds covalently to circulating albumin. Previous studies demonstrated that aldoxorubicin can be administered at doses up to 350 mg/m2 (260 mg/m2doxorubicin equivalents, DE) every 21 days for up to 8 cycles. We have investigated aldoxorubicin pharmacokinetics, including albumin-bound and free doxorubicin and doxorubicinol after administration of 2 dose levels of aldoxorubicin in patients with advanced solid tumors. Methods: Patients with solid tumors and no standard therapy were eligible. Other entry criteria: ECOG PS 0-2, LVEF > 45% of predicted normal for the site, adequate hematological status. Patients were administered either 230 mg/m2 aldoxorubicin (165 mg/m2 DE) or 350 mg/m2 aldoxorubicin (260 mg/m2 DE) iv over 30 minutes on day 1 of cycles 1 and 3. Blood samples were taken prior to administration and at multiple time points up to 72 hr post administration. Serum concentrations of albumin-bound doxorubicin, unbound doxorubicin and doxorubicinol were analyzed. Results: As of January 31, 7 subjects have been entered in the study. 6 subjects have received 230 mg/m2 aldoxorubicin and 1 subject has received 350 mg/m2 aldoxorubicin. No serious adverse events have been reported. Grade 3 or 4 adverse events include neutropenia, thrombocytopenia and anemia. A minor response (20% decrease) was observed in one subject (230 mg/m2aldoxorubicin) with small cell lung cancer who had received 3 prior chemotherapy regimens. For the 230 mg/m2 cohort during cycle 1, median results for albumin-bound doxorubicin include Cmax= 64 µg/mL, tmax= 0.25 hr, t1/2= 19.7 hr, AUC t-∞= 1500 h*µg/mL, CLpred= 0.153 L/h/m2, Vss pred= 3.91 L/m2. Results were similar for cycle 3. Free doxorubicin accounted for only 0.8% of total doxorubicin detected, and doxorubicinol less than 0.0007% of total drug. Results from the 350 mg/m2 cohort are pending. Data from all 12 subjects will be available at presentation. Conclusions: Aldoxorubicin binds rapidly to albumin and is cleared slowly from the circulation. It possess a relatively narrow volume of distribution. These characteristics distinguish aldoxorubicin from published PK data for doxorubicin. Clinical trial information: NCT01706835.

Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11514-11514
Author(s):  
Damon R. Reed ◽  
Sant P. Chawla ◽  
Bhuvana Setty ◽  
Leo Mascarenhas ◽  
Paul A. Meyers ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Ewing Sarcoma ◽  
Phase 1 ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Target Lesion ◽  
Tumor Shrinkage ◽  
Phase 2 ◽  
Phase 1 Trial ◽  
Grade 3

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

A Multicenter Phase 1 Clinical Trial of Tanespimycin (KOS-953) + Bortezomib (BZ): Encouraging Activity and Manageable Toxicity in Heavily Pre-Treated Patients with Relapsed Refractory Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 406-406 ◽  
Author(s):  
Paul Richardson ◽  
Asher Alban Chanan-Khan ◽  
Sagar Lonial ◽  
Amrita Krishnan ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Phase 1 ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Peripheral Neurotoxicity ◽  
Phase 2 Study ◽  
Dose Levels

Abstract Background: Tanespimycin (KOS-953, 17-AAG) disrupts the function of Hsp90, a molecular chaperone of MM client proteins such as IL-6, IGF-1R that are key to growth, survival and drug resistance. In vitro, BZ + KOS-953 show additive cytotoxicity against MM cells. Single-agent KOS-953 produced durable MR and SD (ASH 2005 A#361) in relapsed and refractory MM pts with an MTD ≥ 420 mg/m2. Objectives: Define a phase 2 dose of BZ+KOS-953 in pts with relapsed, refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates. Explore changes in intracellular signaling proteins in PBMCs and CD138+ MM cells. Methods: Pts receive BZ as IVB followed by 1-hr infusion KOS-953 (in a Cremophor formulation) D1,4,8,11 q 21d. Dose escalation occurred in a step-wise manner (KOS-953: 100, 150, 220, 275 and 340 mg/m2; BZ: 0.7, 1.0 and 1.3 mg/m2). Collection of PK and surrogates occurs after D1, 11 dosing. Toxicity is assessed by NCI CTCAE v3.0 and response by EBMT criteria. Results: 40 pts were enrolled in 7 dose levels: 22F/18M; median age/KPS 59y/90; all rel/refy; median # of prior regimens 4 (range 2–16); 97% dex; 73% prior BZ; 87% prior thalidomide; 7% prior lenalidomide; 67% prior SCT. Pts received a median of 4 cycles (range: 1 – 19+). Three episodes of DLT potentially related to KOS-953 were observed (KOS-953/BZ dose): grade (g) 3 pancreatitis (150/1.3); g4 metabolic acidosis with GI hemorrhage secondary to GI amyloidosis (275/1.3); and g3 myalgias/cramps (340/1.3). Other g3–4 toxicity: anemia, back pain and thrombocytopenia (all reversible). Common toxicities (>10%): fatigue, diarrhea, constipation, thrombocytopenia and nausea (predominantly g1-2). Significant cardiotoxicity, peripheral neurotoxicity and DVT were not reported. KOS-953 PK: similar to single-agent trial with no change in clearance on this schedule. Dose (mg) vs exposure to [parent + metabolite] was linear (R2=0.87). 20S proteasome inhibition was similar to published BZ single-agent values. Hsp70 induction was observed in PBMCs prior to D11 infusion, suggesting sustained Hsp90 inhibition on this schedule. Responses (CR+PR+MR) were seen in all dose levels of KOS-953 with BZ ≥ 1.0 mg/m2: BZ-naive pts (5/7 pts; 71%); BZ-refractory pts (defined as PD on BZ-containing regimen prior to study or no response to prior BZ; 2/6 pts; 33%) and BZ-pretreated pts (5/13 pts; 38%); 4 pts were non-evaluable having received ≥ 2 infusions and 10 pts (Cohort 7) are not yet assessable for response. Conclusions: Encouraging anti-MM activity has been observed in all dose groups with KOS-953 with BZ ≥ 1.0 mg/m2. The dose group of 1.3 mg/m2 BZ + 340 mg/m2 KOS-953 is being expanded to assess tolerability; one pt out of 10 experienced DLT at this dose level to date. To date, no additive toxicity or PK interactions are seen. A phase 2 study of the combination in relapsed, refractory MM and a registrational phase 2/3 trial in MM pts in 1st relapse comparing BZ to BZ+KOS-953 are planned.

Study of brain and whole blood PK/PD of bortezomib in rat models

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12036-12036 ◽  
Author(s):  
L. J. Yu ◽  
B. Riordan ◽  
P. Hatsis ◽  
A. Brockman ◽  
S. Daniels ◽  
...  
Keyword(s):  
Whole Blood ◽  
Ex Vivo ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
Constant Infusion ◽  
Vehicle Group ◽  
20S Proteasome ◽  
Blood Contamination ◽  
The Brain ◽  
Brain Tissues

12036 Background: Bortezomib (Btz) is the first in class proteasome inhibitor and has been approved for treatment of multiple myeloma patients who have received at least 1 prior therapy. The potential for Btz to penetrate the CNS was examined in the rat under two conditions: intact blood brain barrier (BBB) and compromised BBB induced by middle cerebral artery occlusion (MCAO). Methods: Intact BBB: healthy rats received an iv bolus followed by a constant infusion of Btz to steady-state (SS). The blood and brain samples were collected for determination of concentration (Conc) of Btz (PK) and of 20S proteasome activity (PD). The brain samples were collected after a perfusion with saline. Inulin was included in the study in order to determine blood contamination in brain tissues. Compromised BBB: rats underwent MCAO surgery and 1 h later were administered Btz via an iv bolus of 0, 0.1, 0.2 or 0.35 mg/kg. The blood and brain samples were collected through 24 h postdose. Conc of Btz was determined by an LC/MS/MS method. The 20S proteasome activity was measured using an ex vivo assay. Results: 1) Intact BBB: at SS the mean blood Conc of Btz was 140 ng/mL, and proteasome activity in the blood was inhibited by ∼80% compared to the vehicle group (p < 0.0001). In contrast, the brain Conc of Btz was extremely low (∼3 ng/g) with the brain-to-blood ratio of ∼0.02. No difference was observed in brain proteasome activity between the vehicle and Btz-treated groups. 2)The MCAO rat: the PK/PD relationship in the blood was best described by a sigmoid Emax model with an EC50 of 110 ng/mL and gamma factor of 3.8. The model also suggests that there is no proteasome inhibition (PI) when the blood Conc is <40 ng/mL (no effective blood Conc, NOEBC). In the brain, the Cmax of Btz was 22.0 ng/g from the highest dose group, in contrast to the blood Cmax of 164 ng/mL. The increased exposure in the brain of a MCAO rat relative to a normal rat was anticipated as its BBB is impaired. However, the brain Concs were all below the NOEBC. No significant PI was observed in all brain tissues (P>0.1). Conclusion: Very poor brain penetration was observed for Btz in rats. Btz showed PI in whole blood but not in the brain either of normal or MCAO rats following administration of Btz. [Table: see text]

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]

AB0026 SELECTIVE INHIBITION OF TYROSINE KINASE 2 WITH AN ORAL AGENT, BMS-986165, COMPARED WITH JANUS KINASE INHIBITORS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1316.1-1316
Author(s):  
A. Chimalakonda ◽  
J. Burke ◽  
L. Cheng ◽  
J. Strnad ◽  
I. Catlett ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Safety Profile ◽  
Whole Blood ◽  
Plasma Concentrations ◽  
Phase 2 ◽  
Functional Selectivity ◽  
Daily Average ◽  
Unique Mode ◽  
Tyrosine Kinase 2

Background:BMS-986165 is an oral, selective inhibitor of tyrosine kinase 2 (TYK2) with a unique mode of binding to the pseudokinase domain of the enzyme rather than the active site within the kinase domain. This unique mode of binding provides high functional selectivity for TYK2 versus other tyrosine kinases (TYKs) in cellular and other in vitro assays.1This approach may provide robust efficacy with a differentiated safety profile due to decreased off-target activity on other kinases. In a 12-week, placebo-controlled Phase 2 trial in patients with moderate to severe plaque psoriasis,2BMS-986165 had a favorable safety profile, and 67%–75% of patients achieved Psoriasis Area and Severity Index 75 (PASI 75) after 12 weeks at doses ≥3 mg twice daily versus 7% with placebo. BMS-986165 is currently under investigation in multiple autoimmune disorders such as psoriatic arthritis, psoriasis, and systemic lupus erythematosus.Objectives:To understand the selectivity of BMS-986165 compared with JAK inhibitors, such as tofacitinib (Tofa), upadacitinib (Upa), and baricitinib (Bari), at clinically relevant doses and plasma concentrations.Methods:In vitro whole blood assays were developed to measure the activity of common pairings of JAKs (JAK 1/3, JAK2/2, and TYK2/JAK2) and concentrations providing half-maximal inhibition (IC50) for BMS-986165, Tofa, Upa, and Bari were determined. The whole blood IC50values were plotted against pharmacokinetic profiles of these agents at approved doses and/or doses evaluated in their respective Phase 2/3 trials. The time that concentrations were >IC50and projected average daily inhibition were evaluated.Results:At clinically relevant doses and exposures, BMS-986165 plasma concentrations were higher than the TYK2 whole blood IC50value for a considerable part of the dosing interval. Additionally, the maximal plasma concentration (Cmax) of BMS-986165 was approximately >9- to 18-fold lower than the JAK 1/3 whole blood IC50value and >52- to >109-fold lower than JAK2/2 whole blood IC50, indicating lack of meaningful inhibition of the JAK 1-3 pathways by BMS-986165 at therapeutic doses. At clinically relevant doses, projected Cmaxvalues of Tofa, Upa, and Bari were many-fold lower than TYK2 IC50, indicating minimal or no meaningful inhibition of the TYK2 pathway. As expected, Tofa, Upa, and Bari had varying degrees of inhibition against JAK1/3 (daily average inhibition range: 70%–94%) and JAK2/2 pathways (daily average inhibition range: 24%–67%) at clinically relevant doses and exposures.Conclusion:These results demonstrate the high TYK2 functional selectivity of BMS-986165 at clinically relevant doses and plasma concentrations compared with Tofa, Upa, and Bari and indicate that BMS-986165 is in a different class compared with JAK 1–3 inhibitors. Ongoing studies in psoriasis and other conditions may confirm the expected safety of BMS-986165 based on the above results. The daily average inhibition of JAK1 and JAK2 likely explains some common laboratory observations and adverse events reported for the JAK1–3 inhibitors.References:[1]Burke JR et al.Sci Transl Med. 2019 Jul 24;11(502); eaaw1736.[2]Papp K et al.N Engl J Med. 2018;379(14):1313-1321.Acknowledgments:This study was sponsored by Bristol-Myers Squibb. Editorial assistance was provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by Bristol-Myers Squibb.Disclosure of Interests:Anjaneya Chimalakonda Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, James Burke Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Lihong Cheng Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Joann Strnad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Ian Catlett Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Aditya Patel Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Jun Shen Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Ihab Girgis Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Subhashis Banerjee Shareholder of: AbbVie, Bristol-Myers Squibb, Lily, Pfizer, Employee of: Bristol-Myers Squibb (current); AbbVie, Lily, Pfizer (past), John Throup Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

scholarly journals Development of a Population Pharmacokinetic Model To Describe Azithromycin Whole-Blood and Plasma Concentrations over Time in Healthy Subjects

2013 ◽  
Vol 57 (7) ◽  
pp. 3194-3201 ◽  
Author(s):  
T. Pene Dumitrescu ◽  
T. Anic-Milic ◽  
K. Oreskovic ◽  
J. Padovan ◽  
K. L. R. Brouwer ◽  
...  
Keyword(s):  
Whole Blood ◽  
Healthy Subjects ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Polymorphonuclear Cells ◽  
Peripheral Blood Mononuclear

ABSTRACTAzithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZICbandCpwere quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose,Cbwas greater thanCp. Importantly,Cb, but notCp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested thatCbwas not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately describedCpandCb, butCpwas somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZICbin healthy subjects, the distribution parameters betweenCpandCb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predictCbfromCpfor AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.)

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